WO2008064265A2 - Compounds modulating c-fms and/or c-kit activity and uses therefor - Google Patents

Compounds modulating c-fms and/or c-kit activity and uses therefor Download PDF

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WO2008064265A2
WO2008064265A2 PCT/US2007/085299 US2007085299W WO2008064265A2 WO 2008064265 A2 WO2008064265 A2 WO 2008064265A2 US 2007085299 W US2007085299 W US 2007085299W WO 2008064265 A2 WO2008064265 A2 WO 2008064265A2
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fluoro
pyridin
lower alkyl
ylmethyl
chloro
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WO2008064265A3 (en
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Chao Zhang
Jiazhong Zhang
Prabha N. Ibrahim
Dean R. Artis
Ryan Bremer
Guoxian Wu
Hongyao Zhu
Marika Nespi
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Plexxikon, Inc.
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Definitions

  • 60/682,051 entitled “Compounds Modulating c-Fms Activity and Uses Therefor", filed May 17, 2005
  • U.S. Provisional App. No. 60/682,042 entitled “Compounds Modulating c-Kit and c-Fms Activity and Uses Therefor", filed May 17, 2005
  • U.S. Provisional App. No. 60/692,750 entitled “Compounds Modulating c-Kit and c-Fms Activity and Uses Therefor” filed June 22, 2005
  • U.S. Provisional App. No. 60/692,960 entitled “Compounds and Methods for Kinase Modulation, and Indications Therefor", filed June 22, 2005, all of which are incorporated herein by reference in their entireties and for all purposes.
  • This invention relates to ligands for c-fms and c-kit, and to methods for use thereof.
  • the information provided is intended solely to assist the understanding of the reader. None of the information provided nor references cited is admitted to be prior art to the present invention. Each of the references cited is incorporated herein in its entirety and for any purpose.
  • C-fms and c-kit are both type III transmembrane receptor protein tyrosine kinases (RPTKs) that regulate key signal transduction cascades that control cellular growth and proliferation. Both receptors have similar structural features comprising five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment.
  • RPTKs type III transmembrane receptor protein tyrosine kinases
  • C-fms is a member of the family of genes originally isolated from the Susan McDonough strain of feline sarcoma viruses.
  • the cellular proto-oncogene FMS (c-fms, cellular feline McDonough sarcoma) codes for the receptor for the macrophage colony-stimulating factor (M- CSF).
  • M- CSF macrophage colony-stimulating factor
  • M-CSF is a cytokine that controls the production, differentiation, and function of macrophages.
  • M-CSF stimulates differentiation of progenitor cells to mature monocytes, and prolongs the survival of monocytes. Furthermore, M-CSF enhances cytotoxicity, superoxide production, phagocytosis, chemotaxis, and secondary cytokine production of additional factors in monocytes and macrophages. Examples of such additional factors include granulocyte colony stimulating factor (G-CSF), interleukin-6 (IL-6), and interleukin-8 (IL-8).
  • G-CSF granulocyte colony stimulating factor
  • IL-6 interleukin-6
  • IL-8 interleukin-8
  • M-CSF stimulates hcmatopoiesis, promotes differentiation and proliferation of osteoclast progenitor cells, and has profound effects on lipid metabolism. Furthermore, M-CSF is important in pregnancy. Physiologically, large amounts of M-CSF are produced in the placenta, and M-CSF is believed to play an essential role in trophoblast differentiation (Motoyoshi, Int J Hematol. 1998, 67: 109-22). The elevated serum levels of M-CSF in early pregnancy may participate in the immunologic mechanisms responsible for the maintenance of the pregnancy (Flanagan & Lader, Curr Opin Hematol. 1998, 5: 181-5).
  • c-fms and c-kit are two glatelet-derived growth factor receptors, alpha (i.e., pdgfra) and beta (pdgfrb) (PDGF).
  • alpha i.e., pdgfra
  • beta pdgfrb
  • PDGF glatelet-derived growth factor receptors
  • the gene coding for pdgfra is located on chromosome 4ql 1- ql2 in the same region of chromosome 4 as the oncogene coding for c-kit.
  • the genes coding for pdgfra and c-fms appear to have evolved from a common ancestral gene by gene duplication, inasmuch as these two genes are tandemly linked on chromosome 5.
  • GIST gastrointestinal stromal tumors
  • SCF Stem Cell Factor
  • KL kit ligand
  • MEF mast cell growth factor
  • SCF is synthesized as a transmembrane protein with a molecular weight of 220 or 248 Dalton, depending on alternative splicing of the mRNA to encode exon 6.
  • the larger protein can be proteolytically cleaved to form a soluble, glycosylated protein which noncovalently dimerizcs. Both the soluble and membrane-bound forms of SCF can bind to and activate c-kit.
  • SCF is predominantly expressed by fibroblasts, keratinocytes, and endothelial cells, which modulate the activity of melanocytes and mast cells expressing c-kit
  • marrow stromal cells express SCF and regulate hematopoiesis of c-kit expressing stem cells.
  • intestinal epithelial cells express SCF and affect the interstitial cells of Cajal and intraepithelial lymphocytes.
  • Sertoli cells and granulosa cells express SCF which regulates spermatogenesis by interaction with c-kit on germ cells.
  • the present invention relates to compounds active on c-fms, c-kit, or both c-fms and c- kit.
  • the invention provides compounds of Formula I, and all sub-generic formulae thereof, as well as methods of using such compounds as described below.
  • the invention provides methods of using compounds that can be used therapeutically and/or prophylactically involving modulation of c-fms, c-kit, or both c-fms and c-kit, or involving one or more of TrkA, TrkB and HGK in addition to c-fms, c-kit, or both c-fms and c-kit,
  • X is N or CR 2
  • X 2 is N or CR 6
  • Y 1 is N or CR 4
  • Y 2 is N or CR 5 , provided, however, that not more than one of X 2 , Yi and Y 2 is N;
  • L 1 is selected from the group consisting of optionally substituted lower alkylenc, -S-, -O-, -C(O)-, -C(S)-, -S(O)-, -S(O) 2 -, and -Nil 7 -;
  • L 2 is selected from the group consisting of a bond, optionally substituted lower alkylene, -(alk) a -S-(alk) b -, -(alk) a -O-(alk) b -, -(alk) a -OC(O)-(alk) b -, -(alk) a -C(O)O-(alk) b -, -(alk) » -OC(S)-(alk) b -, -(alk) a -C(S)O-(alk) b -, -(alk),-C(O)-(alk) b -, -(alk) a -C(S)-(alk) b -, -(alk) a -C(O)NR 9 -(alk) b -, -(alk) a -OC(O)NR'-(alk
  • R 1 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted hctcrocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R 2 , R 4 , R 5 and R 6 are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl. optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 . -NO 2 , -CN, -C(O)OH 5 -C(S)OH, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NHC(O)NH 2 , -NHC(S)NH 2 .
  • F and J are both C or one of F and J is C and the other of F and J is N; P and Q are independently selected from CR, N, NR, O or S; T is selected from CR or N; wherein when n is 1 , F and J are C, and P, T and Q are CR, or any one of P, T and Q is N and the other two of P, T and Q are CR, when n is O and F and J are both C, then one of P and Q are CR, N or NR and the other of P and Q is C, N, NR, O or S, provided both P and Q are not CR, when n is O, one of F and J is N and the other of F and J is C, then one of P and Q is N and the other of P and Q is CR or both P and Q are CR, and R is hydrogen or an optional substituent as defined herein for optionally substituted heteroarylene that provides a stable compound;
  • R- at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that no alkene carbon thereof is bound to any -C(O)-, -C(S)-, -S(O)-, -S(O) 2 -, -0-, -S-, or -N- of any of -OR 3 , -SR 3 , -C(O)R 3 , -C(S)R 3 , -S(O)R 1 , -S(O) 2 R 3 , -C(O)OR 3 , -C(S)OR 3 , -C(O)NHR 3 , -C(O)NR 3 R 3 , -C(S)NIIR 3 , -C(S)NR 3 R 3 , -S(O) 2 NHR 3 , -S(O) 2 NR 3 R 3 , -NHR 1 .
  • R 7 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(O)R 8 , and -S(O) 2 R 8 ;
  • R 8 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl. optionally substituted aryl and optionally substituted heteroaryl;
  • R 9 at each occurrence is independently selected from the group consisting of hydrogen, lower alkyl, and lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mo ⁇ o-alkylamino, fluoro substituted mono- alkylamino, di-alkylamino, fluoro substituted di-alkylamino, and -NR 12 R 13 , provided, however, that when R 9 is substituted lower alkyl, any substitution on the alkyl carbon bound to the -N- of-NR y - is fluoro;
  • R 10 and R 1 1 at each occurrence are independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl. provided, however, that no alkene carbon thereof is bound to the nitrogen of NR 10 R 1 1 , optionally substituted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to the nitrogen Of-NR 10 R 1 ', optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R 10 and R 1 ' together with the nitrogen to which they are attached form a monocyclic 5-7 membered optionally substituted heterocycloalkyl or a monocyclic 5 or 7 membered optionally substituted nitrogen containing heteroaryl; and
  • R 1" and R 13 combine with the nitrogen to which they arc attached to form a 5-7 membered heterocycloalkyl or 5-7 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio; provided, however that when compounds have the structure
  • R la is not phenyl, 4-trifluoromethyl-phenyI, 4- methoxy-phcnyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl-phenyl, 3-fluoro-phenyl or thiophen-2-yl, and compounds do not have the structure
  • azaindole core the core structure shown above with X 1 , X 2 , Yj and Y 2 as CH and with L'-Ar
  • azaindole core reference to ring atoms or ring positions is as shown in the following structure:
  • compounds of Formula I have a structure selected from the following: wherein V, Ar 1 , I/ 2, r R> l 1 , r R> 2 , r R> * , r R> 5 and R" are as defined for Formula J.
  • X) and Xi are N or CH.
  • Xj, X 2 and Yi are N or CII, where in a further embodiment, Y 2 is CR 5 and R 5 is other than hydrogen.
  • , XT and Y 2 are N or CH, where in a further embodiment Yj is CR 4 and R 4 is other than hydrogen.
  • X] , X 2 and Yj are CH, where in a further embodiment, Y 2 is CR 3 and R 3 is other than hydrogen.
  • X), X 2 and Y 2 are CII, where in a further embodiment Yj is CR 4 and R 4 is other than hydrogen.
  • R 4 or R 5 is other than hydrogen, preferably where R 2 and R 6 arc hydrogen.
  • R 2 , R 6 , Yi and Y 2 arc independently CR 2 , CR 6 , CR 4 and CR 5 respectively
  • R 2 , R 5 and R 6 are hydrogen and R 4 is other than hydrogen.
  • R 2 , R 4 and R 6 are hydrogen and R 5 is other than hydrogen.
  • Xi and X 2 arc N or CH, preferably wherein both X 1 and X 2 are CH.
  • L 1 is selected from the group consisting of-S-, -O- lower alkylene, -C(O)-, -C(S)-, -S(O)-, -S(O) 2 -, and -NR 7 -, wherein lower alkylene is optionally substituted with fluoro, and wherein when L 2 is optionally substituted lower alkylene or comprises optionally substituted C ⁇ 3 alkylene, the alkylene is optionally substituted with fluoro or lower alky].
  • L 1 is selected from the group consisting of -S-, -O— , -CH 2 -, -CF 2 -, -C(O)-, -C(S)-, -S(O)-. -S(O) 2 -, and -NH-.
  • L is selected from the group consisting of a bond, optionally substituted lower alkylene, -O-(alk) b -, -OC(O)-(alk) b - » -C(O)O-(alk) b -, -OC(S)-(alk) b -, -C(S)O-(alk) b -, -C(O)-(alk) b -, -C(S)-(alk) b -, -C(O)NR 9 -(alk) b -, -OC(O)NR 9 -(alk) b -.
  • the alkylene is substituted with one or more, preferably 1 , 2, or 3 substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and -NR 12 R 11 , wherein the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylammo or di- alkylamino are optionally substituted with one or more, preferably 1 , 2, or 3 substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alky
  • variables P, J, Q, T, F, and n are selected to provide structures of Aij selected from the group consisting of
  • each R is independently hydrogen or an optional substituent as defined herein for optionally substituted heteroaryl.
  • a compound of Formula I has a structure according to the following sub-generic structure, Formula Ia,
  • Formula Ia all salts, prodrugs, tautomers, and isomers thereof, wherein L 1 , Ar 1 , R 1 , R 2 , R 4 , R s and R 6 are as defined for Formula 1;
  • L 3 is selected from the group consisting of a bond, optionally substituted lower alkylene,-O-(alk) b -, -S-(alk) b -, -NR l4 -(alk) b -, -C(O)-(alk) b -, -C(S)-(alk) b -. -S(O)-(alk) b -.
  • R 2 , R 5 and R 6 are hydrogen, further wherein R 4 is other than hydrogen.
  • R 2 , R 4 and R 6 are hydrogen, further wherein R 5 is other than hydrogen.
  • the compound of Formula I has a structure according to the following sub-generic structure, Formula Ib,
  • V and W are independently selected from the group consisting of N and CH;
  • U and Z are independently selected from the group consisting of N and CR 18 , provided, however, that not more than one of W, U and Z is N;
  • A is selected from the group consisting of -CR 19 R 20 -, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O) 2 -,
  • n O or 1;
  • F and J are both C or one of F and J is C and the other of F and J is N; E and K are selected from C, N, O or S: G is selected from C or N; wherein when n is 1 , F and J are C, and E, G and K are C, or any one of E, G and K is N and the other two of E, G and K are C, provided that when E, G or K is N, R 15 , R 17 and R 16 , respectively, are absent, when n is 0 and F and J are both C, then one of E and K is C or N and the other of E and K is C, N, O or S, provided both E and K are not C, and provided that when both E and K are N.
  • one of R 15 and R 16 is absent, and provided that when one of E and K are N and the other is O or S, R 13 and R 16 are absent.
  • n 0, one of F and J is N and the other of F and J is C, then one of E and K is N and the other of E and K is C, or both E and K are C, provided that when E is N, R 15 is absent and when K is N, R 1 " is absent;
  • R 1 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • R ! ⁇ " is selected from the group consisting of hydrogen, optionally substituted lower alkyl,
  • R 17 is selected from the group consisting of hydrogen, optionally substituted lower alkyl,
  • R 18 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -NO 2 , -CN, -NHC(O)NH 2 . -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -NR 24 R 25 .
  • M is selected from the group consisting of a bond, -(CR 19 R 2 V, -(CR 19 R 20 ) r C(O)-(CR l 9 R 2 V -(CR 19 R 2 VC(S)-(CR 19 R 20 X-, -(CR 19 R 20 X-C(O)O-(CR 19 R 20 X-,
  • no alkene carbon thereof is bound to any -C(O)-, -C(S)-, -S(O) 2 -. -O-. -S-, or -N- of any of -NHR 3 .
  • R 24 and R 25 at each occurrence are independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that no alkene carbon thereof is bound to the nitrogen of -NR 24 R "5 , optionally substituted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to the nitrogen of -NR 24 R 25 , optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R 24 and R 25 together with the nitrogen to which they are attached form a monocyclic 5-7 membered optionally substituted heterocycloalkyl or a monocyclic 5 or 7 membered optionally substituted nitrogen containing heteroaryl;
  • R 26 at each occurrence is independently selected from the group consisting of hydrogen, lower alkyl, and lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH 2 , lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono- alkylamino, di-alkylamino, Iluoro substituted di-alkylamino, and -NR ⁇ 7 R ⁇ S , provided, however, that when R 26 is substituted lower alkyl, any substitution on the lower alkyl carbon bound to the -N- of-NR 2 ⁇ - is fluoro;
  • M is selected from the group consisting of -O-(CR l9 R 20 ) s -, -S-(CR 19 R 20 X-, -OC(O)-(CR 19 R 20 X-, -OC(S)-(CR 19 R 2 V -OC(O)NR 26 -(CR 19 R 20 X-, -OC(S)NR 26 -(CR 19 R 20 ) S -, -C(O)NR 26 -(CR 19 R :0 X-, -C(S)NR 26 -(CR 19 R 20 X-, -S(O) 2 NR 26 -(CR 19 R 20 X-, -NR 26 -(CR 19 R 20 ) s -, -NR 20 C(O)-(CR 19 R 2 V, -NR 26 C(S)-(CR 19 R 2 V, -NR 26 C(O)O-(CR 19 R 20 X-, -
  • R 26 at each occurrence is independently selected from the group consisting of hydrogen, lower alkyl, and lower alkyl substituted with 1, 2, or 3 substituents selected from the group consisting of fluoro, -OH, -NH 2 , alkoxy, lower alkylthio. mono-alkylamino, di-alkylamino and cycloalkylamino. provided that any substitution on the carbon that is bound to the nitrogen of -NR 26 is tluoro.
  • R 1 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl.
  • Z is N or CII, n is 1 , E-R 15 is N or CH, K-R 16 is N or CH, and G-R 17 is N or CH, provided no more than one of E-R 15 , K-R 16 and G- R ⁇ is N.
  • Z is N or CH, n is 1 , and E-R 15 , K-R 16 and G-R 17 are CH,
  • V, W and Z are CH, U is CR lH .
  • n is 1
  • E-R 15 is N or CH
  • K-R 16 is N or CH
  • G-R 17 is N or CH, provided no more than one of E- R 15 , K-R 16 and G-R 17 is N.
  • V, W and Z are CH
  • U is CR ! 8
  • n is 1.
  • E-R 15 , K-R 16 and G-R 17 are CH.
  • Z is N or CH
  • n is 1
  • E-R 15 , K-R 10 and G-R 17 are CH
  • A is -CH 2 -
  • M is -NHCH 2 -
  • R 1 is optionally substituted phenyl.
  • V, Z, U and W are CH
  • n is 1
  • E-R 15 is N or CH
  • K-R 16 is N or CH
  • G-R 17 is N or CH, provided no more than one of E-R 15 , K-R 16 and G-R 17 is N.
  • Z is N or CII
  • n is 1
  • E-R 15 is N or CH
  • K-R 16 is N or CH
  • G-R ⁇ is N or CH, provided no more than one of E-R 15 , K-R 16 and G- R 17 is N
  • R 1 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN.
  • R 29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.
  • V, Z, U and W are CH, n is 1 , E-R 15 , K-R 16 and G-R 17 are CH, A is -CH 2 -, M is -NHCH 2 , and R 1 is optionally substituted phenyl, further wherein R 1 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, optionally substituted lower alkyl and -OR 39 , where R 29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.
  • V. W and Z are CH, U is CR 18 , n is 1 , E-R 15 , K-R 16 and G-R 17 are CH, A is -CH 2 -, M is -MICH 2 , and R 1 is optionally substituted phenyl, further wherein R 1 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, optionally substituted lower alkyl and -OR 29 , where R 29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.
  • n when n is 1 , and E. K and G are C, at least one of R u , R 16 and R 1 ' is other than hydrogen.
  • n is 1 , one of E. K, and ⁇ arc N and the other two of E, K, and G are C and at least one of R 15 , R 16 and R 17 is other than hydrogen.
  • n is 1 , E, K and G are C, and at least one of R 15 , R 16 and R 1 is other than hydrogen
  • n is 1 , V and W aie CH, U and Z are independently CR 18 , one of E, K, and G arc N and the other two of E, K, and G are C and at least one of R 15 , R 16 and R 17 is other than hydrogen.
  • n is 1.
  • V and W are CH, U and Z are independently CR 1 S , E, K and G are C, and at least one of R i 5 , R 16 and R 17 is other than hydrogen.
  • n is 1 , one of E, K, and G arc N and the other two of E, K, and G are C, at least one of R 15 , R 16 and R 17 is other than hydrogen, A is -CH 2 -, M is -NHCH 2 -, further wherein R 1 is optionally substituted phenyl.
  • n is 1 , E, K, and G are C, at least one of R 15 , R 16 and R 1 ' is other than hydrogen, A is -CH 2 -, M is NHCH 2 -, further wherein R 1 is optionally substituted phenyl.
  • n is 1
  • V, Z, U and W are CH
  • one of E, K, and G are N and the other two of E, K, and G are C and at least one of R 15 , R 16 and R 17 is other than hydrogen.
  • V, Z, U and W are CH
  • E, K and G are C
  • at least one of R 15 , R 16 and R 17 is other than hydrogen.
  • Z is CR I S , wherein R 18 is other than hydrogen, n is 1 , E-R 15 is N or CH, K-R 16 is N or CH and G-R 17 is N or CH.
  • Z is CR 18 , wherein R 1 S is other than hydrogen, n is 1. and E-R 15 , K-R 16 and G-R 17 are CH.
  • Z is CR 18 , wherein R i 8 is other than hydrogen, U is CR 18 , V and W are CH, n is 1, and E-R 15 , K-R 1 " and G-R 17 are CH, further wherein U is CH.
  • Z is CR I S , wherein R 18 is other than hydrogen, n is 1 , E-R 15 , K-R 16 and G-R 17 arc CH, A is -CH 2 -, M is -NHCII 2 -, further wherein R 1 is optionally substituted phenyl.
  • Z is CR 18 , wherein R 18 is other than hydrogen, U is CR 1 R , V and W are CH, n is 1 , E-R 1 '. K-R 16 and G-R ' 7 are CH, A is -CH 2 -.
  • M is -NHCH 2 -, further wherein R 1 is optionally substituted phenyl.
  • Z is CR 18 , wherein R I H is other than hydrogen, V, U and W are CH, n is 1, E-R 15 , K-R 16 and G-R p are CH, A is -CH 2 -, M is -NHCH 2 -, further wherein R 1 is optionally substituted phenyl.
  • U is CR 18 , wherein R ! S is other than hydrogen, n is 1 , E-R 15 is N or CH, K-R" is N or CH and G-R 17 is N or CH.
  • U is CR 18 , wherein R 18 is other than hydrogen, n is 1 , and E-R 15 , K-R 16 and G-R 1 ' are CH.
  • U is CR 1 *, wherein R 18 is other than hydrogen, Z is CR 18 , V and W are CH, n is 1 , and E-R 15 , K-R 16 and G-R 17 are CH, further wherein Z is CH.
  • U is CR 18 , wherein R 1S is other than hydrogen, n is 1, E-R 15 , K-R 16 and G-R 1 ' are CH, A is -CH 2 -, M is -NHCH 2 -, further wherein R 1 is optionally substituted phenyl.
  • U is CR 18 , wherein R 18 is other than hydrogen, Z is CR 18 , V and W are CH, n is 1 , E-R 15 , K-R 16 and G-R 17 are CH, A is -CH 2 -, M is - NHCH 2 -, further wherein R 1 is optionally substituted phenyl.
  • U is CR 1 *, wherein R 18 is other than hydrogen, V, Z and W are CH, n is 1 , E-R 15 , K-R 16 and G-R 17 are CH, A is -CH 2 -, M is -NHCH 2 -, further wherein R 1 is optionally substituted phenyl.
  • R 15 , R 6 and R 17 are independently selected from the group consisting of halogen, -OH, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy.
  • R 1 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, optionally substituted lower alkyl and OR 29 , where R 29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.
  • R 18 is selected from the group consisting of halogen, -OH, optionally substituted lower alkyl and -OR 29 , where R 29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl. Further to any of these embodiments.
  • R 1 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH 2 , -NO 2 , -CN, optionally substituted lower alkyl and -OR 29 , where R 29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl,
  • M is a bond and R 1 is other than thiophenyl.
  • Z is N or CR 18 wherein R lg is not hydrogen.
  • E is NR IS or CR 15
  • K is NR 16 or CR 16
  • G is CR 17 , or combinations thereof, wherein at least one of R 15 , R 1 ' and R 1 ' is not hydrogen.
  • a compound of Formula I has a structure according to the following sub-generic structure, Formula Ig,
  • Zi is selected from the group consisting of N and CR 34 ;
  • U 1 is selected from the group consisting of N and CR 35 ;
  • is selected from the group consisting Of -CH 2 - and -C(O)-;
  • M 3 is selected from the group consisting of a bond, -NR 39 -, -S-. -O-, -NR 3 ⁇ CH 2 -,
  • -NR 39 CH(R 40 )-, -SClI 2 -, -OCH 2 -, -C(O)NR 39 -, -S(O) 2 NR 39 -, -CH 2 NR 39 -, -CH(R 40 )NR 3 % -NR 39 C(O)-, and -NR 39 S(O) 2 -;
  • n is O or 1 ;
  • v is O, 1, 2 or 3;
  • Fj and J are both C or one of Fi and Ji is C and the other of F 1 and J
  • Cy is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl;
  • R 34 and R' 5 are independently selected from the group consisting of hydrogen, -OR 41 , -SR 41 , -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 39 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl.
  • lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 14 or R 35 , or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NH 2 .
  • R 45 at each occurrence is independently selected from the group consisting of -OR 41 , -SR 41 , -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 39 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 4 ⁇ or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the
  • R 3 ' is selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy when Ki is C, is absent when K
  • R " " is selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy when Gi is C, or is absent
  • R at each occurrence is independently hydrogen or lower alkyl
  • R 1 ⁇ is lower alkyl or fluoro substituted lower alkyl
  • R 4i is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituenls selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkyltliio, fluoro substituted lower alkylthio, mono-alkylamino, di- alkylarnino, cycloalkyl, heterocycloalkyl, aryl.
  • cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R 4 ' or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -OR 42 , -SR 42 , -NHR 42 , -NR 42 R 42 , -NR 30 C(O)R 42 , -NR 39 S(O) 2 R 42 , -S(O) 2 R 42 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and
  • R " at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, and cycloalkylamino. and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl. lower alkoxy and fluoro substituted lower alkoxy.
  • n 1 , Gi and K) are C, and E is N or C, preferably wherein E is C.
  • M 3 is selected from the group consisting of -NR 39 -, -O-, -NR 39 CH 2 -, -NR 39 CH(R 40 )-, -SCH 2 -, -OCH 2 -, -CH 3 NR 39 -, -NR 39 C(O)-, and -NR 39 S(O) 2 -, preferably wherein M 3 is -NR 39 CH 2 -, -NR 39 CII(R 40 )-, -SCH 2 -, -OCH 2 -, or
  • n is 1 , Gi and Kj are C, and E is N or C. preferably wherein E is C, and M 3 is selected from the group consisting of -NR 39 -, -O-, -NR 19 CH 2 -. -NR 39 CH(R 4 ")-, -SCH 2 -, -OCH 2 -, -CH 2 NR 39 -, -NR 39 C(O)-, and -NR 39 S(O),-. preferably wherein M 1 is -NR 39 CH 2 -, -NR 39 CII(R 40 )-, -SCH 2 -, -OCH,-, or -CH 2 NR 39 -.
  • each R 45 is selected from the group consisting of -OH, -NlI 2 , -CN, -NO 2 , halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower thioalkyl, fluoro substituted lower thioalkyl. mono- alkylamino, di-alkylamino and cycloalkylamino, preferably wherein v is 0, 1 , or 2, also 0 or 1.
  • n is 1, G 1 and K
  • each R 4S is selected from the group consisting of -OH, -NH 2 , -CN, -NO 3 , halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower thioalkyl, fluoro substituted lower thioalkyl, mono-alkylamino, di-alkylamino and cycloalkylamino, preferably wherein v is 0, 1, or 2, also 0 or 1.
  • Z 1 is CR 14
  • U 1 is CR 35
  • R 34 and R 35 are both hydrogen.
  • Zi is CR 34
  • Ui is CR 35
  • R 34 and R 35 arc independently selected from the group consisting of hydrogen, -OR 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -OR 42 , -SR 42 , -NHR 42 , -NR 41 R 42 , -NR 39 C(O)R 42 , -NR 39 S(O) 2 R 42 , -S(O
  • one of R 34 and R 35 is hydrogen
  • the other of R 34 and R' 5 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NII 2 , -C(O)NH 2 , -OR 42 , -SR f3 , -NHR 42 , -NR 42 R 42 , -NR 39 C(O)R 42 , -NR 39 S(O) 2 R 42 , -S(O) 2 R 42 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkyJamino, and wherein lower alkyl and lower alkoxy are optionally substituted with one or more substituents selected from the group consisting of
  • each R 45 is independently selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower thioalkyl. fluoro substituted lower thioalkyl.
  • R 34 and R 35 are independently selected from the group consisting of hydrogen, -OR 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -C(O)NII 2 , -OR 42 , -SR 42 , -NHR 42 , -KR 42 R 42 , -NR 311 C(O)R 4" , -NR 59 S(O) 2 R *12
  • each R 45 is selected from the group consisting of -OH, -NHi, -CN, -NO 2 , halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy. fluoro substituted lower alkoxy, lower thioalkyl, fluoro substituted lower thioalkyl, mono- alkylamino, di-alkylamino and cycloalkylamino, preferably wherein v is O, 1.
  • Z 1 is CR 34 , U, is CR 35 , one of R 34 and R 15 is hydrogen, and the other of R 34 and R 35 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NH 2 .
  • R 34 and R 35 is selected from the group consisting of halogen, lower alkyl, and lower alkoxy, wherein lower alkyl and lower alkoxy are optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio. fluoro substituted lower alkylthio, mono- alkylamino. di-alkylamino, and cycloalkylamino.
  • n is 1 , Gj and Ki are C, and E is N or C, preferably wherein E is C, M 3 is selected from the group consisting of -NR 39 -, -0-, -NR 19 CH 2 -, -NR 39 CH(R 40 )-, -SCH 2 -, -OCH;-, -CH 2 NR 39 -.
  • each R 4 is selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower thioalkyl, fluoro substituted lower thioalkyl, mono-alkylamino, di-alkylamino and cycloalkylamino, preferably wherein v is 0, 1 , or 2, also 0 or 1, Z 1 is CR 34 .
  • U, is CR 35 , and R 34 and R 3S are both hydrogen.
  • n is 1 , Gi a ⁇ d Kj are C, and E is N or C, preferably wherein E is C, M 3 is selected from the group consisting of -NR 39 -, -O-, -NR 31 CH 2 -, -NR 39 CH(R 40 )-, -SCH 2 -.
  • each R 45 is selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower thioalkyl, fluoro substituted lower thioalkyl, mono-alkylamino, di-alkylamino and cycloalkylamino, preferably wherein v is U, 1, or 2, also 0 or 1 , Z 1 is CR 34 and Ui is CR 33 , and R 34 and R 35 are independently selected from the group consisting of
  • one of R 14 and R 35 is hydrogen, and the other of R 34 and R 35 is selected from the group consisting of halogen, lower alkyl, lower alkoxy, aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -OR 42 , -SR 42 , -NHR 42 , -NR 42 R 42 , -NR 39 C(O)R 42 , -NR 19 S(O) 2 R 42 , -S(O) 2 R 42 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino, and wherein lower alkyl and lower alkoxy arc optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, and
  • a compound of Formula I has a structure according to the following sub-generic structure, Formula II,
  • D has a structure selected from the group consisting of
  • a 2 is selected from the group consisting Of -CR 19 R 20 -, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O),-, -NR 21 -, and -O-, provided, however, that when A? is NR 21 , N is not bound to a nitrogen of D;
  • B is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 .
  • M 4 is -NR 39 CH 2 -, -NR 39 CH(R 40 )-, -NR 39 CH 2 CH 2 -, or -NR 39 C(O)-;
  • Ms 1 M 61 My 1 M 9 M ⁇ o , M 1 ] Mi 21 M] 1 M 14 M 15 M 16, M 17 and M 18 are selected from the group consisting of a bond, -(CR 19 R 2 V, -(CR I9 R 20 ) r C(O)-(CR 19 R 2 V -(CR 19 R 2 VC(S)-(CR 19 R 20 ),-, -(CR I9 R 20 ),-C(O)O-(CR l 9 R 20 ) s -,
  • Q 1 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHS(O) 2 R 43 , -NHC(O)R 43 , -NHR 43 , -NR 43 R 43 , -OR 43 , SR 43 , S(O)R 43 , and
  • Q 41 , Q 51 , Q 61 , O 71 , O 81 , 0", O 10 ', O 111 , Q 121 , Q 131 , and Q 141 are selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl;
  • Q 12 is fluoro, chloro or -CF 3 ;
  • Q 13 and Q 14 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl;
  • Q 22 , Q 24 , Q 32 , Q 33 , Q 43 , Q 44 , Q 52 , Q 54 , Q 102 and Q 104 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR 44 R 44 .
  • Q 104 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl;
  • O 62 , Q 74 , Q m , Q 124 , Q 132 , Q 144 , and Q 152 are hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR 44 R 44 , -OR 44 , or -SR 44 ;
  • Q 64 , Q 72 , Q 82 , and Q" 4 are hydrogen, lower alkyl or fluoro substituted lower alkyl;
  • R 43 at each occurrence is independently optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted hetereoaryl;
  • R 39 and R 40 are as defined for Formula Ig; each R 44 is independently hydrogen, lower alkyl or fluoro substituted lower alkyl;
  • w is 1, 2, or 3;
  • R 19 , R 20 , R 21 , R 23 , R 24 , R 25 , R 25 , s, t and u are as defined for Formula Ib; provided, however, that the compound is not
  • D has a structure selected from the gioup consisting of Q in wh iiicchh t ⁇ m inrdliicates the attachment point of D to A 2 of Formula II;
  • a 2 is selected from the group consisting of -CR 19 R 20 -, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O) 2 -, -NR 21 -, and -O-, provided, however, that when A 2 is NR 21 , N is not bound to a nitrogen of D.
  • a 2 is -CH 2 - or -C(O)-;
  • B is selected from the group consisting of hydrogen, -CN, -OR 41 , -SR 41 , -NHR 41 , -NR 41 R 41 .
  • lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as B, or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -C(O)NII 2 , -OR 42 , -SR 42 , -NHR 42 , -NR 42 R 42 , -NR 19 C(O)R 42 , -NR 39 S(O)
  • M 4 is -NR 39 CH 2 -, -NR 39 CH(R 40 )-, -NR 39 CH 2 CH 2 -, or -NR 30 C(O)-, preferably -NHCH 2 - or -NHC(O)-;
  • M 5 are selected from the group consisting of a bond, -(CR I9 R 2O ) U -, -(CR 19 R 20 ) r C(O)-(CR 19 R 20 ),-, -(CR 19 R 20 ) r C(SHCR 1Q R 20 )r, -(CR 19 R 20 X-C(O)O-(CR 1 V 0 ),-, -(CR 1 V) 1 -C(S)O-(CR 19 R 2 V, -(CR 19 R 20 ) r C(O)NR 26 -(CR 19 R 2 V, -(CR 19 R 20 ) r C(S)NR 26 -(CR 19 R 20 ) s -, -(CR 19 R 2 VS(O)-(CR 19 R 20 ),-, -(CR 19 R 2 VS(O) 2 -(CR 19 R 2 V, -(CR 19 R 20 VS(O) 2 NR 2 HCR 19 R
  • M 8 is selected from the group consisting of a bond, -(CR 1 VV, -(CR 1 V 0 X-C(O)-(CR 1 V 0 ),-, -(CR 1 VVC(SMCR 19 R 2 V, -(CR 1 V 0 X-C(O)O-(CR 1 V 0 X-.
  • Q 1 , Q 11 , Q 41 , Q 61 , and Q 141 are aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of , -OR 4 ', -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 19 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocyclo
  • aryl, and heteroaryl as a substitucnt of Q 1 , Q 1 1 , Q 41 , Q 61 , or Q 141 , or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -OR 42 , -SR 42 .
  • Q 1 , Q", Q 41 , Q" 1 , and Q 141 are aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, -NHS(O) 2 R 41 , -NHC(O)R 41 , -NHR 41 , -NR 41 R 41 , -OR 41 or -S(O) 2 R 41 ;
  • Q 12 is fluoro, chloro or -CF 3 ;
  • Q 13 and Q 14 arc independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl;
  • Q ' > 0 " > Q 5 ' aQ d Q 54 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR 44 R 44 , -OR 44 , and -SR 44 , provided, however, that at least one of Q 22 and Q 24 and at least one of Q 52 and Q i4 is hydrogen, fluoro. chloro, lower alkyl or fluoro substituted lower alkyl;
  • Q' 4 and Q 132 are hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR 44 R 44 , -OR 44 , or -SR 44 ;
  • Q " is hydrogen, lower alkyl or fluoro substituted lower alkyl
  • R 19 , R 40 and R 41 are as defined for Formula Ig; each R 44 is independently hydrogen, lower alkyl or fluoro substituted lower alkyl, and
  • R 19 , R 20 , R 21 , R 26 , s, t and u are as defined for Formula Ib,
  • a compound of Formula II has a structure according to the following sub-generic structure, Formula Ha,
  • a 3 is -CH 2 - or -C(O)-;
  • Q la is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , and -OR 41 ;
  • Q 5 is hydrogen.
  • -OR 4 ', -CN fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 4 ', -NR 4 V 1 , -OR 41 and -S(O) 2 R 43 ; and
  • M 4 , Q 12 , Q 13 , Q 14 , R 41 , and R 43 are as defined for Formula II; provided, however, that the compound is not
  • a 3 is -CH 2 - and M 4 is -NHCH 2 -.
  • a 1 is -C(O)- and M 4 is -NHCH 2 -.
  • a 3 is -C(O)- and M 4 is -NIIC(O)-.
  • a 3 is -CH 2 - and M 4 is -NHC(O)-.
  • a 3 is -CH 2 -
  • M 4 is -NHCH 2 -
  • Q 5 is -OR .
  • a 3 is -C(O)-
  • M 4 is -NHCH 2 -
  • Q 5 is -OR 43 , -CN, C
  • a 3 is -C(O)-
  • M 4 is -NHC(O)-
  • Q 5 is -OR 43 , -CN, C 1 . 3 alkyl, fluoro substituted C 1 . 3 alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 43 , -NR 43 R 43 , -OR 43 and -S(O) 2 R 43 , and Q 13 and Q 14 are hydrogen.
  • a 3 is -CH 2 -
  • M 4 is -NHC(O)-
  • Q 3 is -OR 43 , -CN, C
  • a 1 is -CH 2 - or -C(O)-;
  • Q is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alky], -NHR 41 , -NR 41 R 41 , and -OR 41 ;
  • Q 5 is hydrogen, -CN, -OR 41 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , and -OR 41 ;
  • M 4 is -NR 30 CH 2 -, -NR 39 CH(R 40 )-, -NR 39 CH 2 CH 2
  • R 41 is as defined for Formula II.
  • R 4 ' is R as defined for Formula Ig.
  • R 43 is R 42 as defined for Formula Ig,
  • Q la is phenyl or pyridinyl, wherein phenyl or pyridinyl are substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy and trifluoromethoxy;
  • a 3 is -CH 3 -;
  • M 4 is -NHCH 2 -;
  • Q 5 is -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl or heleroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
  • Q la is phenyl mono substituted with chloro, preferably at the 4-position;
  • a 1 is -CH 2 -;
  • M 4 is -NHCII 1 -;
  • Q 5 is -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
  • Q la is pyridin-3-yl monosubstituted with methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy, preferably at the 6-position;
  • a 3 is -CH 2 -;
  • M 4 is -NIICIIi-;
  • Q 5 is -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
  • Q la is phenyl or pyridinyl, wherein phenyl or pyridinyl are substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy and trifluoromethoxy;
  • C/ is hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -CN, or 1 -methyl- 1 H-pyrazole-4-yl;
  • Q 12 is fluoro or chloro; and
  • Q 13 and Q 14 are hydrogen.
  • ⁇ ⁇ is -CH 2 -; M 4 is -NIICII 2 -; Q 1 '' is pyridin-3-yl monosubstituted with methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy, preferably at the 6-position; Q 5 is hydrogen, chloro, methyl, methoxy, -CN, or 1-methyl-l H-pyrazole-4-yl; Q 12 is fluoro or chloro; and Q 13 and Q 14 are hydrogen.
  • the compound is selected from the group consisting of: (4-Chloro-benzyl)-[5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]- amine (P-0132),
  • a compound of Formula II has a structure according to the following sub-generic structure, Formula lib,
  • a 2 is selected from the group consisting of -CR 19 R 20 -, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O) 2 -,
  • Q 15 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -NO 2 , -CN, -NIIC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NII 2 , -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NR 24 R 25 , -NHR 21 , -OR 23 , -SR 23 , -C(O)R 23 , -C(S)R 23 . -S(O)R 23 , -S(O) 2 R 23 , -C(O)NHR 23 , -C(O)NR 21 R 23 ,
  • M 5 is -(CR 19 R 20 ) t -NR 2(l -(CR l9 R 20 ) 5 - or -(CR 19 R 20 X-NR 26 C(O)-(CR 19 R 2 V, preferably -NR 26 -(CR 19 R :o ),- or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CH 2 -, -NR 39 CH(R 40 )- or -NR 39 C(O)-, wherein R 39 is hydrogen or lower alkyl and R 40 is lower alkyl or fluoro substituted lower alkyl.
  • a 2 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Q" is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 .
  • -NR 2 ⁇ R 21 , -OR 23 and -S(O) 2 R 23 and Q 15 is hydrogen, -OR 21 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or hcteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 21 , -NR 21 R", -OR 21 and -S(O) 2 R 23 .
  • Q 22 and Q 24 are independently hydrogen, fluoro, chloro, or -CF 1 , preferably Q 2 " and Q 24 arc hydrogen,
  • M 5 is -(CR l 9 R 2O ) r NR 26 -(CR l9 R ::o V or -(CR 19 R 20 VNR 26 C(OHCR 19 R 20 X-, preferably -NR 2ft -(CR 19 R 20 X- or -NR 16 C(O)-(CR 19 R 20 ),-, more preferably -NR 19 CH 2 -, -NR 39 CH(R 40 )- or -NR 19 C(O)-, and A 2 is -CR 19 R 20 - or -C(O)-, preferably -CH,- or -C(O)-.
  • M is -(CR 19 R 20 ),-NR 26 -(CR 19 R 20 ) s - or -(CR 19 R 20 X-NR 26 C(O)-(CR 19 R 20 X-, preferably -NR 26 -(CR 19 R 20 ) s - or -NR 26 C(O)-(CR 19 R 20 ),-.
  • a 2 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 11 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 21 , -NR 21 R 23 , -OR 23 and -S(O) 2 R 23 ; and
  • Q 15 is hydrogen, -OR 23 , -CN, fluoro, chloro, lower alkyl, ⁇ luoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycl
  • M 5 is -(CR 19 R 20 ) r NR 26 -(CR 19 R 20 ) s - or -(CR 19 R 20 J 1 -NR 25 C(O)-(CR 19 R 20 X-, preferably -NR 26 -(CR 19 R 20 ) s - or -NR 26 C(O)-(CR 19 R 20 X-, more preferably -NR 39 CH 2 -, -NR 39 CH(R 40 )- or -NR 39 C(O)-;
  • a 2 is -CR 19 R 20 - or -C(O)-, preferably -CII 2 - or -C(O)-;
  • Q 1 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted
  • Q 15 is hydrogen, -OR 23 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 21 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 ; and Q 22 and Q 24 are independently hydrogen, fluoro, chloro, or -CFi, preferably Q 22 and Q i4 are hydrogen.
  • M 5 is -NR 19 CII 2 -, -NR 19 CH(R 40 )-, -NR 19 CH 2 CH,-, or -NR 19 C(O)-:
  • a 7 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 11 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 ;
  • Q 15 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloal
  • a 2 is -CH 2 - or -C(O)-, preferably -CHi-; 0 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 39 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy,
  • heterocycloalkyl, aryl, and heteroaryl wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q 1 1 , or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NII 2 , -C(O)NIl 2 , -OR 42 , -SR 4: , -NHR 42 , -NR 42 R 42 , -NR 39 C(O)R 42 , -NR 39 S(O) 2 R 42 , -S(O) 2 R 42 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
  • Q 15 is hydrogen, -CN, -OR 41 , -SR 41 , -S(O)R 41 , -S(
  • a 2 is -CH 2 -;
  • Q 1 1 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, di-alkylamino, and heterocycloalkyl;
  • Q 15 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy;
  • M 5 is -NR 39 CH 2 -, -NR 39 CH 2 CH 2 -, or -NR 39 CH(R 41 )-; and
  • Q 2 ' and Q 24 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy. or fluoro substituted lower alkoxy, provided, however, that at least one
  • each occurrence of R 41 is R 42 as defined for Formula Ig.
  • M 5 is -NHCHXH,-, -NHCH 2 -, -N(CH 1 )CH 2 -, or -NHCH(CHO-, preferably -NHCH 2 -;
  • a 2 is -CH 2 -;
  • Q 11 is cycloalkyl, heterocycloalkyl, phenyl or heteroaryl, wherein phenyl or heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, di-alkylamino, and heterocycloalkyl;
  • Q I S is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy.
  • M 5 is -NHCH 2 -;
  • a 2 is -CH 2 -;
  • Q 1 1 is phenyl substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, fluoro substituted methyl, methoxy, and fluoro substituted methoxy;
  • Q 15 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, preferably hydrogen or chloro; and
  • Q 22 and Q 24 are hydrogen.
  • the compound is selected from the group consisting of:
  • a compound of Formula II has a structure according to the following sub-generic structure.
  • a 4 is selected from the group consisting of -CR 1 V 0 -, -C(O)-. -C(S)-, -S-, -S(O)-, -S(O) 2 -,
  • Q" 3 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted hctcrocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -NO 2 , -CN, -NHC(O)NH 2 , -NHC(S)NlI 2 , -NHS(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NR 24 R 25 , -NHR 2 ', -OR 23 , -SR 23 , -C(O)R 23 , -C(S)R 23 , -S(O)R 23 , -S(O) 2 R 23 , -C(O)NHR 23 , -C(O)NR 23 R 23 , -C(S
  • M d , Q 21 , Q 32 and Q 33 arc as defined for Formula II; and R 19 , R 20 , R 21 , R 23 , R 24 , and R 25 are as defined for Formula Ib.
  • M 6 is -(CR 19 R 20 ) r NR 26 -(CR l9 R 2 °X- or -(CR 19 R 21 VNR 26 C(O)-(CR 19 R 20 V, preferably -NR 26 -(CR 19 R 20 ) s - or -NR 26 C(O)-(CR 19 R 21 V, more preferably -NR 39 CH 2 -, -NR 39 CH(R 40 )- or -NR 39 C(O)-, wherein R 39 is hydrogen or lower alkyl and R 40 is lower alkyl or fluoro substituted lower alkyl.
  • a 4 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Q 21 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR "1 , -NR 23 R 2 ', -OR 1 and -S(O) 2 R 23 and Q 25 is hydrogen, -OR 23 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl.
  • cycloalkyl, heterocycloalkyl, aryl or heteroaryl wherein cycloalkyl, heterocycloalkyl.
  • aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NIIR * " , -NR " R 2 , -OR " and -S(O) 2 R 2 .
  • Q 3 " and Q 33 are independently hydrogen, fluoro, chloro, or -CF 3 ,
  • M 6 is -(CR I9 R 20 ) r NR 2tI -(CR. ⁇ g R 2( V or -(CR 19 R 2 VNR 26 C(O)-(CR 10 R 20 X-, preferably -NR 26 -(CR 19 R 20 ) s - or -NR 26 C(O)-(CR 19 R 2 "),-, more preferably -NR 19 CH 2 -, -NR 39 CH(R 40 )- or -NR 39 C(O)-, and A 4 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • M 3 is -(CR 1 ' ) R 20 ) r NR 26 -(CR 19 R 20 ) s - or -(CR 19 R 20 X-NR 26 C(OHCR 19 R 20 X-, preferably -NR 26 -(CR l9 R 2n ) s - or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CH 2 -, -NR 39 CH(R 40 )- or -NR 39 C(O)-;
  • a 4 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 21 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -
  • heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 .
  • M 6 is or -(CR 19 R 20 ) r NR 26 C(O)-(CR 19 R 20 ) s -, preferably -NR 26 -(CR 19 R 20 ) a - or -NR 211 C(O)-(CR 19 R ⁇ X-, more preferably -NR 39 CH 2 -.
  • a 4 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 21 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 2j , -NR 23 R "1 .
  • Q 25 is hydrogen, -OR 21 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 21 R 23 , -OR 21 and -S(O) 2 R 23 : and Q 32 and Q" are independently hydrogen, fluoro, chloro, or -CF 3 .
  • M 6 is -NR 19 CH 2 -, -NR ⁇ CH(R 40 )- or -NR 39 C(O)-. preferably -NHCH 2 -;
  • a 4 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 21 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 ;
  • Q 25 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, ary
  • a 4 is -CII 2 - or -C(O)-, preferably -CH 2 -;
  • Q 21 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NHR 41 .
  • a 4 is -CH 2 -;
  • Q 2 ' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • Q 25 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy;
  • M 6 is -NR 39 CHi-, -NR 39 CH 2 CH 2 -, or -NR 39 CIl(R 40 )-; and
  • Q 32 and Q 33 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl. lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that at least one of Q 32 and Q 33 is hydrogen, fluoro, chloro
  • each occurrence of R 41 is R 42 as defined for Formula Ig
  • a compound of Formula II has a structure according to the following sub-generic structure, Formula Hd,
  • a 5 is selected from the group consisting of -CR 19 R 20 -, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O) 2 -, -NR 21 -, and -O-;
  • Q 35 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -NO 2 , -CN, -NIIC(O)NH 2 , -NIIC(S)NH 2 , -NHS(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NII 2 , -NR 24 R 25 , -NHR 2 ', -OR 21 , -SR 23 , -C(O)R 23 , -C(S)R 23 , -S(O)R 23 , -S(O) 2 R 23 , -C(O)NIIR 23 , -C(O)NR 21 R 23 , -C(S)NHR 23 ,
  • M 7 , Q 31 , Q 43 and Q 44 are as defined for Formula II;
  • R 19 , R 20 , R 21 , R 23 , R 24 , and R 25 arc as defined for Formula Ib.
  • M 7 is -(CR l9 R 20 ) r NR 2e -(CR l9 R 2 °X- or -(CR 19 R 20 ) r NR 2s C(O)-(CR ! 9 R 20 ) s -, preferably -NR 26 -(CR ! 9 R 20 ) s - or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CII 2 -, -NR 39 CH(R 49 )- or -NR 39 C(O)-, wherein R 39 is hydrogen or lower alkyl and R 40 is lower alkyl or fluoro substituted lower alkyl.
  • a 5 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Q 31 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 2 ', -NR 31 R 21 , -OR 21 and -S(O) 2 R 23 and Q 35 is hydrogen, -OR 23 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, ar>l or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl,
  • M 7 is -(CR 19 R 20 VNR ⁇ -(CR 19 R 20 V or -(CR 19 R 20 VNR 26 C(O)-(CR 1 V' 0 ),-, preferably -NR 26 -(CR 19 R 20 ) S - or -NR 26 C(O)-(CR 19 R 2 "),-, more preferably -NR 39 CH,-, -NR 39 CH(R 40 )- or -NR 39 C(O)-, and A 5 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • M 7 is -(CR 1 "R 20 ) r NR 26 -(CR lt) R 20 ) ⁇ or -(CR 19 R 20 VNR 26 C(O)-(CR 19 R 20 V, preferably -NR 2 ⁇ (CR 1 V°) s - or -NR 26 C(O)-(CR 19 R 20 ),-. more preferably -NR 39 CH 2 -, -NR 19 CH(R 40 )- or -NR 39 C(O)-; A 5 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-; Q 31 is aryl or heteroaryl.
  • aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 ; and Q 35 is hydrogen, -OR 23 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NIIR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 .
  • M 7 is -(CR 19 R 20 VNR 21 HCR 19 R 20 V or -(CR 19 R 20 VNR 26 C(O)-(CR 19 R 20 V, preferably -NR 26 -(CR 19 R 2 °V or -NR 26 C(O)-(CR 19 R 20 V, more preferably -NR 39 CH 2 -, -NR 39 CH(R 40 )- or -NR 39 C(O)-;
  • a 5 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 31 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 21 ;
  • Q 35 is hydrogen, -OR 23 , -
  • cycloalkyl, heterocycloalkyl, aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 2 ' , -OR 23 and -S(O) 2 R 2 '; and Q 4 ' and Q 44 are independently hydrogen, fluoro, chloro, or -CF 1 .
  • M 7 is -NR 39 CH 2 -, -NR 19 CH(R 40 )- or -NR 39 C(O)-, preferably -NHCIl 2 -;
  • a 5 is -CII 2 - or -C(O)-, preferably -CH 2 -;
  • Q 31 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 11 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 ;
  • Q 35 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycl
  • aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 ;
  • Q 43 and Q 44 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably Q 43 and Q 44 are independently hydrogen, fluoro, chloro, or -CF 3 , wherein R 41 is as defined for Formula Ig.
  • a 5 is -CH 2 - or -C(O)-, preferably -CHi-;
  • Q 31 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 .
  • a 5 is -CH 2 -;
  • Q is aryl or heteroaryl. wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • Q 35 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy;
  • M 7 is -NR 39 CH 2 -, -NR 39 CH 2 CH 2 -, or -NR 39 CH(R 40 )-; and
  • Q 43 and Q 44 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that at least one of Q 43 and Q 44 is hydrogen, fluoro, chloro, lower alky
  • each occurrence of R 41 is R 42 as defined for Formula Ig.
  • a compound of Formula II has a structure according to the following sub-generic structure. Formula lie.
  • a 6 is selected from the group consisting Of -CR 1 V 0 -, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)-,
  • Q is selected from the group consisting of hydrogen, halogen, optionally substituted lower alky], optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NII 2 , -NO 2 , -CN, -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NR 24 R 25 , -NIIR 23 , -OR 23 , -SR 23 , -C(O)R 23 , -C(S)R 23 , -S(O)R 23 , -S(O) 2 R 21 , -C(O)NHR 23 , -C(O)NR 21 R 21 , -C(S)NHR 23 , -C
  • M 8 , Q 4! , Q 52 and Q 54 are as defined in Formula II; and R 19 , R 20 , R 21 , R 23 , R 24 , and R 25 are as defined for Formula Ib;
  • Mg is -(CR 19 R 20 ) r C(O)NR 2(1 -(CR 19 R 20 ) s -, preferably -C(O)NR 26 -(CR 19 R 20 ) s -, more preferably -C(O)NR 39 -CR S V°- or -C(O)NR 39 -(CR 80 R 80 ) 2 - > wherein R 39 is hydrogen or lower alkyl and R 8 ⁇ is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen.
  • ⁇ b is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Q 41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substitucnts selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 2 ⁇ -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 and Q 45 is hydrogen, -OR 23 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl
  • M 8 is -(CR l9 R 20 ) t -C(O)NR 2h -(CR' 9 R 20 ) s -, preferably -C(O)NR 26 -(CR I9 R 20 ) s -, more preferably -C(O)NR 39 -CR 80 R S0 - or -C(O)NR 19 -(CR 8 ⁇ R 80 ) 2 -, and A 6 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • M 8 is -(CR !9 R 20 ) t -C(O)NR 26 -(CR l5 R 20 ) s -, preferably -C(O)NR 26 -(CR l 9 R 20 ) s -, more preferably -C(O)NR 39 -CR s0 R 80 - or -C(O)NR 3 ⁇ 3 -(CR 8 V°) 2 -;
  • a 6 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 21 , -NR 21 R "1 , -OR 21 and -S(O) 2 R 2 '; and
  • Q 45 is hydrogen, -OR 21
  • M s is -(CR l9 R 20 ) r C(O)NR 26 -(CR' V),-, preferably -C(O)NR 26 -(CR' 9 R 20 X-, more preferably -C(O)NR 19 -CR 80 R 80 - or -C(O)NR ?9 -(CR 80 R 80 ) 2 -,
  • a 6 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substitucnts selected from the group consisting
  • Q 45 is hydrogen, -OR 23 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 2 ⁇ -OR 23 and -S(O) 2 R 23 ; and Q 52 and Q 54 are independently hydrogen, fluoro, ehloro, methyl, or -CF 3 .
  • M 8 is -C(O)NR 39 -CH 2 -, -C(O)NR 39 CH(CH 3 )-, or -C(O)NR 39 -(CH 2 ) 2 -;
  • a 6 is -CH 2 - or -C(OV, preferably -CH 2 -;
  • Q 41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 ;
  • Q 45 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloal
  • a 6 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 41 is aiyl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 39 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino
  • Q" and Q 54 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R 39 , R 40 , R 41 , R 42 and R 44 are as defined for Formula II.
  • Ag is -CH 2 -;
  • Q 41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • Q 45 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy;
  • Mg is -C(O)NR 19 CH:-, -C(O)NR 39 CH(R 40 )-, or -C(O)NR 39 CH 2 CH 2 -; and
  • Q 52 and Q 54 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that at least one of Q 52 and Q 54 is hydrogen,
  • each occurrence of R 41 is R 42 as defined for Formula Ig.
  • M 8 is -C(O)NHCH 2 -, -C(O)NH-CH(CH 3 )- or -C(O)NH-(CH 2 ) 2 -;
  • a 6 is -CH 2 - or -C(O)-, preferably -CII 2 -;
  • Q 4 ' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, fluoro substituted methyl, methoxy, and fluoro substituted methoxy;
  • Q 45 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably hydrogen or chloro; and
  • Q 52 and Q 14 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably Q 52 and Q
  • the compound is selected from the group consisting of:
  • a compound of Formula II has a structure according to the following sub-generic structure, Formula Hf,
  • a 7 is selected from the group consisting Of -CR 19 R 20 -, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O) 2 -,
  • Q 55 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted hctcrocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -NO 2 , -CN, -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NR 24 R 25 , -NHR 23 , -OR 23 , -SR 23 , -C(O)R 23 , -C(S)R 23 , -S(O)R 23 , -S(O) 2 R 23 , -C(O)NHR 23 , -C(O)NR 23 R 23 , -C(S)NHR 23
  • M 9 , Q 51 . Q fi2 , and Q 64 are as defined for Formula II; and R 19 , R 20 , R 21 , R 23 , R 24 , and R 25 are as defined for Formula Ib.
  • M 9 is -(CR I9 R 20 ) t -NR 2(i -(CR I 9 R 20 ),- or -(CR I 9 R 20 ) r NR 26 C(O)-(CR ll) R 2 V, preferably -NR 26 -(CR 19 R 20 ) s - or -NR 26 C(O)-(CR 19 R 20 X-, more preferably -NR 39 CR 80 R 80 - or -NR 39 (CR 80 R 80 ) r , wherein R 39 is hydrogen or lower alkyl and R 80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen.
  • A- is -CR 19 R' 0 - or -C(O)-, preferably -CH 2 - or -C(O)-
  • Q 51 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 21 and Q 55 is hydrogen, -OR 21 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, hcterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower
  • M 9 is -(CR 1? R 20 ) r NR 26 -(CR l ⁇ ) R 20 ),- or -(CR 19 R 2 VNR 26 C(O)-(CR 19 R 2 V, preferably -NR 26 -(CR 19 R 2 V or -NR 26 C(O)-(CR 1 V V, more preferably -NR 34 CR 80 R 80 - or -NR ⁇ (CR 80 R 80 )-,-, and A 7 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • M 9 is -(CR 19 R 2G ) r NR 26 -(CR ! 5 R 2 V or
  • a 7 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 11 is optionally substituted lower alkyl, aryl or heteroaryl.
  • aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 21 and -S(O) 2 R 21 ; and Q 55 is hydrogen, -OR", -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NIIR 23 , -NR 23 R 23 , -OR 21 and -S(O) 2 R 2 '.
  • M 9 is -(CR 19 R 20 ) r NR 26 -(CR 1C) R 20 ) s - or -(CR 19 R 20 VNR 26 C(O)-(CR 19 R 20 X-, preferably -NR :6 -(CR 19 R 2 V or -NR 2fi C(O)-(CR 19 R 20 ) s - more preferably -NR 39 CR 80 R 80 -, -NR 19 (CR 8 V 0 ) ; -; Ai is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-; Q 51 is optionally substituted lower alkyl, aryl or heteroaryl.
  • aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 21 . -NR 23 R 21 , -OR 21 and -S(O) 2 R 23 ;
  • Q 55 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein aryl or heteroaiyl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 21 R 21 .
  • M 9 is -NR 19 CH 2 - or -NR iy -(CH 2 ) ; -; A, is -CH 2 - or -C(O)-, preferably -CH 2 -; Q 5 ' is aryl or hcteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 4i R 41 , -OR 41 and -S(O) 2 R 41 ; Q 55 is hydrogen, -CN, fluoro, chloro.
  • a 7 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 5 ' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 4 ', -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 19 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkyla
  • aryl, and heteroaryl wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q 51 , or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 .
  • Q 55 is hydrogen, -CN, -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NIIR 41 , -NR 41 R 4' ', -NR 39 C(O)R 41 , -NR 19 S(O) 2 R 41 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting
  • Q 62 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR 44 R 44 , -OR 44 , or -SR 44 ; and Q 64 is hydrogen, lower alkyl. or fluoro substituted lower alkyl, wherein R' 9 , R 40 , R 41 , R 42 and R 44 are as defined for Formula II.
  • A? is -CH 2 -;
  • Q ' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • Q 55 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy;
  • M 9 is -NR 34 CH 2 -, -NR 39 CH 3 CH 2 -, or -NR 39 CH(R 40 )-;
  • Q 62 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy;
  • Q 64 is hydrogen, lower alkyl, or fluoro substituted lower alkyl.
  • each occurrence of R " " is R 42 as defined for Formula Ig.
  • a compound of Formula II has a structure according to the following sub-generic structure, Formula Ug,
  • a 8 is selected from the group consisting Of -CR 19 R 20 -, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O) 2 -,
  • Q 65 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -NO 2 , -CN, -NHC(O)NH 2 , - NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 7 , -NR 24 R 25 , -NHR 23 , -OR 23 , -SR 23 , -C(O)R 23 , -C(S)R 23 , -S(O)R 23 , -S(O) 2 R", -C(O)NHR 23 , -C(O)NR 21 R 23 , -C(S)NHR 23 , -C(
  • M 10 , Q 61 , Q 72 , Q 74 are as defined for Formula II; and R 19 , R 20 , R 21 . R 23 , R 24 , and R 25 , R 20 are as defined for Formula Ib.
  • M 10 is -(CR I9 R 20 ) t -NR 2tJ -(CR l 9 R 2 ⁇ ) ⁇ - or -(CR 19 R 2 VNR 26 C(O)-(CR 19 R 20 X-, preferably -NR 26 -(CR 19 R 20 ) s - or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CR 80 R 80 - or -NR 39 (CR 80 R 80 ) 2 -, wherein R 39 is hydrogen or lower alkyl and R 80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen.
  • a 8 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Q 61 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, iluoro substituted lower alkyl.
  • -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 and Q M is hydrogen, -OR 21 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cyeloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 .
  • Q 74 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
  • M 10 is -(CR 1 ⁇ ) R :!0 ) r NR 26 -(CR 19 R 20 ) i - or -(CR 19 R 20 ) r NR 26 C(O)-(CR 19 R 20 ) 5 -, preferably -NR 26 -(CR 19 R 20 ) s - or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 19 CR 80 R 80 - or -NR 39 (CR 80 R 80 ) 2 -, and A 3 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-. In one embodiment. M 10 is -(CR 19 R 20 ) r NR 26 -(CR 19 R 20 ) s - or
  • a 8 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 61 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 2 ', -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 : and
  • Q" 5 is hydrogen, -OR 23 , -CN
  • M 10 is -(CR 19 R 20 ),-NR 26 -(CR 19 R 20 ) s - or -(CR 19 R 20 VNR 26 C(O)-(CR 19 R 20 X-, preferably -NR 2 ⁇ (CR 19 R 20 ),- or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CR 80 R 80 - or -NR 39 (CR 8O R 8I1 ) 2 -;
  • a 8 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 61 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 2 ', -NR 23 R 23 , -OR 23 and -S
  • M 10 is -NR 39 CH 2 - or -NR !I) -(CH 2 ) 2 -;
  • a s is -CH;- or -C(O)-, preferably -CH 2 -;
  • Q 61 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 ;
  • Q 65 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optional
  • a 8 is -CH 2 - or -C(O)-, preferably -CH ? -;
  • Q 6 ' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NHR 41 , -NR 41 R 41 , -NR 19 C(O)R 41 , -NR 19 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkyla
  • Ag is -CH 2 -;
  • Q 61 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy.
  • Q 65 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy;
  • M 10 is -NR 39 CH 2 -, -NR ig CH,CH 2 - ( or -NR 39 CH(R*)-;
  • Q 74 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; and
  • Q 72 is hydrogen, lower alkyl, or fluoro substituted lower alkyl.
  • each occurrence of R 41 is R 42 as defined for Formula Ig.
  • M 10 is -NHCH 2 -, A 8 is -CH;-, Q 0 ' is phenyl optionally substituted with 1 or 2 substituents selected from the group consisting of fluoro. chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromefhoxy, Q 65 is hydrogen, fluoro, -CN, or l -methyl-pyrazol-4-yl, Q 72 is lower alkyl or fluoro substituted lower alkyl, and Q 74 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl.
  • M] 0 is -NIICH 2 -
  • a 8 is -CH 2 -
  • C/ 1 is 4-fluoro-phenyl
  • Q 65 is hydrogen, chloro, -CN, or 1 -methyl - pyrazol-4-yl
  • Q 72 is methyl or ethyl
  • Q 74 is hydrogen or chloro.
  • the compound of Formula Hg is selected from the group consisting of :
  • a compound of Formula II has a structure according to the following sub-generic structure, Formula Ilh,
  • a 9 is selected from the group consisting Of -CR 1 V 0 -, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O) 2 -,
  • 0 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -NO 2 , -CN, -NIIC(O)NH 2 , -NHC(S)NII 2 , -NHS(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NR 24 R 25 , -NHR 23 , -OR 23 , -SR 23 , -C(O)R 23 , -C(S)R 23 , -S(O)R 23 , -S(O) 2 R 23 , -C(O)NHR 21 , -C(O)NR 23 R 23 , -C(S)NHR 23 ,
  • M H , Q' ', and Q 82 are as defined for Formula II; and R 19 , R 20 , R 21 , R 23 , R 24 , and R 25 are as defined for Formula Ib.
  • M n is or -(CR 19 R 20 VNR 26 C(O)-(CR 19 R 20 X-, preferably -NR 26 -(CR l9 R 20 ) s - or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CR 80 R 80 - or -NR 39 (CR 80 R%-, wherein RTM is hydrogen or lower alkyl and R S ⁇ is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen.
  • a 9 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Q 71 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 2 ', -NR 23 Rr 3 , -OR 23 and -S(O) 2 R 23 and Q 75 is hydrogen, -CN.
  • M 1 1 is -(CR i9 R 20 ) t -NR 26 -(CR
  • M 1 is -(CR 1 V 0 ) t -NR 26 -(CR i ⁇ R 20 ) s - or
  • a 9 is -CR 19 R 20 - or -C(O)-, preferably -CII 2 - or -C(O)-;
  • Q 71 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 ; and
  • Q/ 5 is hydrogen, -OR 23 , -CN, fluoro, chloro, lower alkyl
  • M 1 1 is -NR 39 CH 2 - or -NR 39 -(CH 2 ) 2 -;
  • a 9 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 71 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 ;
  • Q 75 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, helerocycloalkyl.
  • aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 , wherein R 41 is as defined for Formula Ig.
  • a 9 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 7 ' is aryl or heteroaryl. wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 39 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamin
  • aryl, and heteroaryl as a substituent of Q ' , or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NII:, -C(O)NII 2 , -OR 42 , -SR 42 , -NHR 42 , -NR 42 R 42 , -NR 39 C(O)R 42 , -NR 39 S(O) 2 R 42 , -S(O) 2 R 42 , halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylami.no;
  • Q s is hydrogen, -CN, -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NIIR 41 , -NR 41 R 41 , -NR (9 C(O)
  • ⁇ 9 is -CH 2 -;
  • Q 71 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • Q 7 ' is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl.
  • M n is -NR 39 CH 2 -, -NR 39 CH 2 CH 2 -, or -NR 39 CH(R 40 )-; and Q 82 is hydrogen, lower alkyl, or fluoro substituted lower alkyl.
  • each occurrence of R 41 is R 42 as defined for Formula Ig.
  • a compound of Formula II has a structure according to the following sub-generic structure, Formula Hi,
  • Ai 0 is selected from the group consisting Of -CR 19 R 20 -, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O),-,
  • Q H ⁇ is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl. optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl. -OH, -NH 2 , -NO 2 , -CN. -NHC(O)NH;.
  • -S(O) 2 NR 21 R 23 -NHC(O)R", -NR 21 C(O)R 21 , - NHC(S)R 23 , -NR 21 C(S)R 23 .
  • Mi 2 , Q 81 , and Q M are as defined for Formula II;
  • R 19 , R 20 , R 21 , R 21 , R 24 , and R 25 are as defined for Formula Ib.
  • M 12 is -(CR 19 R 2 VNR 26 -(CR'"R 2 V or -(CR 1 V) 1 -NR 26 C(O)-(CR 19 R 20 V, preferably -NR 26 -(CR 19 R 20 ),- or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CR 80 R 80 - or -NR 19 (CR 80 R 80 ) r , wherein R 19 is hydrogen or lower alkyl and R 80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen.
  • A) 0 is -CR 19 R 20 - or -C(O)-, preferably -CII 2 - or -C(O)-.
  • Q 81 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, rluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 21 and -S(O) 2 R 21 and Q 85 is hydrogen, -OR 23 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen,
  • M 12 is or -(CR 19 R 20 VNR 26 C(O)-(CR 19 R 20 X-, preferably -NR 26 -(CR !9 R 20 ) s - or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CR 80 R 80 - or -NR 39 (CR 80 R 80 ),-, and A 10 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Mi 2 is -(CR 19 R 20 ) r NR 26 -(CR 19 R 20 ) s - or
  • Q 81 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl aie optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 21 R 23 , -OR 23 and -S(O) 2 R 21 ; and Q" is hydrogen, -OR 21 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR".
  • M 12 is -KR 39 CII 2 - or -NR 39 -(CII 2 ) 2 -; ⁇
  • Q 81 is aryl or heteroaryl. wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 ;
  • Q 85 is hydrogen, -CN, fluoro, chloro.
  • cycloalkyl, heterocycloalkyl, aryl or heteroaryl wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 , wherein R 41 is as defined for Formula Ig.
  • a 10 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 81 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 39 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more subslituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy.
  • lower alkylthio fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl.
  • heterocycloalkyl, aryl, and heteroaryl wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q 81 , or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NH 2 , -C(O)NH 2 , -OR 42 , -SR 42 , -NHR 42 , -NR 42 R 42 , -NR 39 C(O)R 42 , -NR 39 S(O) 2 R 42 .
  • Q 85 is hydrogen, -CN, -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NHR 41 , -NH 41 R 41 , -NR 19 C(O)R 41 , -NR 111 S(O) 2 R 41 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alky], fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , and -OR 41 ; M 12 is a bond, -NR 19 -, -S-, -0-, -NR 19 CH 2 -, -
  • Ai 0 is -CH 2 -;
  • Q 81 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • Q 85 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy;
  • M 12 is -NR 19 CH 2 -, -NR 19 CH 2 CH 2 -, or -NR 39 CH(R 40 )-; and
  • Q" 4 is hydrogen, lower alkyl, or fluoro substituted lower alkyl.
  • each occurrence of R 41 is R 42 as defined for Formula Ig.
  • a compound of Formula II has a structure according to the following sub-generic structure, Formula Hj,
  • a 1 is selected from the group consisting Of -CR 19 R 20 -, -C(O)-, -C(S)-, -S(O)-, and -S(O) 2 -;
  • Q 95 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -NO 2 , -CN, -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NR 24 R 25 , -NHR 23 , -OR 23 , -SR 23 , -C(O)R 23 , -C(S)R 23 ,
  • M 13 , Q" 1 , Q 102 and Q 104 are as defined for Formula II; and R 19 , R 20 , R 23 , R 24 , and R 25 are as defined for Formula Ib,
  • M 13 is -(CR 19 R 20 ) , -NR 26 -(CR
  • An is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Q 91 is optionally substituted lower alkyl, aryl or hcteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 2 ', -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 and Q 95 is hydrogen, -OR 23 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl.
  • heterocycloalkyl aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 .
  • Q 10 " and Q 104 are independently hydrogen, fluoro, chloro, methyl, or -CF 3 .
  • M 13 is -(CR 19 R 20 ) t -NR 26 -(CR 19 R 20 ) s - or -(CR 19 R 2 VNR 26 C(O)-(CR 111 R 20 X-, preferably -NR 26 -(CR 19 R 20 ) s - or -NR 25 C(O)-(CR 19 R 20 ).,-, more preferably -NR 39 CR 80 R 80 - or -NR 39 (CR S0 R 8O ) r , and A 11 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • M 13 is -(CR 19 R 20 ) r NR 26 -(CR 19 R 20 ) s - or
  • n is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 91 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 ; and
  • Q 95 is hydrogen, -OR' , -CN, fluor
  • M 13 is -(CR 19 R 20 ),-NR 26 -(CR 19 R 20 ) s - or -(CR 19 R 20 ) r NR 26 C(O)-(CR 19 R 20 ) s -, preferably -NR 26 -(CR 19 R 2 V or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CR 80 R 80 - or -NR 39 (CR S0 R 80 ),-;
  • a 1 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 91 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -
  • M 13 is -NR 39 CH 2 - or -NR 3M -(CH 2 ) 2 -;
  • An is -CII 2 - or -C(O)-, preferably -CH 2 -;
  • Q 91 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 ;
  • Q 95 is hydrogen, -CN, fluoro, ehloro.
  • Au is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q ' is aryl or heteroaryl, wherein aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 4 ', -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 19 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamin
  • An is -CH 2 -;
  • Q 91 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy:
  • Q 95 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy;
  • M ]3 is -NR CH 2 -, -NR 39 CH 2 CH 2 -, or -NR 39 CH(R 40 )-; and
  • Q 102 and Q 104 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that at least one of Q I(P and Q 104 is hydrogen, fluoro
  • each occurrence of R 41 is R 42 as defined for Formula Ig,
  • a compound of Formula II has a structure according to the followi ⁇ sub-gcnc ⁇ c structure, Formula Hk,
  • A is selected from the group consisting Of -CR 19 R 20 -, -C(O)-, -C(S)-, -S(O)-, and -S(O) 2 -;
  • Q 105 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -NO 2 , -CN, -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NR 24 R 25 , -NHR 21 , -OR 23 , -SR 23 , -C(O)R 21 , -C(S)R 21 ,
  • -NIIC(O)NHR 21 -NR 23 C(O)NH 2 , -NR 21 C(O)NHR 23 , -NHC(O)NR 23 R 23 , -NR 21 C(O)NR 23 R 23 , -NHC(S)NHR 21 , -NR 21 C(S)NH 2 , -NR 21 C(S)NHR 23 , -NHC(S)NR 23 R 23 , -NR 21 C(S)NR 21 R 21 .
  • Mi 4 , Q l ⁇ l , and Q 1 12 are as defined for Formula II; and R 19 , R 20 , R 23 , R 24 , and R 25 are as defined for Formula Ib.
  • M 14 is -(CR 19 R 20 ) r NR 2() -(CR l 9 R 20 ) s - or -(CR 19 R 2 VNR 26 C(O)-(CR 19 R 20 V, preferably -NR 25 -(CR 19 R 2 V or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 19 CR 80 R 80 - or -NR 39 (CR 80 R 80 ) 2 -, wherein R 39 is hydrogen or lower alkyl and R 80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen.
  • Ai 2 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Q 101 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alk ⁇ l.
  • fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 and Q 105 is hydrogen, -OR 2 ⁇ -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 .
  • Q 1 12 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
  • M 14 is -(CR 19 R 20 ),-NR 26 -(CR 19 R :o ) s - or -(CR I 9 R 20 ) ⁇ NR 26 C(O)-(CR 19 R 20 ) S -, preferably -NR 26 -(CR 19 R 20 ) s - or -NR 26 C(O)-(CR 1 V 1 V. more preferably -NR 39 CR 80 R 80 - or -NR 39 (CR 80 R 80 ) 2 -, and A 12 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • M 14 is -(CR 19 R 20 ) r NR 26 -(CR 19 R 2 V or
  • n is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 101 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 ; and
  • Q 105 is hydrogen, -OR" " , -CN, fluoro, chloro, lower alkyl
  • M 14 is -(CR I 9 R 20 ),-NR 26 -(CR 19 R 20 ) s - or -(CR 19 R 20 ) r NR 26 C(O)-(CR l9 R 20 ) s -, preferably -NR 26 -(CR' 9 R 20 X- or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CR 80 R 80 - or -NR 3g (CR 8O R 8O ) 2 -;
  • a 12 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 101 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23
  • lower alkyl fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 ; and Q 112 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
  • M 14 is -NR 39 CH 2 - or -NR 19 -(CH;) : -;
  • a 17 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 101 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 .;
  • Q 1 " 5 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy.
  • cycloalkyl, heterocycloalkyl, aryl or heteroaryl wherein cycloalkyl, heterocycloalkyl.
  • aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 4 ', -OR 41 and -S(O) 2 R 41 ; and
  • Q 112 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R 41 is as defined for Formula Ig.
  • a 12 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 101 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR "11 , -S(O)R 41 , -S(O) 2 R 4 ' , -NHR", -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 59 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamin
  • -NR 39 S(O) 2 R 41 fluoro, chl ⁇ ro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , and -OR 41 , M 14 is a bond, -NR 1 "-, -S-, -0-, -NR 39 CH 2 -.
  • a 12 is -CII 2 -;
  • Q 101 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • Q 105 is hydrogen, -CN, fluoro, chloro.
  • each occurrence of R 41 is R 4 " as defined for Formula Ig.
  • a compound of Formula II has a structure according to the following sub-generic structure, Formula Hm, "
  • a n is selected from the group consisting Of -CR 19 R 20 -, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O) 2 -,
  • Q l b is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -NO 2 , -CN, -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NR 24 R 25 , -NHR 21 , -OR 23 . -SR 23 , -C(O)R 23 .
  • -C(S)R 23 -S(O)R 23 , -S(O) 2 R 23 , -C(O)NHR 21 , -C(O)NR 23 R 21 , -C(S)NHR 23 , -C(S)NR 23 R 23 , -S(O) 2 NHR 23 , -S(O) 2 NR 23 R 23 , -NHC(O)R 23 , -NR 23 C(O)R 2 ', -NHC(S)R 23 , -NR 23 C(S)R 23 , -NHS(O) 2 R 23 , -NR 23 S(O) 2 R 23 , -NHC(O)NHR 21 .
  • Mi 5 , Q 1 ". and Q 124 are as defined for Formula IT: and R 19 , R 20 , R 21 , R 23 , R 24 , and R 25 are as defined for Formula Ib,
  • M 15 is -(CR 19 R 20 ) r NR 26 -(CR
  • Q 1 " is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 3 R 23 and Q 1 15 is hydrogen,
  • -OR 23 -CN, fluoro, chloro. lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, hcterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 21 , -NR 23 R 2 ', -OR 23 and -S(O) 2 R 23 , Further to any of the above embodiments.
  • Q 124 is hydrogen, fluoro, chloro. lower alkyl or fluoro substituted lower alkyl.
  • M 13 - is -(CR 19 R 20 ) t -NR 2 ⁇ ) -(CR' 9 R 20 ) i - or -(CR 1 V) 1 -NR 26 C(O)-(CR 19 R 20 ),-, preferably -NR 26 -(CR 19 R 20 ) 4 - or -NR 26 C(O)-(CR 19 R 20 ),-. more preferably -NR 39 CR 80 R 80 - or -NR 39 (CR 80 R 80 ) 2 -, and A 13 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • M 15 is -(CR 19 R 20 ) r NR 2o -(CR' 9 R 20 ) s - or -(CR 19 R 20 VNR 26 C(O)-(CR 19 R 20 X-, preferably -NR 26 -(CR 1 S R 2O ) S - or -NR 26 C(O)-(CR 19 R 2 V, more preferably -NR 39 CR 80 R 80 - or -NR 39 (CR 80 R 80 ),-;
  • a 1 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 11 1 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -
  • M 15 is -(CR 19 R 20 ) r NR 26 -(CR 1 ⁇ ) R 20 ) s - or -(CR 19 R 20 ) t -NR 26 C(O)-(CR 19 R 20 ) r , preferably -NR 76 -(CR'VV or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CR 80 R 80 - or -NR 39 (CR 80 R 80 ) 2 -,
  • a n is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 1 " is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -
  • Mn is -NR 39 CH 2 - or -NR 19 -(CH 2 ) 2 -;
  • An is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 1 " is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 .
  • Q 115 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 42 , -NR 42 R 42 , -OR 42 and -S(O) 2 R 42 ; and Q 124 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R 41 is as defined for Formula Ig,
  • a 13 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 1 " is aryl or heteroaryl, wherein aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 39 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamin
  • M 15 is a bond, -NR 39 -, -S-, -0-, -NR 39 CII 2 -, -NR 39 CII 2 CII 2 -, -NR 39 CH(R 40 )-, -SCH 2 -, -OCH 2 -, -C(O)NR 39 -, -S(O) 2 NR 19 -.
  • Q 124 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR 44 R 44 , -OR 44 , or -SR 44 , wherein R 39 , R 40 , R 41 , R 42 and R 44 are as defined for Formula II.
  • a n is -CH 2 -;
  • Q " is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl. lower alkoxy, and fluoro substituted lower alkoxy;
  • Q 115 is hydrogen, -CN. fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy.
  • Mn is -NR 39 CH 2 -, -NR 39 CHpCH 2 -, or -NR 39 CH(R 40 )-; and Q 124 is hydrogen, fluoro. chloro. lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
  • each occurrence of R 41 is R 42 as defined for Formula Ig.
  • a compound of Formula Il has a structure according to the following sub-generic structure, Formula Hn,
  • a 14 is selected from the group consisting Of -CR 19 R 20 -, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O) 2 -, -NR 21 -, and -0-;
  • Q 125 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alky], optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -NO 2 , -CN, -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NR 24 R 25 .
  • R 19 , R 2 ", R 21 , R 23 , R 24 , and R 25 are as defined for Formula Ib.
  • M 16 is -(CR 19 R 20 ) r NR :6 -(CR 19 R 2u ) s - or -(CR 19 R 21 YNR 26 C(O)-(CR 19 R 20 V, preferably -NR 26 -(CR I9 R 2 °V or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CR 8 V 0 - or -NR 39 (CR 80 R 80 ) 2 -, wherein R 39 is hydrogen or lower alkyl and R 80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen.
  • Ai 4 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Q 121 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 and Q 125 is hydrogen, -OR 23 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl,
  • M 16 is -(CR 19 R 20 ) r NR 26 -(CR 19 R 20 ) b - or -(CR 19 R 20 JrNR 26 C(O)-(CR 19 R 20 X-, preferably -NR ⁇ -(CR 19 R 2 "),- or -NR 25 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CR 80 R 80 - or -NR 39 (CR S0 R so ) 2 -. and A 14 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • M 16 is -(CR 1 V°),-NR 26 -(CR 19 R 2O ) S - or
  • a 14 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 1 ' is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 2 ⁇ -NR 21 R 23 , -OR 23 and -S(O) 7 R 23 ; and
  • Q 125 is hydrogen, -OR 23 , -CN, fluoro, chloro, lower alkyl,
  • M 15 is -(CR 19 R 20 ),-NR 26 -(CR 19 R 20 ) s - or -(CR l9 R 20 ) r NR M C(O)-(CR ig R ; V, preferably -NR 26 -(CR I9 R I0 ) s - or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CR 30 R 80 - or -NR 19 (CR 80 R 8l %-;
  • a 14 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 121 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 21 ,
  • -CN fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 21 and -S(O) 2 R 23 ; and Q 132 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
  • Mi 6 is -NR 19 CH 2 - or -NR 19 -(CH 2 ) 2 -;
  • A] 4 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 121 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 42 , -NR 42 R 42 , -OR 42 and -S(O) 2 R 42 ;
  • Q 125 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, ary
  • a 14 is -CII 2 - or -C(O)-, preferably -CH 2 -;
  • Q 13 ' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 4 '.
  • Q 125 is hydrogen, -CN 1 -OR 41 .
  • M 16 is a bond, -NR 19 -, -S-, -0-, -NR 39 CH 2 -, -NR 39 CH 2 CH 2 -, -NR 35 CH(R 40 )-, -SCH 2 -, -OCH 2 -.
  • a 14 is -CH 2 -;
  • Q 121 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • Q 125 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy;
  • Mi 6 is -NR 39 CH 2 -, -NR 39 CH 2 CH 2 -, or -NR 39 CH(R 40 )-; and
  • Q 132 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
  • each occurrence of R 41 is R 4 ' as defined for Formula Ig.
  • a compound of Formula II has a structure according to the following sub-generic structure, Formula Ho,
  • a 15 is selected from the group consisting Of -CR 19 R 20 -. -C(O)-, -C(S)-, -S-, -S(O)-, -S(O) 2 -,
  • Q 115 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -NO 2 , -CN, -NHC(O)NH 2 , -NHC(S)NH 2 , -NHS(O) 2 NH 2 , -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NR 24 R 25 , -OR 23 , -SR 23 , -C(O)R 21 , -C(S)R 21 , -S(O)R 23 , -S(O) 2 R 23 , -C(O)NHR 23 , -C(O)NR 23 R 21 , -C(S)NIIR 23 , -C(S)NR 23
  • M n , Q 111 , and Q 144 are as defined for Fo ⁇ nula II;
  • R 19 , R 20 , R 21 , R 23 , R 24 , and R 25 are as defined for Formula Ib.
  • M 17 is -(CR 19 R 20 ) r NR 26 -(CR l9 R 2 V or -(CR 1 V) 1 -NR 26 C(OXCR 19 R 20 ),-, preferably -NR 26 -(CR 19 R 20 ) s - or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 19 CR 80 R 80 - or -NR 39 (CR 80 R 80 ) 2 -, wherein R 39 is hydrogen or lower alkyl and R 80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment.
  • a 15 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Q 131 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 and Q 115 is hydrogen, -OR 21 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted
  • M 7 is -(CR 19 R M ) r NR 26 -(CR l 9 R : V or -(CR 1 V 0 X-NR 26 C(O)-(CR 11 V 0 X-, preferably -NR 26 -(CR' V°) S - or -NR 26 C(O)-(CR 19 R 20 ),-, more preferably -NR 39 CR 8 V 1 -, -NR 39 (CR 8 V°) 2 ⁇ .
  • a 15 is -CR 1 V 0 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • M n is -(CR 1 V ⁇ ) r NR 26 -(CR' V 0 ),- or
  • a 15 is -CR 1 V 0 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • QTM is optionally substituted lower alkyl, aryl or heteroaryl, w herein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 21 , -NR 2 V.
  • Q n ⁇ is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 2 V ⁇ -OR 11 and -S(O) 2 R 23 .
  • M 17 is -(CR'VVNVHCR'VX- or -(CR 1 V 0 X-NR 26 C(O)-(CR 1 V 0 ),-, preferably -NR 26 -(CR' V 0 X- or -NR 26 C(O)-(CR 1 V 0 X-, more preferably -NR 39 CR 80 R 80 -, -NR' 9 (CR 8 V ⁇ ) 2 -; Ai 5 is -CR 1 V 0 - or -C(O)-, preferably -CH 2 - ur -C(O)-; Q 111 is optionally substituted lower alkyl.
  • aryl or heteroaryl wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 2 V 3 , -OR 23 and -S(O) 2 R 21 ,
  • Q 135 is hydrogen, -OR 23 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl.
  • fluoro substituted lower alkyl -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 ; and Q 144 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl.
  • Mi 7 is -NR 19 CH 2 - or -NR 39 -(CH 2 ) 2 -;
  • Ai 5 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q' 3 ' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 42 , -NR 42 R 42 , -OR 42 and -S(O) 2 R 12 ;
  • Q 115 is hydrogen.
  • -CN fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl.
  • fluoro substituted lower alkyl -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 ; and Q !44 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, wherein R 41 is as defined for Formula Ig.
  • a i5 is -CH 3 - or -C(O)-, preferably -CH 2 -;
  • Q H1 is aryl or heteroaryl, wherein aryl or hcteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 19 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio
  • heterocycloalkyl aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q 131 , or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 , -S(O) 2 NH;., -C(O)NH 2 .
  • Q 135 is hydrogen, -CN, -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 19 S(O) 2 R 4 ', fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -
  • R 144 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR 44 R 44 , -OR 44 , or -SR 44 , wherein R 39 , R 40 , R 41 , R 4: and R 44 are as defined for Formula II.
  • Ais is -CH 2 -;
  • Q n i is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
  • Q 135 is hydrogen, -CN, fluoro.
  • M 15 is -NR 19 CH 2 -, -NR 39 CH 2 CII 2 -, or -NR 39 CH(R 40 )-; and Q 144 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
  • each occurrence of R 41 is R 42 as defined for Formula Ig.
  • a compound of Formula II has a structure according to the following sub-generic structure, Formula lip,
  • a 16 is selected from the group consisling Of -CR 19 R 20 -, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O) 2 -,
  • Q 145 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH 2 , -NO 2 , -CN, -NHC(O)NH 2 , - NHC(S)NH 2 , -NHS(O) 2 NH,, -C(O)NH 2 , -C(S)NH 2 , -S(O) 2 NH 2 , -NR 24 R 25 , -NHR 23 , -OR 21 , -SR 23 , -C(O)R 23 , -C(S)R 23 , -S(O)R 23 , -S(O) 2 R 23 , -C(O)NHR 23 , -C(O)NR 21 R 21 , -C(S)NHR 23 , -
  • M 13 , Q H1 , and Q 1 " are as defined for Formula II; and R 19 , R 20 , R 21 , R 21 , R 24 , and R 25 are as defined for Formula Ib;
  • s is -(CR 19 R 20 ) r NR 2t) -(CR 19 R 20 ) s - or -(CR 19 R 2 VNR 26 C(O)-(CR 19 R 20 V, preferably -NR 26 -(CR
  • a 1 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Q 141 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 13 R 23 , -OR 23 and -S(O) 2 R 21 and Q 143 is hydrogen, -0R : ⁇ -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R 23
  • M 18 is -(CR 1 V 0 ) r NR 26 ⁇ (CR 19 R 20 ) s - or -(CR 19 R 2 VNR 26 C(O)-(CR 19 R 2 V, preferably -NR 26 -(CR 19 R 2O ) S - or -NR 26 C(O)-(CR 19 R 2 V, more preferably -NR 39 CR 80 R 80 - or -NR 39 (CR 80 R 8 ⁇ ) 2 -, and A, 6 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-.
  • Mj 8 is -(CR I9 R 20 ) r NR 26 -(CR llJ R 20 ) i - or
  • a 16 is -CR 19 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 141 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 21 and -S(O) 2 R 2 '; and
  • Q 145 is hydrogen, -0R /3 , -CN, fluoro, chlor
  • aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 . -NR 23 R 23 , -OR 23 and -S(O) 2 R 23 .
  • M 18 is -(CR !
  • a 16 is -CR 10 R 20 - or -C(O)-, preferably -CH 2 - or -C(O)-;
  • Q 141 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 23 , -NR 23 R 23 , -OR 23 and -S(O) 2 R
  • M 18 is -NR 39 CH 2 - or -NR 39 -(CH 2 ) 2 -;
  • a 16 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 141 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 ;
  • Q H5 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy.
  • A] 6 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q 141 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 2 R 41 , -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 39 S(O) 2 R 41 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino
  • cycloalkyl, heterocycloalkyl, aryl, and heteroaryl wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q 4 , or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH 2 , -CN, -NO 2 .
  • Q 145 is hydrogen, -CN, -OR 41 , -SR 41 , -S(O)R 41 , -S(O) 1 R 41 , -NHR 41 , -NR 41 R 41 , -NR 39 C(O)R 41 , -NR 39 S(O) 2 R 41 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of
  • Q 152 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR 44 R 44 , -OR 44 , or -SR 44 , wherein R 19 , R 40 , R 41 , R 4: and R 44 are as defined for Formula TT.
  • Ais is -CH 2 -;
  • Q 141 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro.
  • each occurrence of R 41 is R 42 as defined for Formula Ig.
  • M 18 is -NH-CH 2 - or -NH-(CH ⁇ ) 2 -, preferably -NH-CH 2 -;
  • A] 6 is -CH 2 - or -C(O)-, preferably -CH 2 -;
  • Q' 41 is aiyl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, and heterocyc Io alkyl;
  • Q 145 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably hydrogen, -CN, or chloro;
  • Q 152 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl
  • the compound of Formula 111 is selected from the group consisting of
  • a compound of Formula I has a structure according to the following sub-generic structure, Formula III,
  • L 4 is -CH 2 -, -CH 2 CH 2 -, -CH(R 40 )-, -C(O)-, or -C(O)NH-;
  • R 81 is selected from the group consisting of hydrogen, -OR 41 , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 ;
  • R H1 is selected from the group consisting of hydrogen, CV 3 alkyl, fluoro substituted C 2 . ? alkyl, OH, C 1 . 3 alkoxy, and fluoro substituted Cu alkoxy;
  • R 83 is heterocycloalkyl, heteroaryl, or ⁇ _ j n w hich ? indicates the attachment point of R ⁇ to L 4 of Formula III, wherein heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NIIR 41 , -NR 41 R 41 . -OR 41 and -S(O) 2 R 41 ;
  • R QZ , R 1 ", R t)4 , R 95 , and R 96 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NHS(O) 2 R 41 , -NHC(O)R 41 , -NIIR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 ; and
  • R 4 ⁇ and R 41 are as defined for Formula Ig;
  • L 4 is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or -C(O)-
  • R 81 is hydrogen, fiuoro, chloro, -CN, lower alkyl, fluoro substituted lower alkyl, lower
  • R 82 is hydrogen
  • R 83 is f wherein R 9* ,
  • R 91 , R 94 , R 93 . and R 96 are independently hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that when R M is fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, at least one of R 92 , R 93 , R 9> , and R 96 is fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
  • L 4 is -CH 2 -, -CH 2 CH 2 -, -CH(CH 3 )- or -C(O)-, R 81 is hydrogen, fluoro, chloro, -CN, methyl, or methoxy, preferably hydrogen, chloro,
  • R 8 ' is hydrogen
  • R" is , wherein R 92 , R 9 ⁇ R 94 , R 9 ⁇ and R 96 are independently hydrogen, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy, preferably hydrogen, chloro, methyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy, provided, however, that when R 94 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy, at least one of R 9: .
  • R* 3 , R 93 , and R 96 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
  • L 4 is -CIL-
  • R 81 is fluoro, chloro, -CN.
  • R 82 is hydrogen
  • R 83 is wherein R 94 is hydrogen and R 92 , R 93 , R 95 , and R 96 are independently hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
  • L 4 is -CH 2 -, -CH 2 CH 2 -, -C(O)-, or -CII(CII 3 )-, preferably -CII 2 - or -C(O)-, R 8 ' is hydrogen, flouro, R 82 is hydrogen, R 83 is
  • R 92 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, methyl, or trifluoromethyl
  • R 93 , R 91 , R 95 . and R 96 are independently hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, preferably hydrogen or fluoro.
  • L 4 is -CH 2 -, -C(O)-, or -CH(CH 3 )-
  • R 8 ' is hydrogen
  • R 82 is hydrogen
  • R 92 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, methyl, or trifluoromethyl
  • R 93 , R 94 , R 95 , and R 96 are hydrogen.
  • L 4 is -CH 2 -, -C(O)-, or -CH(CH 3 )-
  • R S1 is hydrogen
  • R 82 is hydrogen
  • R 92 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, methyl, or trifluoromethyl
  • R 4 , R ⁇ and R are hydrogen
  • R 93 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, trifluoromethyl or methoxy, more preferably fluoro.
  • L 4 is -CH 2 -, -C(O)-, or -CH(CH 3 )-
  • R 81 is hydrogen
  • R 82 is hydrogen
  • R 92 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, methyl, or trifluoromethyl
  • R 93 , R 95 , and R 96 are hydrogen
  • R 94 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, methyl or trifluoromethyl, more preferably fluoro.
  • L 4 is -ClLCIL- or -C(O)-
  • R 81 is hydrogen
  • R 82 is hydrogen
  • R 92 , R 95 , and R 96 are hydrogen
  • R 93 is hydrogen, fluoro. chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, or trifluoromethoxy, more preferably fluoro, chloro, trifluoromethyl or methoxy
  • R 94 is hydrogen, fluoro.
  • L 4 is -CH 2 CH 2 -
  • R 81 is hydrogen
  • R 82 is hydrogen
  • R 92 , R" 4 , R* ⁇ and R"" are hydrogen
  • R 9 * is hydrogen, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably hydrogen or fluoro.
  • L 4 is -C(O)-
  • R ni is hydrogen
  • R 82 is hydrogen
  • R 92 , R 95 , and R 96 are hydrogen
  • R 93 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, trifluoromethyl or methoxy
  • R 94 is hydrogen, fluoro, or chloro.
  • R 83 is pyrrolidine, morpholine. pyridine, pyrimidine, pyrazine, pyrazole, isoxazole, imidazol, or benzimidazole, wherein R 8 ' is optionally substituted with one or more substituents independently selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NHR 41 , -NR 41 R 41 , -OR 41 and -S(O) 2 R 41 , preferably wherein R 83 is optionally substituted with 1 or 2 substituents independently selected from fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, or cycloalkylamino, more preferably ⁇ uoro, chloro, methyl, trifluoromethyl, methoxy or morpholine.
  • L 4 is -CH 2 -, -CH 2 CH 2 -, -CH(CH 1 )- or -C(O)-, preferably -CH 2 -, -CH 2 CH 2 -, or -C(O)-,
  • R 81 is hydrogen, fluoro, chloro, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably hydrogen, chloro, methyl or -CN
  • R 82 is hydrogen
  • R 83 is pyrrolidine, morpholine, pyridine, pyrimidine, pyrazine, pyrazole, isoxazole, imidazole, or benzimidazole, wherein R 83 is optionally substituted with 1 or 2 substituents independently selected from fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy
  • the compound is selected from the group consisting of:
  • a compound of the invention is:
  • compounds are excluded where N (except where N is a heteroaryl ring atom), O, or S is bound to a carbon that is also bound to N (except where N is a heteroaryl ring atom), O, or S, except where the carbon forms a double bond with one of the heteroatoms. such as in an amide, carboxylic acid, and the like; or where N (except where N is a heteroaryl ring atom), O, C(S). C(O).
  • n is 0-2
  • compounds which include linkages such as the following are excluded from the present invention: -NR-CH 2 -NR-, -0-CH 2 -NR-.
  • the invention provides methods for treating a c-kit-mediated disease or condition in an animal subject (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e g., a disease or condition characterized by abnormal c-kit activity (e.g. kinase activity).
  • Invention methods involve administering to the subject suffering from or at risk of a c-kit- mediated disease or condition an effective amount of a compound of Formula II or Formula III, and all sub-embodiments thereof.
  • the c-kit mediated disease is selected from the group consisting of malignancies, including, but not limited to.
  • mast cell tumors small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canine mast cell tumors, and inflammatory diseases, including, but not limited to, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and hypereosinophilia.
  • GISTs gastrointestinal stromal tumors
  • glioblastoma astrocytoma
  • neuroblastoma carcinomas of the female genital tract
  • compounds of Formula II or Formula III. and all sub-embodiments thereof can be used in the preparation of a medicament for the treatment of a c-kit-mediated disease or condition selected from the group consisting of malignancies, including, but not limited to, mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic leukemia chronic myelogenous leukemia, mastocytosis, melanoma, and canme mast cell tumors and inflammatory diseases, including, but not limited to, asthma, rheumatoid arthritis, allergic rhinitis, multiple
  • the invention provides methods for treating a c-fms-mediated disease or condition in an animal subject (e g a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e g , a disease or condition characterized by abnormal c-fms activity (e g kinase activity)
  • Invention methods mvolve administering to the subject suffering from or at risk of a c- fms-mcdiated disease or condition an effective amount of compound of Formula II or Formula III, and all sub-embodiments thereof
  • the c-fhib mediated disease is selected from the group consisting of immune disorders, including, but not limited to, rheumatoid arthritis, systemic lupus erythematosa (SLE), and transplant rejection, inflammatory diseases including, but not limited to, osteoarthritis, inflammatory bowel syndrome, ulcerative
  • compounds of Formula II or Formula III. and all sub-embodiments thereof can be used m the preparation of a medicament for the treatment of a c-fms-mediated disease or condition selected from the group consisting of immune disorders, including, but not limited to rheumatoid arthritis, systemic lupus erythematosa (SLE), and transplant rejection inflammatory' diseases including, but not limited to, osteoarthritis, inflammatory bow el syndrome, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD) emphv sema, Kawasaki's Disease, hemophag ⁇ cvtic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis, metabolic disorders, including, but not limited to, I ype I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesitv, and hpolysis, disorders of bone structure, mineralization and
  • the invention provides methods for treating a c-fms-mediated disease or condition in an animal subject (e g a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e g , a disease or condition characterized by abnormal c-fms activity (e g kinase activity)
  • Invention methods involve administering to the subject suffering from or at risk of a c- fms-mediated disease or condition an effective amount of compound of formula 1, Formula Ia, Formula Ib, or Formula Ig, and all sub -embodiments thereof
  • the c-fms mediated disease is selected from the group consisting of osteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, l
  • compounds of Formula I, Formula Ia, Formula Ib, or Formula Ig, and all sub-embodiments thereof can be used in the preparation of a medicament for the treatment of a c-fms-mediated disease or condition selected from the group consisting of osteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, Type I diabetes, I ype II diabetes, obesity, Paget's disease, infection-mediated osteolysis (e g osteomyelitis), pen-prosthetic or wear-deb ⁇ s-mediated osteolysis, endometriosis, diabetic nephropathy, multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease, inflammatory pain chronic pain, bone pain, prostate cancer, melanoma, glioblastoma multiforme, and metastasis of tumors to tissues other than
  • the invention provides methods for treating, in an animal subject (e g a mammal such as a human, other p ⁇ mates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), a disease or condition mediated by c-fms and c-kit, e g , a disease or condition characterized by abnormal c-fms activity and/or c- kit activity (e g kinase activity)
  • Invention methods involve administering to the subject suffering from or at risk of a disease or condition mediated by c-fms and c-kit an effective amount of compound of Formula II or Formula III, and all sub-embodiments thereof
  • the condition mediated by c-fms and c-kit is selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors, glioblastoma, astrocytoma, neuroblastoma
  • osteoporosis increased risk of fracture, Paget's disease, hypercalcemia, mtcction-mediated osteolysis (e g osteomyelitis), pe ⁇ -prosthctic or wear-deb ⁇ s-mediated osteolysis, endometriosis, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, stroke, Alzheimer's disease, Parkinson's disease, inflammatory pain, chrome pam, and bone pain
  • compounds of Formula II or Formula III can be used m the preparation of a medicament tor the treatment of a c-fms-mediated and/or c-kit mediated disease or condition selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer gastrointestinal stromal tumors, glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasm associated with neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma, breast cancer, ovarian cancer, prostate cancer, canme mast cell tumors, metastasis of cancer to bone or other tissues, chronic myelopioh
  • the compound has an ICso of less than 100 nM, less than 50 tiM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay
  • the selectivity of the compound is such that the compound is at least 2-fold, 5-fold, 10-fold, or 100-fold more active on c-kit than on Ret, PDGF, or both Ret and PDGF
  • the selectivity of the compound is such that the compound is at least 2-fold, 5-fold, 10-fold, or 100-fold more active on c-kit than on c-ftns
  • the selectivity of the compound is such that the compound is at least 2-fold, 5-fold, 10-fold, or 100-fold moie active on c-fms than on c-kit
  • the compound has in combination each pairing of activity (e g IC ⁇ 0 ) and/or selectivity as specified in this
  • the compound has an IC 50 of less than 100 nM, lesb than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay for c-kit, c-fms, or both c-kit and c-fms kinase activity
  • the selectivity of the compound is such that the compound is at least 2-fold, 5-fold, 10- fold, or 100-fold more active on c-kit, c-fms, or both c-kit and c-fms than on Ret, PDGF, or both Ret and PDGf
  • the compound has an IC 50 of less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay for c-kit, c-fms, or both c-kit and c-fms kinase activity, and further has an IC 50 of less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay for at least one of HGK, TrkA, or l rkB kinase activity
  • compositions that include a therapeutically effective amount of a compound of Formula II or Formula IIIand all sub- embodiments thereof and at least one pharmaceutically acceptable car ⁇ ei, excipient, and or diluent, including combinations of any two or more compounds of Formula II or Formula III
  • the composition can further include one or more different pharmacologically active compounds, which can include one or more compounds of Formula I (including Formula Ia, Ib, and Ig, and all sub- embodiments thereof), Formula II or Formula III
  • the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including a compound of Formula II or Formula 111, in combination with one or more other therapies or medical procedures effective in treating the cancer
  • Other therapies or medical procedures include suitable anticancer therapy (e g drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedure (e g surgery, radiation treatment, hyperthermia heating, bone marrow or stem cell transplant)
  • the one or more suitable anticancer therapies or medical procedures is selected from treatment with a chemotherapeutic agent (e g chemolherapeutic drug), radiation treatment (c g x-ray, 7-ray, or electron, proton, neutron, or a particle beam), hyperthermia heating (e g microwav e, ultrasound, radiofrequcncy ablation), Vaccine therapy (e g AFP gene hepatocellulai carcinoma vaccine, AFP adenoviral vector vaccine, AG-858.
  • a chemotherapeutic agent e
  • GM-CSF-secretion breast cancer vaccine dendritic cell peptide vaccines
  • gene therapy e g Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha
  • photodynamic therapy c g aminolevulinic acid motexafm lutetium
  • the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including a compound of Formula II or Formula III, in combination with one or more suitable chemothcrapcutic agents
  • the one or more suitable chemotherapeutic agents is selected from an alkylating agent, including, but not limited to, adozelesm, altretamme, bizelesm, busulfan, carboplatm, carboquone, carmushne, chlorambucil, cisplatm cyclophosphamide dacarbazme, estramustme fotemustme, hepsulfam, lfosfamide, improsulfan, irofulven, lomustinc, mechlorethamme, melphalan, oxaliplatm, piposulfan, semustme, streptozocm, temozolomide, thiotepa, and

Abstract

Compounds active on the receptor protein tyrosine kinases c-kit and/or c-fms are provided herewith. Also provided herewith are compositions useful for treatment of c-kit mediated diseases or conditions and/or c-fms-mediated diseases or conditions, and methods for the use thereof.

Description

COMPOUNDS MODULATING C-FMS AND/OR C-KIT ACTIVITY
AND USES THEREFOR
RELATED PATENT APPLICATIONS
[0001] This application claims priority to U.S. Provisional App. No. 60/860,749, entitled "Compounds Modulating c-Fms and c-Kit Activity and Uses Therefor", filed November 22, 2006. and is related to U.S. Patent Λpp. No. 11/435,381, entitled "Compounds Modulating c-Kit and c- Fms Activity and Uses Therefor", filed May 16. 2006, which claims the benefit of U.S. Provisional App. No. 60/682,063, entitled "Compounds Modulating c-Kit Activity and Uses Therefor", filed May 17, 2005, U.S. Provisional App. No. 60/682,051 , entitled "Compounds Modulating c-Fms Activity and Uses Therefor", filed May 17, 2005, U.S. Provisional App. No. 60/682,042, entitled "Compounds Modulating c-Kit and c-Fms Activity and Uses Therefor", filed May 17, 2005, U.S. Provisional App. No. 60/692,750, entitled "Compounds Modulating c-Kit and c-Fms Activity and Uses Therefor", filed June 22, 2005, and U.S. Provisional App. No. 60/692,960, entitled "Compounds and Methods for Kinase Modulation, and Indications Therefor", filed June 22, 2005, all of which are incorporated herein by reference in their entireties and for all purposes.
FIELD OF THE INVENTION
|0002] This invention relates to ligands for c-fms and c-kit, and to methods for use thereof. The information provided is intended solely to assist the understanding of the reader. None of the information provided nor references cited is admitted to be prior art to the present invention. Each of the references cited is incorporated herein in its entirety and for any purpose.
BACKGROUND OF THE INVENTION
[0003] C-fms and c-kit are both type III transmembrane receptor protein tyrosine kinases (RPTKs) that regulate key signal transduction cascades that control cellular growth and proliferation. Both receptors have similar structural features comprising five extracellular immunoglobulin (IG) domains, a single transmembrane domain, and a split cytoplasmic kinase domain separated by a kinase insert segment. c-Fms
[0004] C-fms is a member of the family of genes originally isolated from the Susan McDonough strain of feline sarcoma viruses. The cellular proto-oncogene FMS (c-fms, cellular feline McDonough sarcoma) codes for the receptor for the macrophage colony-stimulating factor (M- CSF). C-fms is crucial for the growth and differentiation of the monocyte-macrophage lineage, and upon binding of M-CSF to the extracellular domain of c-fins, the receptor dimerizes and trans- autophosphorylates cytoplasmic tyrosine residues.
[0005] M-CSF, first described by Robinson and co-workers (Blood. 1969, 33 :396-9), is a cytokine that controls the production, differentiation, and function of macrophages. M-CSF stimulates differentiation of progenitor cells to mature monocytes, and prolongs the survival of monocytes. Furthermore, M-CSF enhances cytotoxicity, superoxide production, phagocytosis, chemotaxis, and secondary cytokine production of additional factors in monocytes and macrophages. Examples of such additional factors include granulocyte colony stimulating factor (G-CSF), interleukin-6 (IL-6), and interleukin-8 (IL-8). M-CSF stimulates hcmatopoiesis, promotes differentiation and proliferation of osteoclast progenitor cells, and has profound effects on lipid metabolism. Furthermore, M-CSF is important in pregnancy. Physiologically, large amounts of M-CSF are produced in the placenta, and M-CSF is believed to play an essential role in trophoblast differentiation (Motoyoshi, Int J Hematol. 1998, 67: 109-22). The elevated serum levels of M-CSF in early pregnancy may participate in the immunologic mechanisms responsible for the maintenance of the pregnancy (Flanagan & Lader, Curr Opin Hematol. 1998, 5: 181-5).
[0006] Related to c-fms and c-kit are two glatelet-derived growth factor receptors, alpha (i.e., pdgfra) and beta (pdgfrb) (PDGF). The gene coding for pdgfra is located on chromosome 4ql 1- ql2 in the same region of chromosome 4 as the oncogene coding for c-kit. The genes coding for pdgfra and c-fms appear to have evolved from a common ancestral gene by gene duplication, inasmuch as these two genes are tandemly linked on chromosome 5. They are oriented head-to- tail with the 5-prime exon of the c-fms gene located only 500 bp from the last 3-prime exon of the gene coding for pdgfra. Most gastrointestinal stromal tumors (GIST) have activating mutations in c-kit, and most patients with GISTs respond well to Gleevec, which inhibits c-kit. Heinrich et al. (Science 2003, 299:708-10) have shown that approximately 35% of GISTs lacking c-kit mutations have intragenic activation mutations in the gene encoding pdgfra, and that tumors expressing c-kit or pdgfra arc indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Thus, c-kit and pdgfra mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs. [0007] Similarly, the observation that production of M-CSF, the major macrophage growth factor, is increased in tissues during inflammation points out a role for c-fms in diseases, such as for example inflammatory diseases. More particularly, because elevated levels of M-CSF are found in the disease state, modulation of the activity of c-fms can ameliorate disease associated with increased levels of M-CSF.
c-Kit
[0008J The Stem Cell Factor (SCF) receptor c-kit plays an important role in the development of melanocytes and mast, germ and hematopoietic cells. Stem Cell Factor (SCF) is a protein encoded by the Sl locus, and has also been called "kit ligand" (KL) and mast cell growth factor (MGF), based on the biological properties used to identify it (reviewed in Tsujimura, Pathol Int 1996, 46:933-938; Loveland, et al., J, Endocrinol 1997, 153:337-344; Vliagoftis, et al., Clin Immunol 1997, 100:435-440; Broudy, Blood 1997, 90:1345-1364; Pignon, Hermatol Cell Ther 1997, 39: 1 14-1 16; and Lyman, et al., Blood 1998, 91 : 1 101-1 134.). Herein the abbreviation SCF refers to the physiological ligand for c-kit.
[0009] SCF is synthesized as a transmembrane protein with a molecular weight of 220 or 248 Dalton, depending on alternative splicing of the mRNA to encode exon 6. The larger protein can be proteolytically cleaved to form a soluble, glycosylated protein which noncovalently dimerizcs. Both the soluble and membrane-bound forms of SCF can bind to and activate c-kit. For example, in the skin, SCF is predominantly expressed by fibroblasts, keratinocytes, and endothelial cells, which modulate the activity of melanocytes and mast cells expressing c-kit, In bone, marrow stromal cells express SCF and regulate hematopoiesis of c-kit expressing stem cells. In the gastrointestinal tract, intestinal epithelial cells express SCF and affect the interstitial cells of Cajal and intraepithelial lymphocytes. In the testis, Sertoli cells and granulosa cells express SCF which regulates spermatogenesis by interaction with c-kit on germ cells.
SUMMARY OF THE INVENTION
[0010] The present invention relates to compounds active on c-fms, c-kit, or both c-fms and c- kit. In accordance with one aspect of the present invention, it has been discovered that in the treatment of diseases amenable to treatment by an effective amount of a modulator of either c-fms alone or c-kit alone, the efficacy of treatment can be enhanced if said compounds are dual inhibitors of both c-fms and c-kit. In another aspect of the present invention, compounds active on c-fms, c-kit, or both c-fms and c-kit are also active on one or more of TrkA, TrkB and HGK. In particular, the invention provides compounds of Formula I, and all sub-generic formulae thereof, as well as methods of using such compounds as described below. Thus, the invention provides methods of using compounds that can be used therapeutically and/or prophylactically involving modulation of c-fms, c-kit, or both c-fms and c-kit, or involving one or more of TrkA, TrkB and HGK in addition to c-fms, c-kit, or both c-fms and c-kit,
[UUI l] The compounds of Formula 1 have the following structure:
Figure imgf000005_0001
Formula I, all salts, prodrugs, tautomers, and isomers thereof, wherein:
X, is N or CR2, X2 is N or CR6, Y1 is N or CR4, and Y2 is N or CR5, provided, however, that not more than one of X2, Yi and Y2 is N;
L1 is selected from the group consisting of optionally substituted lower alkylenc, -S-, -O-, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, and -Nil7-;
L2 is selected from the group consisting of a bond, optionally substituted lower alkylene, -(alk)a-S-(alk)b-, -(alk)a-O-(alk)b-, -(alk)a-OC(O)-(alk)b-, -(alk)a-C(O)O-(alk)b-, -(alk)»-OC(S)-(alk)b-, -(alk)a-C(S)O-(alk)b-, -(alk),-C(O)-(alk)b-, -(alk)a-C(S)-(alk)b-, -(alk)a-C(O)NR9-(alk)b-, -(alk)a-OC(O)NR'-(alk)b-, -(alk)a-OC(S)NR9-(alk)b-, -(alk)a-C(S)NR9-(alk)b-, -(alk)a-S(O)-(alk)b-, -(alk)a-S(O)2-(alk)b-, -(alk)a-S(O)2NR9-(alk)b- -(alk)I1-NR9-(alk)b-, -(alk)a-NR9C(O)-(alk)b-, -(alk)a-NR9C(S)-(alk)b-, -(alk)a-NR9C(O)NR9-(alk)b-, -(alk)a-NR9C(S)NR9-(alk)b-, -(alk)a-NR9C(O)O-(alk)h-, -(alk)a-NR9C(S)O-(alk)b-, -(alk)a~NR9S(O)2-(alk)b-. and -(alk)a-NR9S(O)2NR9-(alk)b-, wherein alk is optionally substituted C1^ alkylene and a and b are independently 0 or 1 ;
R1 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted hctcrocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R2, R4, R5 and R6 are independently selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl. optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2. -NO2, -CN, -C(O)OH5 -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2. -NHS(O)2NH2, -NR10R1 1, -NHR3, -OR3, -SR3, -C(O)R3, -C(S)R3, -S(O)R3, -S(O)2R3, -C(O)OR3, -C(S)OR3, -C(O)NHR3, -C(O)NR3R3, -C(S)NHR3, -C(S)NR1R1, -S(O)2NHR3, -S(O)2NR3R3, -NHC(O)R3, -NR3C(O)R3. -NHC(S)R3, -NR3C(S)R3, -NHS(O)2R1, -NR3S(O)2R3, -NHC(O)OR3, -NR3C(O)OH, -NR3C(O)OR3, -NHC(S)OR3, -NR3C(S)OH, -NR3C(S)OR3, -NHC(O)NHR3, -NHC(O)NR3R3, -NR3C(O)NH2, -NR3C(O)NHR3, -NR3C(O)NR3R3, -NHC(S)NHR3, -NHC(S)NR3R3, -NR3C(S)NH2, -NR3C(S)NHR3, -NR3C(S)NR3R3, -NHS(O)2NHR3, -NHS(O)2NR3R3, -NR3S(O)2NH,, -NR3S(O)2NHR3, and -NR3S(O)2NRV; Ar1 is a 5 or 6 membered optionally substituted heteroarylene having the structure
Figure imgf000006_0001
wherein > indicates the point of attachment of L and " indicates the point of attachment of L2, and wherein the indicated N is either =N- or N=; n is O or 1 ;
F and J are both C or one of F and J is C and the other of F and J is N; P and Q are independently selected from CR, N, NR, O or S; T is selected from CR or N; wherein when n is 1 , F and J are C, and P, T and Q are CR, or any one of P, T and Q is N and the other two of P, T and Q are CR, when n is O and F and J are both C, then one of P and Q are CR, N or NR and the other of P and Q is C, N, NR, O or S, provided both P and Q are not CR, when n is O, one of F and J is N and the other of F and J is C, then one of P and Q is N and the other of P and Q is CR or both P and Q are CR, and R is hydrogen or an optional substituent as defined herein for optionally substituted heteroarylene that provides a stable compound;
R- at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that no alkene carbon thereof is bound to any -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -0-, -S-, or -N- of any of -OR3, -SR3, -C(O)R3, -C(S)R3, -S(O)R1, -S(O)2R3, -C(O)OR3, -C(S)OR3, -C(O)NHR3, -C(O)NR3R3, -C(S)NIIR3, -C(S)NR3R3, -S(O)2NHR3, -S(O)2NR3R3, -NHR1. -NHC(O)R3, -NR3C(O)R3, -NHC(S)R3, -NR3C(S)R3, -NHS(O)2R3, -NR3S(O)2R3, -NHC(0)0R\ -NR3C(O)OH, -NR3C(O)OR3, -NHC(S)OR3, -NR3C(S)OH, -NR3C(S)OR1, -NHC(O)NHR3, -NHC(O)NR3R3, -NR3C(O)NH2, -NR1C(O)NHR', -NR1C(O)NRV, -NHC(S)NHR3, -NHC(S)NR3R3, -NR3C(S)NII2, -NR3C(S)NHR3, -NR3C(S)NR3R3, -NHS(O)2NHR3, -NHS(O) -NR3R3, -NR1S(O)2NH2, -NR3S(O)2NHR3, or -NR3S(O)2NR1R1. optionally substituted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to any -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -0-, -S-, or -N- of any of -OR4, -SR', -C(O)R3, -C(S)R3, -S(O)R3, -S(O)2R3, -C(O)OR1, -C(S)OR3, -C(O)NHR1. -C(O)NR1R1, -C(S)NHR3, -C(S)NR3R3, -S(O)2NHR3, -S(O)2NR3R1, -NHR3, -NHC(O)R3. -NR1C(O)R1. -NHC(S)R', -NR1C(S)R1, -NHS(O)2R3, -NR3S(O)2R1, -NHC(O)OR3, -NR1C(O)OH, -NR3C(O)OR3, -NHC(S)OR3, -NR3C(S)OH, -NR1C(S)OR3, -NHC(O)NHR5, -NHC(O)NR3R1, -NR1C(O)NH2, -NR3C(O)NIIR1, -NR3C(O)NR3R1, -NHC(S)NHR1, -NHC(S)NR3R3, -NR3C(S)NH2, -NR1C(S)NHR3, -NR3C(S)NR1R1, -NHS(O)2NHR1, -NHS(O)2NR3R3, -NR1S(O)2NH2, -NR1S(O)2NHR3, or -NR1S(O)2NR3R3, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R7 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(O)R8, and -S(O)2R8; R8 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl. optionally substituted aryl and optionally substituted heteroaryl;
R9 at each occurrence is independently selected from the group consisting of hydrogen, lower alkyl, and lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, moπo-alkylamino, fluoro substituted mono- alkylamino, di-alkylamino, fluoro substituted di-alkylamino, and -NR12R13, provided, however, that when R9 is substituted lower alkyl, any substitution on the alkyl carbon bound to the -N- of-NRy- is fluoro;
R10 and R1 1 at each occurrence are independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl. provided, however, that no alkene carbon thereof is bound to the nitrogen of NR10R1 1, optionally substituted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to the nitrogen Of-NR10R1', optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R10 and R1 ' together with the nitrogen to which they are attached form a monocyclic 5-7 membered optionally substituted heterocycloalkyl or a monocyclic 5 or 7 membered optionally substituted nitrogen containing heteroaryl; and
R1" and R13 combine with the nitrogen to which they arc attached to form a 5-7 membered heterocycloalkyl or 5-7 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, and fluoro substituted lower alkylthio; provided, however that when compounds have the structure
Figure imgf000008_0001
and Ll a is ^CH2-, -CH(OH)-, or -C(O)-, then Rla is not phenyl, 4-trifluoromethyl-phenyI, 4- methoxy-phcnyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4-methyl-phenyl, 3-fluoro-phenyl or thiophen-2-yl, and compounds do not have the structure
Figure imgf000008_0002
[0012] In reference to Formula I, the core structure shown above with X1, X2, Yj and Y2 as CH and with L'-Ar|-L2-R' replaced with II is referred to as the "azaindole core." For that azaindole core, reference to ring atoms or ring positions is as shown in the following structure:
Figure imgf000008_0003
10013] In one embodiment of compounds of Formula I, compounds have a structure selected from the following:
Figure imgf000009_0001
wherein V, Ar1, I/ 2, r R> l1, r R> 2 , r R> * , r R> 5 and R" are as defined for Formula J.
[0014] In one embodiment of compounds of Formula I, X) and Xi are N or CH. In another embodiment, Xj, X2 and Yi are N or CII, where in a further embodiment, Y2 is CR5 and R5 is other than hydrogen. In another embodiment, X|, XT and Y2 are N or CH, where in a further embodiment Yj is CR4 and R4 is other than hydrogen. In another embodiment, X] , X2 and Yj are CH, where in a further embodiment, Y2 is CR3 and R3 is other than hydrogen. In another embodiment, X), X2 and Y2 are CII, where in a further embodiment Yj is CR4 and R4 is other than hydrogen.
[0015] In one embodiment of compounds of Formula I, wherein X1, X2, Y1 and Y2 are independently CR2, CR6, CR4 and CR5 respectively, one of R4 or R5 is other than hydrogen, preferably where R2 and R6 arc hydrogen. In one embodiment, wherein X,, X2, Yi and Y2 arc independently CR2, CR6, CR4 and CR5 respectively, R2, R5 and R6 are hydrogen and R4 is other than hydrogen. In one embodiment, wherein X], X2, Y] and Y2 are independently CR2, CRft, CR4 and CR5 respectively, R2, R4 and R6 are hydrogen and R5 is other than hydrogen.
|0016] In one embodiment of compounds of Formula I, Xi and X2 arc N or CH, preferably wherein both X1 and X2 are CH.
[0017] In one embodiment of compounds of Formula I, L1 is selected from the group consisting of-S-, -O- lower alkylene, -C(O)-, -C(S)-, -S(O)-, -S(O)2-, and -NR7-, wherein lower alkylene is optionally substituted with fluoro, and wherein when L2 is optionally substituted lower alkylene or comprises optionally substituted C^3 alkylene, the alkylene is optionally substituted with fluoro or lower alky]. In one embodiment, L1 is selected from the group consisting of -S-, -O— , -CH2-, -CF2-, -C(O)-, -C(S)-, -S(O)-. -S(O)2-, and -NH-.
[0018] In one embodiment of compounds of Formula I, L is selected from the group consisting of a bond, optionally substituted lower alkylene, -O-(alk)b-, -OC(O)-(alk)b-» -C(O)O-(alk)b-, -OC(S)-(alk)b-, -C(S)O-(alk)b-, -C(O)-(alk)b-, -C(S)-(alk)b-, -C(O)NR9-(alk)b-, -OC(O)NR9-(alk)b-. -OC(S)NR9-(alk)b-, -C(S)NR9-(alk)b-, -S(O)-(alk)b-, -S(O)2-(alk)b-, S(O)3NR9-(alk)b-, -NR9-(aIk)b-, -NR9C(O)-(alk)b-, -NR9C(O)O-(alk)b-, -NR9C(S)-(alk)b-, -NR9C(S)O-(alk)b-, -NR'C(O)NR9-(alk)b-, -NR9C(S)NR9-(alk)b-, -NR9S(O)2-(alk)b-, and -NR9S(O)2NR"-(alk)b-.
[0019] Further to any of the above embodiments of Formula I, when L1 is substituted lower alkylene or when L" is substituted lower alkylene or comprises substituted Ci.3 alkylene, the alkylene is substituted with one or more, preferably 1 , 2, or 3 substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, lower alkylthio, mono-alkylamino, di-alkylamino, and -NR12R11, wherein the alkyl chain(s) of lower alkoxy, lower alkylthio, mono-alkylammo or di- alkylamino are optionally substituted with one or more, preferably 1 , 2, or 3 substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, or cycloalkylamino.
[0020] In one embodiment of the compounds of Formula I, the variables P, J, Q, T, F, and n are selected to provide structures of Aij selected from the group consisting of
Figure imgf000010_0001
Figure imgf000011_0001
, and , where each R is independently hydrogen or an optional substituent as defined herein for optionally substituted heteroaryl.
[0021] In one embodiment, a compound of Formula I has a structure according to the following sub-generic structure, Formula Ia,
Figure imgf000012_0001
Formula Ia all salts, prodrugs, tautomers, and isomers thereof, wherein L1, Ar1, R1, R2, R4, Rs and R6 are as defined for Formula 1;
L3 is selected from the group consisting of a bond, optionally substituted lower alkylene,-O-(alk)b-, -S-(alk)b-, -NRl4-(alk)b-, -C(O)-(alk)b-, -C(S)-(alk)b-. -S(O)-(alk)b-. -S(O)2-(alk)b-, -NR14C(O)-(alk)b-, -C(O)NR14-(alk)b-, -S(O):NR14-(alk)b-, -NR14S(O)2-(alk)b-, -NRl4C(O)NR14-(alk)b-, -NR!4C(S)NR14-(alk)b-, and -NR14S(O)2NR14-(alk)b-; alk is optionally substituted Cu alkylene; b is 0 or 1 ; and R14 is hydrogen or lower alkyl.
|0022] In another embodiment of compounds of Formula Ia, R2, R5 and R6 are hydrogen, further wherein R4 is other than hydrogen. In another embodiment, R2, R4 and R6 are hydrogen, further wherein R5 is other than hydrogen.
[0023] In particular embodiments the compound of Formula I has a structure according to the following sub-generic structure, Formula Ib,
Figure imgf000012_0002
Formula Ib all salts, prodrugs, tautomers, and isomers thereof, wherein:
V and W are independently selected from the group consisting of N and CH; U and Z are independently selected from the group consisting of N and CR18, provided, however, that not more than one of W, U and Z is N; A is selected from the group consisting of -CR19R20-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)2-,
-NR2'-, and -O-; n is O or 1;
F and J are both C or one of F and J is C and the other of F and J is N; E and K are selected from C, N, O or S: G is selected from C or N; wherein when n is 1 , F and J are C, and E, G and K are C, or any one of E, G and K is N and the other two of E, G and K are C, provided that when E, G or K is N, R15, R17 and R16, respectively, are absent, when n is 0 and F and J are both C, then one of E and K is C or N and the other of E and K is C, N, O or S, provided both E and K are not C, and provided that when both E and K are N. one of R15 and R16 is absent, and provided that when one of E and K are N and the other is O or S, R13 and R16 are absent. when n is 0, one of F and J is N and the other of F and J is C, then one of E and K is N and the other of E and K is C, or both E and K are C, provided that when E is N, R15 is absent and when K is N, R1" is absent;
R1 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; R!<" is selected from the group consisting of hydrogen, optionally substituted lower alkyl,
-OR22, -SR72 and halogen when E is C, is absent when E is O or S or when n=l and E is N, and is absent or selected from the group consisting of hydrogen and optionally substituted lower alkyl when n=0 and E is N;
R16 is selected from the group consisting of hydrogen, optionally substituted lower alkyl, -OR22, -SR22 and halogen when K is C, is absent when K is O or S or when n=l and K is N, and is absent or selected from the group consisting of hydrogen and optionally substituted lower alkyl when n=0 and K is N; R17 is selected from the group consisting of hydrogen, optionally substituted lower alkyl,
-OR22, -SR23 and halogen when G is C, or is absent when G is N;
R18 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2. -NHC(S)NH2, -NHS(O)2NH2, -NR24R25. -NHR23, -OR23, -SR21, -NHC(0)R2\ -NR23C(O)R23, -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R2', -NR21S(O)2R2', -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR21, -NR23C(S)NH,, -NR21C(S)NHR23, -NHC(S)NR23R2', -NR23C(S)NR21R23, -NHS(O)2NHR2', -NR23S(O)2NH2, -NR23S(O)2NHR2', -NHS(O)2NR23R23, and -NR23S(O)2NR23R23;
M is selected from the group consisting of a bond, -(CR19R2V, -(CR19R20)rC(O)-(CRl 9R2V -(CR19R2VC(S)-(CR19R20X-, -(CR19R20X-C(O)O-(CR19R20X-,
-(CR19R2VC(S)O-(CR19R2V -(CRl9R2VC(O)NR2t>-(CR19R2V, -(CR")R20)rC(S)NR26-(CR19R20)s-, -(CR19R1VS(O)-(CRμ>R20)b-(
-(CR19R2VS(OMCR19R2V -(CR19R2VS(O)2NR26-(CRI9R2V
-(CR19R20X-O-(CR19R2V -(CR19R2VOC(OHCR19R2V, -(CR19R2VOC(S)-(CR19R20),-, -(CR19R2VθC(O)NR26-(CR19R2V -(CRI 9R2VθC(S)NR26-(CR19R2lV -(CR19R-Vs-(CR19R20),-, -(CR19R2 VNR26-(CR' 9R2V -(CR19R20X-NR26C(O)-(CR19R20X-, -(CR19R20)rNR26C(SHCR ' 9R20X-, -(CR19R20J1-NR26C(O)O-(CR19R20),-, -(CR!9R20)rNR26C(S)O-(CR19R20)s-, -(CRiqR20)rNR26C(O)NR26-(CRl9Rz0)s-, -(CR19R20)t-NR26C(S)NR2f>-(CR19R20),-, -(CR19R20)rNR2f)S(O)2-(CR19R2V and -(CR19R20X-NR26S(O)2NR2fJ-(CRI9R20X-; wherein R19 and R20 at each occurrence are independently selected from the group consisting of hydrogen, fluoro, -OH, -NH2, lower alkyl, lower alkoxy, lower alklylthio, mono- alkylamino, di-alkylamino, and -NR27R2S, wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or any two of R19 and R20 on the same or different carbons combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl and any others of R19 and R20 are independently selected from the group consisting of hydrogen, fluoro, -OH, -NH2, lower alkyl, lower alkoxy, lower alklylthio, mono-alkylamino, di-alkylamino, and -NR27R28, wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, and cycloalkylamino, and wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; R"1 and R22 at each occurrence are independently hydrogen or optionally substituted lower alkyl; R"3 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided.
Figure imgf000015_0001
that no alkene carbon thereof is bound to any -C(O)-, -C(S)-, -S(O)2-. -O-. -S-, or -N- of any of -NHR3. -OR23, -SR23, -NHC(O)R23, -NR23C(O)R23, -NHC(S)R25, -NR11C(S)R23, -NHS(O)2R23, -NR23S(O)2R23. -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR21R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH;. -NR23C(S)NHR23, -NHC(S)NR23R23, -NR23C(S)NR23R23, -NHS(O)1NHR23, -NR23S(O)2NH2, -NR23S(O)2NlIR23, -NHS(O)2NR23R23, Or -NR23S(O)2NR21R2', optionally substituted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to any -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -0-, -S-, or -N- of any of -NHR23, -OR23, -SR23, -NIIC(O)R23, -NR23C(O)R23, -NHC(S)R21, -NR21C(S)R23, -NHS(O)2R23, -NR23S(O)2R2'. -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R2', -NR23C(S)NR23R23, -NHS(O)2NHR21, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R23, or -NR23S(O)2NR23R23, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
R24 and R25 at each occurrence are independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that no alkene carbon thereof is bound to the nitrogen of -NR24R"5, optionally substituted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to the nitrogen of -NR24R25, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R24 and R25 together with the nitrogen to which they are attached form a monocyclic 5-7 membered optionally substituted heterocycloalkyl or a monocyclic 5 or 7 membered optionally substituted nitrogen containing heteroaryl;
R26 at each occurrence is independently selected from the group consisting of hydrogen, lower alkyl, and lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, fluoro substituted mono- alkylamino, di-alkylamino, Iluoro substituted di-alkylamino, and -NR~7R~S, provided, however, that when R26 is substituted lower alkyl, any substitution on the lower alkyl carbon bound to the -N- of-NR- is fluoro;
R27 and R2S combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or 5-7 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkyl, fluoro substituted lower alkyl. lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio. and fluoro substituted lower alkylthio; u is 1 -6; t is 0-3; and s is 0-3; piovided that when V, W, U and Z are CH, n=l, E, F, G, J, and K are C, R15, R16 and R17 are H. A is -CH2-, -CH(OH)-, or -C(O)-, and M is -NHCH2-, then R1 is not phenyl, 4- trifluoromethyl-phenyl, 4-methoxy-phenyl, 4-chloro-phenyl, 4-fluoro-phenyl, 4- methyl -phenyl, 3-fluoro-phenyl or thiophen-2-yl, when V, W, U and Z are CH, n=l , E, F, G, J, and K are C, R15, R16 and R17 are H. and
A is -CH2-, then M-R1 is not -NIICII2CH(CH3)2, when V, W, and U are CH, n=l , E, F, G, J, and K arc C, R15, R16 and R17 are H, A is
-CH2-, M-R! is -OCH3, and Z is CR18, then R18 is not thiophen-3-yl, and when V, W, and U are CH, n=0, F, J, and K are C, E is N, R15 is CH3, R16 is H, A is -C(O)-, M-R1 is -CH(CH3)3, and Z is CR18, then R1S is not 3-((E)-2-carboxy- vinyl)phenyl,
[0024] In one embodiment of the eompounds of Formula Ib, E, J, K, G, F, n, R15, R16 and R17 are selected to provide structures selected from the group consisting of
Figure imgf000016_0001
Figure imgf000017_0001
and , wherein R15, R16 and R1 ' are as defined for compounds
of Formula Ib and wherein
Figure imgf000017_0002
indicates the point of attachment of A and indicates the point of attachment of M.
[0025] In one embodiment of compounds of Formula Ib, M is selected from the group consisting of -O-(CRl9R20)s-, -S-(CR19R20X-, -OC(O)-(CR19R20X-, -OC(S)-(CR19R2V -OC(O)NR26-(CR19R20X-, -OC(S)NR26-(CR19R20)S-, -C(O)NR26-(CR19R:0X-, -C(S)NR26-(CR19R20X-, -S(O)2NR26-(CR19R20X-, -NR26-(CR19R20)s-, -NR20C(O)-(CR19R2V, -NR26C(S)-(CR19R2V, -NR26C(O)O-(CR19R20X-, -NR26C(S)O-(CR19R20X-, -NR26C(O)NR26-(CR 19R20X-, -NR26C(S)NR^-(CR19R20),-, -NR26S(O)2-(CR19R70X-, and -NR26S(O)2NR26-(CR19R20χ-.
[0026] In one embodiment of compounds of Formula Ib, R26 at each occurrence is independently selected from the group consisting of hydrogen, lower alkyl, and lower alkyl substituted with 1, 2, or 3 substituents selected from the group consisting of fluoro, -OH, -NH2, alkoxy, lower alkylthio. mono-alkylamino, di-alkylamino and cycloalkylamino. provided that any substitution on the carbon that is bound to the nitrogen of -NR26 is tluoro.
|0027] In one embodiment of compounds of Formula Ib, R1 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl. [0028] In one embodiment of the compounds of Formula Ib, Z is N or CII, n is 1 , E-R15 is N or CH, K-R16 is N or CH, and G-R17 is N or CH, provided no more than one of E-R15, K-R16 and G- Rπ is N. In one embodiment, Z is N or CH, n is 1 , and E-R15, K-R16 and G-R17 are CH,
[0029] In one embodiment of the compounds of Formula Ib, V, W and Z are CH, U is CRlH. n is 1 , E-R15 is N or CH, K-R16 is N or CH, and G-R17 is N or CH, provided no more than one of E- R15, K-R16 and G-R17 is N. In another embodiment, V, W and Z are CH, U is CR! 8, n is 1. and E-R15, K-R16 and G-R17 are CH.
[0030] In one embodiment of the compounds of Formula Ib, Z is N or CH, n is 1 , E-R15, K-R10 and G-R17 are CH, A is -CH2-, M is -NHCH2-, further wherein R1 is optionally substituted phenyl. In another embodiment, V, Z, U and W are CH, n is 1 , E-R15 is N or CH, K-R16 is N or CH, and G-R17 is N or CH, provided no more than one of E-R15, K-R16 and G-R17 is N.
[0031] In one embodiment of the compounds of Formula Ib, Z is N or CII, n is 1 , E-R15 is N or CH, K-R16 is N or CH, and G-Rπ is N or CH, provided no more than one of E-R15, K-R16 and G- R17 is N, and R1 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN. optionally substituted lower alkyl and -OR 9, where R29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.
[0032] In one embodiment of the compounds of Formula Ib, V, Z, U and W are CH, n is 1 , E-R15, K-R16 and G-R17 are CH, A is -CH2-, M is -NHCH2, and R1 is optionally substituted phenyl, further wherein R1 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, optionally substituted lower alkyl and -OR39, where R29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.
[0033] In one embodiment of the compounds of Formula Ib, V. W and Z are CH, U is CR18, n is 1 , E-R15, K-R16 and G-R17 are CH, A is -CH2-, M is -MICH2, and R1 is optionally substituted phenyl, further wherein R1 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, optionally substituted lower alkyl and -OR29, where R29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl. [0034] In one embodiment of the compounds of Formula Ib, when n is 1 , and E. K and G are C, at least one of Ru, R16 and R1 ' is other than hydrogen. In another embodiment, n is 1 , one of E. K, and ϋ arc N and the other two of E, K, and G are C and at least one of R15, R16 and R17 is other than hydrogen. In another embodiment, n is 1 , E, K and G are C, and at least one of R15, R16 and R1 is other than hydrogen,
[0035] In one embodiment of the compounds of Formula Ib, n is 1 , V and W aie CH, U and Z are independently CR18, one of E, K, and G arc N and the other two of E, K, and G are C and at least one of R15, R16 and R17 is other than hydrogen. In another embodiment, n is 1. V and W are CH, U and Z are independently CR1 S, E, K and G are C, and at least one of Ri 5, R16 and R17 is other than hydrogen.
[0036] In one embodiment of the compounds of Formula Ib, n is 1 , one of E, K, and G arc N and the other two of E, K, and G are C, at least one of R15, R16 and R17 is other than hydrogen, A is -CH2-, M is -NHCH2-, further wherein R1 is optionally substituted phenyl. In another embodiment, n is 1 , E, K, and G are C, at least one of R15, R16 and R1 ' is other than hydrogen, A is -CH2-, M is NHCH2-, further wherein R1 is optionally substituted phenyl.
[0037] In one embodiment of the compounds of Formula Ib, n is 1 , V, Z, U and W are CH, one of E, K, and G are N and the other two of E, K, and G are C and at least one of R15, R16 and R17 is other than hydrogen. In another embodiment, V, Z, U and W are CH, E, K and G are C, and at least one of R15, R16 and R17 is other than hydrogen.
[0038] In one embodiment of the compounds of Formula Ib, Z is CRI S, wherein R18 is other than hydrogen, n is 1 , E-R15 is N or CH, K-R16 is N or CH and G-R17 is N or CH. In another embodiment, Z is CR18, wherein R1 S is other than hydrogen, n is 1. and E-R15, K-R16 and G-R17 are CH. In another embodiment, Z is CR18, wherein Ri 8 is other than hydrogen, U is CR18, V and W are CH, n is 1, and E-R15, K-R1" and G-R17 are CH, further wherein U is CH.
[0039] In one embodiment of the compounds of Formula Ib, Z is CRI S, wherein R18 is other than hydrogen, n is 1 , E-R15, K-R16 and G-R17 arc CH, A is -CH2-, M is -NHCII2-, further wherein R1 is optionally substituted phenyl. In a further embodiment, Z is CR18, wherein R18 is other than hydrogen, U is CR1 R, V and W are CH, n is 1 , E-R1'. K-R16 and G-R' 7 are CH, A is -CH2-. M is -NHCH2-, further wherein R1 is optionally substituted phenyl. In a further embodiment, Z is CR18, wherein RI H is other than hydrogen, V, U and W are CH, n is 1, E-R15, K-R16 and G-Rp are CH, A is -CH2-, M is -NHCH2-, further wherein R1 is optionally substituted phenyl. [0040] In one embodiment of the compounds of Formula Ib, U is CR18, wherein R! S is other than hydrogen, n is 1 , E-R15 is N or CH, K-R" is N or CH and G-R17 is N or CH. In another embodiment, U is CR18, wherein R18 is other than hydrogen, n is 1 , and E-R15, K-R16 and G-R1 ' are CH. In another embodiment, U is CR1*, wherein R18 is other than hydrogen, Z is CR18, V and W are CH, n is 1 , and E-R15, K-R16 and G-R17 are CH, further wherein Z is CH.
[0041] In one embodiment of the compounds of Formula Ib, U is CR18, wherein R1S is other than hydrogen, n is 1, E-R15, K-R16 and G-R1 ' are CH, A is -CH2-, M is -NHCH2-, further wherein R1 is optionally substituted phenyl. In a further embodiment, U is CR18, wherein R18 is other than hydrogen, Z is CR18, V and W are CH, n is 1 , E-R15, K-R16 and G-R17 are CH, A is -CH2-, M is - NHCH2-, further wherein R1 is optionally substituted phenyl. In a further embodiment, U is CR1*, wherein R18 is other than hydrogen, V, Z and W are CH, n is 1 , E-R15, K-R16 and G-R17 are CH, A is -CH2-, M is -NHCH2-, further wherein R1 is optionally substituted phenyl.
[0042] In one embodiment of the compounds of Formula Ib, further to any of the above embodiments, R15, R 6 and R17 are independently selected from the group consisting of halogen, -OH, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy. Further to any of these embodiments R1 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, optionally substituted lower alkyl and OR29, where R29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl.
[0043] In one embodiment of the compounds of Formula Ib, further to any of the above embodiments, R18 is selected from the group consisting of halogen, -OH, optionally substituted lower alkyl and -OR29, where R29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl. Further to any of these embodiments. R1 is phenyl optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, optionally substituted lower alkyl and -OR29, where R29 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl,
[0044] In another embodiment of compounds of Formula Ib, M is a bond and R1 is other than thiophenyl. [0045J In another embodiment of the compounds of Formula Ib, Z is N or CR18 wherein Rlg is not hydrogen. Further to this embodiment, as allowed in the description of Formula Ib, E is NRIS or CR15, K is NR16 or CR16 and G is CR17, or combinations thereof, wherein at least one of R15, R1' and R1 ' is not hydrogen.
[0046) In one embodiment, a compound of Formula I has a structure according to the following sub-generic structure, Formula Ig,
Figure imgf000021_0001
Formula Ig, all salts, prodrugs, tautomers, and isomers thereof, wherein:
Zi is selected from the group consisting of N and CR34;
U1 is selected from the group consisting of N and CR35;
A| is selected from the group consisting Of -CH2- and -C(O)-;
M3 is selected from the group consisting of a bond, -NR39-, -S-. -O-, -NR3^CH2-,
-NR39CH(R40)-, -SClI2-, -OCH2-, -C(O)NR39-, -S(O)2NR39-, -CH2NR39-, -CH(R40)NR3% -NR39C(O)-, and -NR39S(O)2-; n is O or 1 ; v is O, 1, 2 or 3;
Fj and J( are both C or one of Fi and Ji is C and the other of F1 and J| is N; Ei and Ki are independently selected from C, N, O or S; Gi is selected from C or N; wherein when n is 1 , Fi and J) are C, and Ej, Gi and Ki are C, or any one of Eb G] and K: is N and the other two of Eb G, and Ki are C, provided that when Ei, Gi or Ki is N, Kv\ R37 and R38, respectively, are absent; when n is 0 and F] and Ji are both C, then one Of E1 and Ki is C or N and the other of Ei and Ki is C, N, O or S, provided both Ei and Kj are not C, and provided that when both Ej and Ki are N, one of R36 and R37 is absent, and provided that when one of E] and K) are N and the other is O or S, R36 and R3' are absent; when n is 0, one of F] and Ji is N and the other of Ft and J] is C, then one Of E1 and Ki is N and the other of Ei and Ki is C, or both Ei and K1 are C, provided that when Ei is N, R36 is absent and when K1 is N, R37 is absent;
Cy is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl and heteroaryl; R34 and R'5 are independently selected from the group consisting of hydrogen, -OR41, -SR41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl. wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R14 or R35, or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2. -C(O)NH2, -OR42, -SR42, -NHR42. -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R45 at each occurrence is independently selected from the group consisting of -OR41, -SR41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R4\ or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R'6 is selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy when E) is C, is absent when E) is O or S or when n=l and E] is N, and is absent or selected from the group consisting of hydrogen, lower alkyl, and fluoro substituted lower alkyl when n=0 and E1 is N;
R3' is selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy when Ki is C, is absent when K| is O or S or when n=l and Kj is N, and is absent or selected from the group consisting of hydrogen, lower alkyl, and fluoro substituted lower alkyl when n=0 and K1 is N; R "" is selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy when Gi is C, or is absent
R at each occurrence is independently hydrogen or lower alkyl;
R is lower alkyl or fluoro substituted lower alkyl;
R4i is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituenls selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkyltliio, fluoro substituted lower alkylthio, mono-alkylamino, di- alkylarnino, cycloalkyl, heterocycloalkyl, aryl. and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R4' or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR30C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and
R " at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, and cycloalkylamino. and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl. lower alkoxy and fluoro substituted lower alkoxy.
[0047] In one embodiment of compounds of Formula Ig, n is 1 , Gi and K) are C, and E is N or C, preferably wherein E is C.
[0048] In one embodiment of compounds of Formula Ig, M3 is selected from the group consisting of -NR39-, -O-, -NR39CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, -CH3NR39-, -NR39C(O)-, and -NR39S(O)2-, preferably wherein M3 is -NR39CH2-, -NR39CII(R40)-, -SCH2-, -OCH2-, or
-CH2NR19-.
(0049] In one embodiment of compounds of Formula Ig, n is 1 , Gi and Kj are C, and E is N or C. preferably wherein E is C, and M3 is selected from the group consisting of -NR39-, -O-, -NR19CH2-. -NR39CH(R4")-, -SCH2-, -OCH2-, -CH2NR39-, -NR39C(O)-, and -NR39S(O),-. preferably wherein M1 is -NR39CH2-, -NR39CII(R40)-, -SCH2-, -OCH,-, or -CH2NR39-. (0050] In one embodiment of compounds of Formula Ig. each R45 is selected from the group consisting of -OH, -NlI2, -CN, -NO2, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower thioalkyl, fluoro substituted lower thioalkyl. mono- alkylamino, di-alkylamino and cycloalkylamino, preferably wherein v is 0, 1 , or 2, also 0 or 1.
[0051] hi one embodiment of compounds of Formula Ig, n is 1, G1 and K| are C, and E is N or C. preferably wherein E is C, Mj is selected from the group consisting of -NR39-, -O-, -NR3^CII2--. -NR39CH(R40H -SCH2-, -OCH2-, -CH2NR'9-, -NR19C(O)-, and -NR39S(O)2-, preferably wherein M3 is -NR39CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, or -CH2NR39-, and each R4S is selected from the group consisting of -OH, -NH2, -CN, -NO3, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower thioalkyl, fluoro substituted lower thioalkyl, mono-alkylamino, di-alkylamino and cycloalkylamino, preferably wherein v is 0, 1, or 2, also 0 or 1.
[0052] In one embodiment of compounds of Formula Ig, Z1 is CR14, U1 is CR35, and R34 and R35 are both hydrogen. In one embodiment, Zi is CR34, Ui is CR35, and R34 and R35 arc independently selected from the group consisting of hydrogen, -OR41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR41R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alky], fluoro substituted lower alkyl, and cycloalkylamino, and wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino. In a further embodiment, one of R34 and R35 is hydrogen, and the other of R34 and R'5 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NII2, -C(O)NH2, -OR42, -SRf3, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkyJamino, and wherein lower alkyl and lower alkoxy are optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, further wherein the other of Rj4 and R" is selected from the group consisting of halogen, lower alkyl, and lower alkoxy, wherein lower alkyl and lower alkoxy are optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio. fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino. [0053] In one embodiment of compounds of Formula Ig, each R45 is independently selected from the group consisting of -OH, -NH2, -CN, -NO2, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower thioalkyl. fluoro substituted lower thioalkyl. mono-alkylamino, di-alkylamino and cycloalkylamino, preferably wherein v is 0, 1 , or 2, also 0 or 1 , Zj is CR14, Ui is CR35, and R34 and R35 are independently selected from the group consisting of hydrogen, -OR41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NII2, -OR42, -SR42, -NHR42, -KR42R42, -NR311C(O)R4", -NR59S(O)2R*12, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino, and wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino. di-alkylamino, and cycloalkylamino. In a further embodiment, both of R34 and R15 are hydrogen.
10054] In one embodiment of compounds of Formula Ig, each R45 is selected from the group consisting of -OH, -NHi, -CN, -NO2, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy. fluoro substituted lower alkoxy, lower thioalkyl, fluoro substituted lower thioalkyl, mono- alkylamino, di-alkylamino and cycloalkylamino, preferably wherein v is O, 1. or 2, also O or 1, Z1 is CR34, U, is CR35, one of R34 and R15 is hydrogen, and the other of R34 and R35 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkoxy, aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2. -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR3gC(O)R42, -NR39S(O)2R42, -S(O)2R42. halogen, lower alkyl, fluoro substituted lower alkyl. and cycloalkylamino, and wherein lower alkyl and lower alkoxy are optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino. and cycloalkylamino, further wherein the other of R34 and R35 is selected from the group consisting of halogen, lower alkyl, and lower alkoxy, wherein lower alkyl and lower alkoxy are optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio. fluoro substituted lower alkylthio, mono- alkylamino. di-alkylamino, and cycloalkylamino.
[0055] In one embodiment of compounds of Formula Ig, n is 1 , Gj and Ki are C, and E is N or C, preferably wherein E is C, M3 is selected from the group consisting of -NR39-, -0-, -NR19CH2-, -NR39CH(R40)-, -SCH2-, -OCH;-, -CH2NR39-. -NR39C(O)-, and -NR39S(O)2-, preferably wherein M3 is -NR39CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, or -CH2NR39-, each R4; is selected from the group consisting of -OH, -NH2, -CN, -NO2, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower thioalkyl, fluoro substituted lower thioalkyl, mono-alkylamino, di-alkylamino and cycloalkylamino, preferably wherein v is 0, 1 , or 2, also 0 or 1, Z1 is CR34. U, is CR35, and R34 and R3S are both hydrogen.
[0056] In one embodiment of compounds of Formula Ig, n is 1 , Gi d Kj are C, and E is N or C, preferably wherein E is C, M3 is selected from the group consisting of -NR39-, -O-, -NR31CH2-, -NR39CH(R40)-, -SCH2-. -OCH2-, -CH2NR39-, -NR39C(O)-, and -NR39S(O)2-, preferably wherein M3 is -NR35CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, or -CH2NR39-, each R45 is selected from the group consisting of -OH, -NH2, -CN, -NO2, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower thioalkyl, fluoro substituted lower thioalkyl, mono-alkylamino, di-alkylamino and cycloalkylamino, preferably wherein v is U, 1, or 2, also 0 or 1 , Z1 is CR34 and Ui is CR33, and R34 and R35 are independently selected from the group consisting of hydrogen, -OR41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino, and wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino. In a further embodiment, one of R14 and R35 is hydrogen, and the other of R34 and R35 is selected from the group consisting of halogen, lower alkyl, lower alkoxy, aryl and heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR19S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino, and wherein lower alkyl and lower alkoxy arc optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, further wherein the other of R34 and R35 is selected from the group consisting of halogen, lower alkyl, and lower alkoxy, wherein lower alkyl and lower alkoxy arc optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, further wherein R34 is hydrogen.
|0057] In one embodiment, a compound of Formula I has a structure according to the following sub-generic structure, Formula II,
Figure imgf000027_0001
Formula II all salts, prodrugs, tautomers, and isomers thereof, wherein:
D has a structure selected from the group consisting of
Figure imgf000027_0002
Figure imgf000027_0003
in which <? indicates the attachment point of D to A2 of Formula II; A2 is selected from the group consisting Of -CR19R20-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O),-, -NR21-, and -O-, provided, however, that when A? is NR21, N is not bound to a nitrogen of D; B is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2. -NO2, -CN, -NHC(O)NH2, -NHC(S)NH,, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR23, -OR2',
Figure imgf000028_0001
-C(O)R23, -C(S)R23, -S(O)R2', -S(O)2R21, -C(O)NHR23, -C(O)NR21R23, -C(S)NHR2', -C(S)NR23R23, -S(O)2NHR23. -S(O)2NR21R2', -NHC(O)R'3, -NR;3C(0)RM, -NHC(S)R23, -NR23C(S)R23, -NIIS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R2', -NHC(S)NHR2', -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R2', -NR23C(S)NR23R23, -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR21R2', and -NR23S(O)2NR23R23;
M4 is -NR39CH2-, -NR39CH(R40)-, -NR39CH2CH2-, or -NR39C(O)-;
Ms1 M61 My1 M9 Mιo, M1 ] Mi21 M]1 M 14 M15 M 16, M17 and M18 are selected from the group consisting of a bond, -(CR19R2V, -(CRI9R20)rC(O)-(CR19R2V -(CR19R2VC(S)-(CR19R20),-, -(CRI9R20),-C(O)O-(CRl 9R20)s-,
-(CR19R2VC(S)O-(CR19R2V, -(CRI 9R:VC(O)NR26-(CRI9R2V, -(CRl 9R2VC(S)NR26-(CR| gR20)s-, -(CR19R2VS(O)-(CR19R20X-, -(CRl9R20)rS(O)2-(CRI9R20)s-, -(CR19R20)t-S(O)2NR26-(CRl 9R20)s-,
-(CR19R2Vo-(CR19R2V -(CR19R2VOC(O)-(CR19R2V -(CR19R20)»-OC(S)-(CRI9R2V, -(CR! 9R2VθC(O)NR26-(CRI 9R2V -(CRI9R20)rOC(S)NR26-(CRI 9R2V, -(CR19R2VS-(CR19R2V -(CR19R20)t-NR-(CR19R2V -(CR19R2VNR26C(O)-(CR19R20X-, -(CR19R2VNR26C(S)-(CR19R20),-,
-(CR19R2VNR26C(O)O-(CR19R20X-. -(CR19R20)ΓNR26C(S)O-(CR19R2V, -(CR19R20)rNR26C(O)NR26-(CR19R20X-, -(CR19R20)t-NR26C(S)NR26-(CRι eR20)s-) -(CR19R2VNR26S(O)--(CR19R2V and -(CRI9R20),-NR25S(O)2NR2<> -(CR19R1V M8 is selected from the group consisting of a bond, -(CR19R2V. -(CR19R20)t-C(O)-(CR 19R20K-, -(CR19R2VC(S)-(CR19R20),-, -(CRI9R20)rC(O)O-(CR19R20)s-, -(CR19R211X-C(S)O-(CR19R211X-, -(CR19R20)rC(O)NR26-(CRiqR20)s-,
-(CR 19R20X-C(S)NR26-(CR 19R2V -(CR19R20X-S(O)-(CR19R2V -(CR19R20)t-S(O)2-(CRIQR2V -(CR19R20)l-S(O)2NR2<)-(CRlt'R20)a-, -(CR19R20^-O-(CR19R20X-, -(CR19R2V-OC(O)-(CR19R20),-, -(CR19R21V-OC(S)-(CR19R20),-, -(CR19R)w-OC(O)NR2('-(CR19R20X-, -(CR ' 9R20X -OC(S)NR26-(CR I9R20)s-, -(CR19R2V-S-(CR19R20),-, -(CR19R2VNR26-(CR19R2V -(CR19R2V-NR26C(O)-(CR19R20),-, -(CR1VVNR26C(S)-(CR19R2V, -(CR19R20X-NR26C(O)O-(CR19R20),-, -(CR19R2V-NR25C(S)O-(CR19R2V, -(CR19R'U)W-NR26C(O)NR26-(CR19R2V -(CR"'R::fl)w-NR2"C(S)Ml2('-(CR19R20)i-, -(CR10R20^-NR26S(O)2-(CR19R20),-, and
-(CR19R~Qχv-NR26S(O)2NR-(CR19R20)s-; Q1 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHS(O)2R43, -NHC(O)R43, -NHR43, -NR43R43, -OR43, SR43, S(O)R43, and
-S(O)2R43; Q", Q21, O31. Q41, Q51, Q61, O71, O81, 0", O10', O111, Q121, Q131, and Q141 are selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; Q12 is fluoro, chloro or -CF3; Q13 and Q14 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl; Q22, Q24, Q32, Q33, Q43, Q44, Q52, Q54, Q102 and Q104 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR44R44.
-OR44, and -SR44, provided, however, that at least one of Q22 and Q24, at least one of Q32 and Q", at least one of Q43 and Q44, at least one of Q52 and Q54, and at least one of Qlo: and
Q104 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl; O62, Q74, Qm, Q124, Q132, Q144, and Q152 are hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44;
Q64, Q72, Q82, and Q"4 are hydrogen, lower alkyl or fluoro substituted lower alkyl; R43 at each occurrence is independently optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted hetereoaryl; R39 and R40 are as defined for Formula Ig; each R44 is independently hydrogen, lower alkyl or fluoro substituted lower alkyl; w is 1, 2, or 3; and
R19, R20, R21, R23, R24, R25, R25, s, t and u are as defined for Formula Ib; provided, however, that the compound is not
Figure imgf000029_0001
Figure imgf000030_0001
[0058] In one embodiment of compounds of Formula II,
D has a structure selected from the gioup consisting of
Figure imgf000030_0002
Q
Figure imgf000030_0003
in wh iiicchh t ^ m inrdliicates the attachment point of D to A2 of Formula II; A2 is selected from the group consisting of -CR19R20-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)2-, -NR21-, and -O-, provided, however, that when A2 is NR21, N is not bound to a nitrogen of D. preferably A2 is -CH2- or -C(O)-;
B is selected from the group consisting of hydrogen, -CN, -OR41, -SR41, -NHR41, -NR41R41. -NR39C(O)R41, -NR39S(O)2R41, -C(O)NR39R41, -C(O)R41, -S(O)2NR39R4', -S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl. aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as B, or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NII2, -OR42, -SR42, -NHR42, -NR42R42, -NR19C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
M4 is -NR39CH2-, -NR39CH(R40)-, -NR39CH2CH2-, or -NR30C(O)-, preferably -NHCH2- or -NHC(O)-;
M5, Mio, and Mi s are selected from the group consisting of a bond, -(CRI9R2O)U-, -(CR19R20)rC(O)-(CR19R20),-, -(CR19R20)rC(SHCR1QR20)r, -(CR19R20X-C(O)O-(CR1V0),-, -(CR1V)1-C(S)O-(CR19R2V, -(CR19R20)rC(O)NR26-(CR19R2V, -(CR19R20)rC(S)NR26-(CR19R20)s-, -(CR19R2VS(O)-(CR19R20),-, -(CR19R2VS(O)2-(CR19R2V, -(CR19R20VS(O)2NR2HCR19R20),-, -(CR19R20JrO-(CR19R20X-, -(CR19R2VOC(O)-(CR19R2V, -(CR19R20X-OC(S)-(CR19R20),-, -(CR19R2VOC(O)NR2HCR19R20X-, -(CR19R20)t-OC(S)NR2HCR19R20)s-, -(CR19R2Vs-(CR19R2V, -(CR19R2VNR2HCR19R20),-, -(CR19R2^rNR26C(O)-(CR19R20X-, -(CR19R20X-NR26C(S)-(CR19R20),-,
-(CR1VVNR26C(O)O-(CR19R2V, -(CR19R20)t-NR2riC(S)O-(CR19R2V, -(CR1VVNR26C(O)NR2HCR19R2V, -(CR19R2VNR26C(S)NR2HCR19R2V, -(CR19R2VNR26S(O)2-(CR19R2V, and -(CR19R20)t-NR26S(O)2NR26-(CR19R20)i-, preferably a bond, -NR39-, -S-. -0-, -NR39CH2-, -NR39CH2CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, -C(O)NR19-, -S(O)2NR"-, -CH2NR'"-, -CH(R40)NR19-, -NR39C(O)-, or -NR39S(O):-, more preferably -NR39CH2-, -NR39CH(R40)- or -NR19C(O)-, more preferably -NHCH2-, -NHCH(CH,)- or -NHC(O)-;
M8 is selected from the group consisting of a bond, -(CR1VV, -(CR1V0X-C(O)-(CR1V0),-, -(CR1VVC(SMCR19R2V, -(CR1V0X-C(O)O-(CR1V0X-. -(CR1V0X-C(S)O-(CR1V0),-, -(CR1 VVC(O)NR26-(CR' V0X-, -(CRl9R-0)t-C(S)NR26-(CRl9R20)s-) -(CR19R2VS(O)-(CR19R20)s-(
-(CR1V)1-S(O)2-(CR111R2V5 -(CR1 V°)rS(O)2NR26-(CR19R20)r. -(CR19R20X, -C)-(CR10R2V, -(CR19R2V-OC(O)-(CR19R20X-,
-(CRloR20)w-υC(S)-(CRl9R)s-, -(CRl9R20)w-OC(O)NK26-(CR 19R2V, -(CR19R20)ιv-OC(S)NR26-(CR19R2V, -(CR19R2V-S-(CR19R20X-, -(CRI9R2V-NR26-(CR19R2V -(CR1VV-NR26C(O)-(CR19R2V, -(CR19R20)w-NR2()C(S)-(CR19R20)b-, -(CR19R2V-NR25C(O)O-(CR1V1X-, -(CR19R2Vv-NR26C(S)O-(CR19R20X-, -(CRl 9R2V-NR26C(O)NR26-(CR19R20)s-, -(CR19R20)w-NR26C(S)NR26-(CRιgR2V-, -(CR19R2V-NR26S(O)2-(CR19R20),-, and -(CR19R2V -NR26S(O):NR26-(CR19R2V, preferably a bond, -CH2-, -CH2C(O)-, -S(O)2-, -S(O)2CH2-, -S(O)2CH(CII3)-, -S(O)2CH2CH2-, -S(O)2NR39-, -S(O)2NR19CH2-, -S(O)2NR39CH(CH,)-, -S(O)2NR39CH2CH2-, -C(O)-, -C(O)CII2-, -C(O)CH(CH,)-. -C(O)CH2CH2-, -C(O)NR19-, -C(O)NR39CH2-, -C(O)NR39CH(CH1)-, and -C(O)NR39CH2CH2-, more preferably -C(O)NR39CH2-, -C(O)NR19CH(R40)- or -C(O)NR39CH2CH2-, more preferably -C(O)NIICH2-, -C(O)NHCH(CH1)- or -C(O)NHCH2CH2-;
Q1, Q11, Q41, Q61, and Q141 are aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of , -OR4', -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR19S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl. aryl, and heteroaryl as a substitucnt of Q1, Q1 1, Q41, Q61, or Q141, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42. -NHR42, -NR42R42, -NR19C(O)R42, -NR19S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino, preferably Q1, Q", Q41, Q"1, and Q 141 are aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, -NHS(O)2R41, -NHC(O)R41, -NHR41, -NR41R41, -OR41 or -S(O)2R41;
Q12 is fluoro, chloro or -CF3;
Q13 and Q14 arc independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl; Q '> 0" > Q5' aQd Q54 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, and -SR44, provided, however, that at least one of Q22 and Q24 and at least one of Q52 and Qi4 is hydrogen, fluoro. chloro, lower alkyl or fluoro substituted lower alkyl;
Q'4 and Q132 are hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44;
Q " is hydrogen, lower alkyl or fluoro substituted lower alkyl;
R19, R40 and R41 are as defined for Formula Ig; each R44 is independently hydrogen, lower alkyl or fluoro substituted lower alkyl, and
R19, R20, R21, R26, s, t and u are as defined for Formula Ib,
[0059] In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula Ha,
Figure imgf000033_0001
Formula Ha, all salts, prodrugs, tautomcrs, and isomers thereof, wherein:
A3 is -CH2- or -C(O)-;
Qla is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; Q5 is hydrogen. -OR4', -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR4', -NR4V1, -OR41 and -S(O)2R43; and
M4, Q12, Q13, Q14, R41, and R43 are as defined for Formula II; provided, however, that the compound is not
Figure imgf000033_0002
[0060] In one embodiment of compounds of Formula Ha, A3 is -CH2- and M4 is -NHCH2-. In one embodiment A1 is -C(O)- and M4 is -NHCH2-. In one embodiment A3 is -C(O)- and M4 is -NIIC(O)-. In one embodiment A3 is -CH2- and M4 is -NHC(O)-.
[0061J In one embodiment of compounds of Formula Ila, A3 is -CH2-, M4 is -NHCH2-, Q5 is -OR . -CN, Ci_3 alkyl, fluoro substituted Cu alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substitucnts selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR"13, -NR43R43, -OR43 and -S(O)2R43, and Q13 and Q14 are hydrogen.
[0062] In one embodiment of compounds of Formula Ha, A3 is -C(O)-, M4 is -NHCH2-, Q5 is -OR43, -CN, C|_3 alkyl, fluoro substituted C1.3 alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR43, -NR43R41, -OR43 and -S(O)2R45, and Q13 and Q14 are hydrogen.
[0063] In one embodiment of compounds of Formula Ha, A3 is -C(O)-, M4 is -NHC(O)-, Q5 is -OR43, -CN, C1.3 alkyl, fluoro substituted C1.3 alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR43, -NR43R43, -OR43 and -S(O)2R43, and Q13 and Q14 are hydrogen.
[0064] In one embodiment of compounds of Formula Ha, A3 is -CH2-, M4 is -NHC(O)-, Q3 is -OR43, -CN, C|_3 alkyl, fluoro substituted C].3 alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR43, -NR43R41, -OR43 and -S(O)2R43, and Q13 and Q14 arc hydrogen.
[0065] In one embodiment of compounds of Formula Ha, A1 is -CH2- or -C(O)-; Q is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alky], -NHR41, -NR41R41, and -OR41; Q5 is hydrogen, -CN, -OR41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; M4 is -NR30CH2-, -NR39CH(R40)-, -NR39CH2CH2-, or -NR39C(O)-; Q12 is fluoro, chloro or -CF3; and Q13 and Q14 are independently hydrogen, fluoro. chloro, lower alkyl, or fluoro substituted lower alkyl, wherein R41 is as defined for Formula II. [0066] In one embodiment, farther to any of the embodiments of Formula Ha above, R4' is R as defined for Formula Ig. In one embodiment, further to any of the embodiments of Formula IIa above, R43 is R42 as defined for Formula Ig,
[0067] In one embodiment, further to any of the embodiments of Formula Ha above, Qla is phenyl or pyridinyl, wherein phenyl or pyridinyl are substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy and trifluoromethoxy; A3 is -CH3-; M4 is -NHCH2-; and Q5 is -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl or heleroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy. In one embodiment, further to any of the embodiments of Formula Ha above, Qla is phenyl mono substituted with chloro, preferably at the 4-position; A1 is -CH2-; M4 is -NHCII1-; and Q5 is -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy. In one embodiment, further to any of the embodiments of Formula Ha, Qla is pyridin-3-yl monosubstituted with methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy, preferably at the 6-position; A3 is -CH2-; M4 is -NIICIIi-; Q5 is -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
[0068] In one embodiment of compounds of Formula Ha, A3 is -CH2-; M4 is -NHCH2-; Qla is phenyl or pyridinyl, wherein phenyl or pyridinyl are substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy and trifluoromethoxy; C/ is hydrogen, fluoro, chloro, methyl, methoxy, trifluoromethyl, trifluoromethoxy, -CN, or 1 -methyl- 1 H-pyrazole-4-yl; Q12 is fluoro or chloro; and Q13 and Q14 are hydrogen. In one embodiment, A3 is -CII2-; M4 is -NHCH2-; QIa is phenyl mono substituted with chloro, preferably at the 4-position, Q5 is hydrogen, chloro, methyl, methoxy, or -CN; Q12 is fluoro or chloro; and Q13 and Q14 are hydrogen. In one embodiment. Λ< is -CH2-; M4 is -NIICII2-; Q1'' is pyridin-3-yl monosubstituted with methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy, preferably at the 6-position; Q5 is hydrogen, chloro, methyl, methoxy, -CN, or 1-methyl-l H-pyrazole-4-yl; Q12 is fluoro or chloro; and Q13 and Q14 are hydrogen.
[0069] In one embodiment of compounds of Formula Ha, the compound is selected from the group consisting of: (4-Chloro-benzyl)-[5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]- amine (P-0132),
(4-Chloro-benzyl)-[6-chloro-5-(l H-pyπOlo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-Ol 61),
[6-Chloro-5-(l H-pyrrolo[2.3-b]pyridm-3-ylmethyl)-pyridin-2-yl]-(6-trifluorϋπiethyl-pyridin-3- ylmethyl)-amine (P-Ol 74),
[6-Chloro-5-(5-chloiO-lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl- pyridin-3-ylmethyl)-amine (P-0176),
{6-Chloro-5-[5-(l-methyl-lH-pyrazol-4-yl)-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl]-pyridin-2-yl} -
(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (P-0179),
[5-(5-Chloro-lH-pyrrolo[2)3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-trifluoromethyl- pyridin-3-ylmethyl)-amine (P-0186),
[6-Fluoro-5-(5-methoxy-lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl- pyridin-3-ylmethyl)-amine (P-Ol 87),
[6-Fluoro-5-(lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3- ylmethyl)-amine (P-0188),
3- {2-Chloro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl} -1 H- pyrrolo[2,3-b]pyridine-5-carbonitrile (P-0232),
[6-Chloro-5-(5-melhyl-lH-pytτolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl- pyridin-3 -ylmethyl)-amine (P-0233),
[6-Chloro-5-(5-methyl-lH-pyrrϋlo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl- pyridin-3-ylmethyl)-amine (P-0234),
[6-Fluoro-5-(lH-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)- amine (P-0378),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3- ylmethyl)-amine (P-0379),
(5-Fluoro-pyridin-3-ylmethyl)-[6-fluoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0414),
3-{2-Fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmcthyl}-lH-pyrrolo[2,3- b]pyridine-5-carbonitrile (P-0415),
3-[6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-ylmethyl]-lH-pyrrolo[2.3-b]pyridine-5- carbonitrile (P-0432), and all salts, prodrugs, tautomers, and isomers thereof.
[0070] In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula lib,
Figure imgf000037_0001
Formula lib, all salts, prodrugs, tautomcrs, and isomers thereof, wherein:
A2 is selected from the group consisting of -CR19R20-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)2-,
-NR21-. and -0-;
Q15 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NIIC(O)NH2, -NHC(S)NH2, -NHS(O)2NII2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR21, -OR23, -SR23, -C(O)R23, -C(S)R23. -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR21R23,
-C(S)NHR ,223', -C(S)NR >2-"3DR23 , -S(O)2NHR" \ -S(O)2NR21R , -NHC(O)R23, -NR2T(O)R2
-NHC(S)R2', -NR"C(S)RiJ, -NHS(O)2R , -NR'JS(0)2R , -NHC(O)NHR2'. -NR23C(O)NII2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2. -NR23C(S)NHR23, -NHC(S)NR21R21, -NR91C(S)NR21R2', -NHS(O)2NHR21, -NR21S(O)2NH2, -NR21S(O)2NHR23, -NHS(O)2NR21R23, and -NR23S(O)2NR23R23; M5 , Q1 1 , Q22 and Q24 are as defined for Formula II; and R19, R20, R21, R23, R24, and R25 are as defined for Formula Ib;
provided, however, that the compound is not
Figure imgf000037_0002
[0071] In one embodiment of compounds of Formula lib, M5 is -(CR19R20)t-NR2(l-(CRl9R20)5- or -(CR19R20X-NR26C(O)-(CR19R2V, preferably -NR26-(CR19R:o),- or -NR26C(O)-(CR19R20),-, more preferably -NR39CH2-, -NR39CH(R40)- or -NR39C(O)-, wherein R39 is hydrogen or lower alkyl and R40 is lower alkyl or fluoro substituted lower alkyl. In one embodiment, A2 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Q" is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23. -NR2<R21, -OR23 and -S(O)2R23 and Q15 is hydrogen, -OR21, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or hcteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR21, -NR21R", -OR21 and -S(O)2R23. Further to any of the above embodiments, Q22 and Q24 are independently hydrogen, fluoro, chloro, or -CF1, preferably Q2" and Q24 arc hydrogen,
[00721 In one embodiment of compounds of Formula lib, M5 is -(CRl 9R2O)rNR26-(CRl9R::oV or -(CR19R20VNR26C(OHCR19R20X-, preferably -NR2ft-(CR 19R20X- or -NR16C(O)-(CR19R20),-, more preferably -NR19CH2-, -NR39CH(R40)- or -NR19C(O)-, and A2 is -CR19R20- or -C(O)-, preferably -CH,- or -C(O)-. In one embodiment, M, is -(CR19R20),-NR26-(CR19R20)s- or -(CR19R20X-NR26C(O)-(CR19R20X-, preferably -NR26-(CR19R20)s- or -NR26C(O)-(CR19R20),-. more preferably -NR39CH2-, -NR39CH(R40)- or -NR39C(O)-; A2 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q11 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR21, -NR21R23, -OR23 and -S(O)2R23; and Q15 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, ±luoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR \ -NR23R23, -OR23 and -S(O)2R23. In one embodiment, M5 is -(CR19R20)rNR26-(CR19R20)s- or -(CR19R20J1-NR25C(O)-(CR19R20X-, preferably -NR26-(CR19R20)s- or -NR26C(O)-(CR19R20X-, more preferably -NR39CH2-, -NR39CH(R40)- or -NR39C(O)-; A2 is -CR19R20- or -C(O)-, preferably -CII2- or -C(O)-; Q1 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR21. -NR21R21, -OR23 and -S(O)2R21; Q15 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR21, -NR23R23, -OR23 and -S(O)2R23; and Q22 and Q24 are independently hydrogen, fluoro, chloro, or -CFi, preferably Q22 and Qi4 are hydrogen.
[0073] In one embodiment of compounds of Formula lib, M5 is -NR19CII2-, -NR19CH(R40)-, -NR19CH2CH,-, or -NR19C(O)-: A7 is -CH2- or -C(O)-, preferably -CH2-; Q11 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; Q15 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substitucnts selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; Q22 and Q24 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably hydrogen, fluoro. chloro, or -CF3, more preferably both Q22 and Q24 are hydrogen, wherein R41 is as defined for Formula Ig.
[00741 In one embodiment of compounds of Formula lib, A2 is -CH2- or -C(O)-, preferably -CHi-; 0 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl. heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q1 1, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NII2, -C(O)NIl2, -OR42, -SR4:, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q15 is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; M5 is a bond, -NR39-, -S-, -0-, -NR39CH2-, -NR39CH2CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, -C(O)NR39-, -S(O)2NR39-, -CH2NR39-, -CH(R40)NR39-, -NR39C(O)-, or -NR39S(O)2-; and Q22, and Q24 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44, provided, however, that at least one of Q22 and Q24 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R19, R40, R41, and R42 are as defined for Formula Ig, and R44 is as defined for Formula II.
[0075] In one embodiment of compounds of Formula lib, A2 is -CH2-; Q1 1 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, di-alkylamino, and heterocycloalkyl; Q15 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M5 is -NR39CH2-, -NR39CH2CH2-, or -NR39CH(R41)-; and Q2' and Q24 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy. or fluoro substituted lower alkoxy, provided, however, that at least one of Qi2 and Q24 is hydrogen, fluoro. chloro, lower alkyl or fluoro substituted lower alkyl.
[0076| In one embodiment, further to any of the embodiments of Formula Hb above, each occurrence of R41 is R42 as defined for Formula Ig.
[0077] In one embodiment of compounds of Formula lib, M5 is -NHCHXH,-, -NHCH2-, -N(CH1)CH2-, or -NHCH(CHO-, preferably -NHCH2-; A2 is -CH2-; Q11 is cycloalkyl, heterocycloalkyl, phenyl or heteroaryl, wherein phenyl or heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, di-alkylamino, and heterocycloalkyl; QI S is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy. fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; and Q22 and Q24 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably hydrogen, fluoro, chloro, or -CF3, more preferably both Q22 and Q24 arc hydrogen.
[0078] In one embodiment of compounds of Formula lib, M5 is -NHCH2-; A2 is -CH2-; Q1 1 is phenyl substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, fluoro substituted methyl, methoxy, and fluoro substituted methoxy; Q15 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, preferably hydrogen or chloro; and Q22 and Q24 are hydrogen.
[0079] In one embodiment of compounds of Formula Hb, the compound is selected from the group consisting of:
(4-Chloro-benzyl)-[5-(5-chloro-l H-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0260),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,6-difluoro-benzyl)-amine
(P-0261),
[5-(5-Chloro-lII-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-yl]-(2-trifluoromethyI -benzyl)- amine (P-0262),
(2-Chloro-benzyl)-[5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-aminc
(P-0263),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-benzyl)-amine (P-0264),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,4-difluoro-benzyl)-amine
(P-0265),
L5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyπ- amine (P-0266),
[5-(5-Chloro-l H-ρyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,5-difluoro-bcnzyl)-amme
(P-0267),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-trifIuoromethyl-benzyl)- amine (P-0268).
[5-(5-Chloro-lH-pyrrolo[2,3-b]ρyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-5-trifluoromethyl- benzyl)-ammc (P-0289),
(2-Fluoro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0291),
(2,5-Difluoro-benzyl)-[5-(lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0292),
(2-Chloro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolof2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0293),
(3-Fluoro-5-trifluorϋmethyl-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0294),
(3,5-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyτimidin-2-yl]-amine (P-0295),
(2-Fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0300),
(2-Chloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyτidin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0301),
[5-(lII-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine
(P-0302),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-benzyl)-amine
(P-0303),
(5-Chloro-2-fluoro-bcnzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0304),
(2,4-Dich]oro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl] -amine (P-0305),
(2,4-Difluoro-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0306),
(4-Chloro-bcnzyl)-L5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0307),
[5-(lH-Pyrrolo[2,3-b]pyτidin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)-amine
(P-0308),
(2-F]υoro-3-trifTuoromethyl-benzyl)-[5-(lII-pyπOlo[2.3-b]pyridin-3-ylmethyl)-pyπmidin-2-yl]- amine (P-0309),
(2,5-Dichloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl] -amine (P-0310),
(3-Chloro-2-fluϋrϋ-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amme (P-0311),
(2-Difluoromethoxy-ben2yl)-[5-(l H-pyrrolof2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yI]-amine
(P-0312),
(2,3-Dichloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yI]-amine (P-0313),
(4-Chloro-2-fluoro-benzyl)-[5-(lH-pyrrϋlϋ[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0314),
(5-Fluoro-2-trifluoromcthyl-bcnzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0315),
(2-Chloro-4-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0316),
(5-Chloro-2-methyl-benzyl)-t5-( lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0317),
(5-Fluoro-2-methyl-benzyl)-[5-(lH-pyiτolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylJ-aminc
(P-0318),
(2-Fluoro-4-tπfluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0319),
(4-Fluoro-2-triiluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylJ- amine (P-0320),
[5-(5-Chloro-lH-pyrrolof2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-difluoromethoxy-ben2yl)- amine (P-0390),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-tπfluoromethyl- benzyl)-amine (P-0391),
(3-Chloro-2-fluoro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0392),
[5-(5-Chloro-l H-pyττolof2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-3-tπfluoromethyl- benzyl)-amine (P-0393),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-4-trifluoromethyl- benzyl)-aminc (P-0394),
[5-(5-Chloro-l H-pyiτolo[2,3-b]pyτidin-3-ylmethyl)-pyrimidin-2-yl]-(2,3-difluoro-benzyl)-amine
(P-0395).
(2-Chloro-4-fluoro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0396),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-benzyD- amine (P-0402),
(2-Chloro-5-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidiπ-2-yl]-amine
(P-0407), (2-Chluro-5-fluoro-ben2yl)-[5-(5-chloro-lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0408),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-4-ylmethyl-amine
(P-0416),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-pyrrolidin-l-yl-ethyl)- amine (P-0417),
Benzyl-[5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0418),
Benzyl-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidm-2-yl]-melhyl-amine
(P-0419),
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyτidin-3-ylmethyl)-pyπmidin-2-yl]-(4-trifluoromethoxy-benzyl)- amine (P-0420),
(3-Chloro-benzyl)-[5-(5-chloro-lH-pyrτolϋ[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0421),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-3-ylmethyl-amine
(P-0422),
[5-(5-Chloru-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluoro-benzyl)-amme
(P-0423),
(3-Chloro-benzyl)-[5-(5-chloro-lH-p>τrolo[2,3-blpyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl- amine (P-0424),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyriinidin-2-yl]-(3,5-difluoro-benzyl)-amine
(P-0425),
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[l-(2-fIuoro-phenyl)-ethyl]- amine (P-0426),
[l-(4-Chloro-pheπyl)-ethyl]-[5-(5-chloro-lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylJ- amine (P-0427),
[5-(5-Chloro-lH-pyrrolor2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[(S)-l -(4-fluoro-phenyl)- ethyl]-amine (P-0428),
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(6-trifluoromethyl-pyridin-3- ylmethyl)-aminc (P-0429),
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl- amine (P-0430),
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methyl-benzyl)-amme
(P-0431).
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-benzyl)-amine
(P-0433),
[5-(5-Chloro-l II-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-ylJ-(2-morpholin-4-yl-ethyl)- amine (P-0434),
[5-(5-Ch]oro-lH-p\τiOlo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-cyclohexylmethyl-aininc
(P-0435),
[5-(5-Chloro-lH-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-2-ylmethyl-amine
(P-0436),
[2-(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0437),
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-difluoromethoxy-benzyl)- amine (P-0438),
[5-(5-Chloro- l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-mcthoxy-bcnzyl)-amine
(P-0439),
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-benzyl)-amine
(P-0440),
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidm-2-yl]-(2-methoxy-ethyl)-amine
(P-0441),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-πuoro-benzyl)-amine
(P-0442),
(3-Chloro-4-fluoro-benzyl)-[5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0443),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-ethoxy-benzyl)-amine
(P-0444),
[5-(5-Chloro-l H-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-morpholin-4-yl-benzyl)- amine (P-0445),
[5-(5-Ch]oro-lH-pyrrolo[2,3-b]pyridiπ-3-ylmethyl)-pyrimidin-2-yl]-(3-difluoiOmethoxy-benzyl)- amine (P-0446),
(4-Chloro-3-fluoro-benzyl)-[5-(5-chloro-lH-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0447),
[5-(5-Chlorϋ-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[1 -(3-fIuora-phenyl)-ethyl]- amine (P-0448),
[5-(5-Chloro-l H-pyτrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-dimethylamino-benzyl)- amine (P-0449), and all salts, prodmgs, tautomers, and isomers thereof.
[0080] In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure. Formula Hc,
Figure imgf000045_0001
Formula Hc, all salts, prodrugs, tautomcrs, and isomers thereof, wherein:
A4 is selected from the group consisting of -CR1 V0-, -C(O)-. -C(S)-, -S-, -S(O)-, -S(O)2-,
-NR21-, and -0-;
Q"3 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted hctcrocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NlI2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR2', -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR23R23, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R21, -NHC(S)R23, -NR23C(S)R21, -NHS(O)2R2', -NR23S(O)2R23, -NHC(O)NHR21, -NR23C(O)NH2, -NR23C(O)NIIR23, -NHC(O)NR23R23, -NR23C(O)NR2 'R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR21R23, -NR21C(S)NR21R21, -NHS(O)2NHR21, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R23, and -NR23S(O)2NR23R23;
Md, Q21, Q32 and Q33 arc as defined for Formula II; and R19, R20, R21, R23, R24, and R25 are as defined for Formula Ib.
[0081] In one embodiment of compounds of Formula Hc, M6 is -(CR19R20)rNR26-(CRl9R2°X- or -(CR19R21VNR26C(O)-(CR19R20V, preferably -NR26-(CR19R20)s- or -NR26C(O)-(CR19R21V, more preferably -NR39CH2-, -NR39CH(R40)- or -NR39C(O)-, wherein R39 is hydrogen or lower alkyl and R40 is lower alkyl or fluoro substituted lower alkyl. In one embodiment, A4 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Q21 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR"1, -NR23R2', -OR 1 and -S(O)2R23 and Q25 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl. cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl. aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NIIR*" , -NR" R2 , -OR" and -S(O)2R2 . Further to any of the above embodiments, Q3" and Q33 are independently hydrogen, fluoro, chloro, or -CF3,
10082] In one embodiment of compounds of Formula Hc, M6 is -(CRI9R20)rNR2tI-(CR.ι gR2(V or -(CR19R2VNR26C(O)-(CR10R20X-, preferably -NR26-(CR19R20)s- or -NR26C(O)-(CR19R2"),-, more preferably -NR19CH2-, -NR39CH(R40)- or -NR39C(O)-, and A4 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, M3 is -(CR1')R20)rNR26-(CR19R20)s- or -(CR19R20X-NR26C(OHCR19R20X-, preferably -NR26-(CRl9R2n)s- or -NR26C(O)-(CR19R20),-, more preferably -NR39CH2-, -NR39CH(R40)- or -NR39C(O)-; A4 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q21 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; and Q25 is hydrogen, -OR2', -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl. heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23. In one embodiment, M6 is
Figure imgf000046_0001
or -(CR19R20)rNR26C(O)-(CR19R20)s-, preferably -NR26-(CR19R20)a- or -NR211C(O)-(CR19R^X-, more preferably -NR39CH2-. -NR39CH(R43)- or -NR39C(O)-; A4 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q21 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR2j, -NR23R"1. -OR23 and -S(O)2R23; Q25 is hydrogen, -OR21, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR21R23, -OR21 and -S(O)2R23: and Q32 and Q" are independently hydrogen, fluoro, chloro, or -CF3.
[0083] In one embodiment of compounds of Formula He, M6 is -NR19CH2-, -NR^CH(R40)- or -NR39C(O)-. preferably -NHCH2-; A4 is -CH2- or -C(O)-, preferably -CH2-; Q21 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; Q25 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NIIR41, -NR41R41, -OR41 and -S(O)2R41; Q12 and Q1' are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably Qx' and Q" are independently hydrogen fluoro, chloro, or -CF3, wherein R41 is as defined for Formula Ig,
[0084] In one embodiment of compounds of Formula lie, A4 is -CII2- or -C(O)-, preferably -CH2-; Q21 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41. -NR41R41, -NR39C(O)R4', -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, tluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q2i, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q25 is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; M6 is a bond, -NR'% .S-, -0-, -NR39CH2-, -NR39CH2CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, -C(O)NR39-, -S(O)2NR3"-, -CH2NR39-, -CH(R40)NR™-, -NR39C(O)-, or -NR39S(O)2-; and Q32 and Q33 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR 4, provided, however, that at least one of Q " and Q is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R39, R40, R41, R42 and R44 are as defined for Formula II.
|0085] In one embodiment of compounds of Formula Hc, A4 is -CH2-; Q2' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q25 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M6 is -NR39CHi-, -NR39CH2CH2-, or -NR39CIl(R40)-; and Q32 and Q33 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl. lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that at least one of Q32 and Q33 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
[0086] In one embodiment, further to any of the embodiments of Formula Hc above, each occurrence of R41 is R42 as defined for Formula Ig, [0087] In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula Hd,
Figure imgf000048_0001
Formula Hd, all salts, prodrugs, tautomers, and isomers thereof, wherein:
A5 is selected from the group consisting of -CR19R20-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)2-, -NR21-, and -O-;
Q35 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NIIC(O)NH2, - NIIC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NII2, -NR24R25, -NHR2', -OR21, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NIIR23, -C(O)NR21R23, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R2', - NHC(S)R23, -NR21C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R21, -NR21C(S)NR23R23, -NHS(O)2NIIR23, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R21, and -NR23S(O)2NR23R2';
M7, Q31, Q43 and Q44 are as defined for Formula II; and
R19, R20, R21, R23, R24, and R25 arc as defined for Formula Ib.
[0088] In one embodiment of compounds of Formula lid, M7 is -(CRl9R20)rNR2e-(CRl9R2°X- or -(CR19R20)rNR2sC(O)-(CR! 9R20)s-, preferably -NR26-(CR! 9R20)s- or -NR26C(O)-(CR19R20),-, more preferably -NR39CII2-, -NR39CH(R49)- or -NR39C(O)-, wherein R39 is hydrogen or lower alkyl and R40 is lower alkyl or fluoro substituted lower alkyl. In one embodiment, A5 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Q31 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR2', -NR31R21, -OR21 and -S(O)2R23 and Q35 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, ar>l or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR21R21, -OR'1 and -S(O)2R" . Further to any of the above embodiments, Q ' and Q44 are independently hydrogen, fluoro, chloro, or -CFi.
[0089] In one embodiment of compounds of Formula Hd, M7 is -(CR19R20VNR^-(CR19R20V or -(CR19R20VNR26C(O)-(CR1V'0),-, preferably -NR26-(CR19R20)S- or -NR26C(O)-(CR19R2"),-, more preferably -NR39CH,-, -NR39CH(R40)- or -NR39C(O)-, and A5 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, M7 is -(CR1"R20)rNR26-(CRlt)R20)^ or -(CR19R20VNR26C(O)-(CR19R20V, preferably -NR2^(CR1 V°)s- or -NR26C(O)-(CR19R20),-. more preferably -NR39CH2-, -NR19CH(R40)- or -NR39C(O)-; A5 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q31 is aryl or heteroaryl. wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; and Q35 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NIIR23, -NR23R23, -OR23 and -S(O)2R23. In one embodiment, M7 is -(CR19R20VNR21HCR19R20V or -(CR19R20VNR26C(O)-(CR19R20V, preferably -NR26-(CR19R2°V or -NR26C(O)-(CR19R20V, more preferably -NR39CH2-, -NR39CH(R40)- or -NR39C(O)-; A5 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q31 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R21; Q35 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R2 ', -OR23 and -S(O)2R2'; and Q4' and Q44 are independently hydrogen, fluoro, chloro, or -CF1.
[0090] In one embodiment of compounds of Formula Hd, M7 is -NR39CH2-, -NR19CH(R40)- or -NR39C(O)-, preferably -NHCIl2-; A5 is -CII2- or -C(O)-, preferably -CH2-; Q31 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR11, -NR41R41, -OR41 and -S(O)2R41; Q35 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl. aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; Q43 and Q44 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably Q43 and Q44 are independently hydrogen, fluoro, chloro, or -CF3, wherein R41 is as defined for Formula Ig.
[0091] In one embodiment of compounds of Formula Hd. A5 is -CH2- or -C(O)-, preferably -CHi-; Q31 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41 , -S(O)2R41, -NHR41, -NR41R41 , -NR39C(O)R41. -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkyl thio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q11, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH1, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR19S(O)2R42, -S(O)2R12, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q35 is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R4', -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; M7 is a bond, -NRW-, -S-, -0-, -NR39CH2-, -NR39CH2CH2-, -NR^CH(R40)-, -SCH2-, -OCH2-, -C(O)NR39-, -S(O)2NR19-, -CH2NR3"-, -CH(R40)NR39-, -NR39C(O)-, or -NR39S(O)2-; and Q43 and Q44 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44, provided, however, that at least one of Q 3 and Q''4 is hydrogen, fluoro, chloro. lower alkyl or fluoro substituted lower alkyl, wherein R39, R, R41, R42 and R44 are as defined for Formula II.
[00921 In one embodiment of compounds of Formula Hd, A5 is -CH2-; Q is aryl or heteroaryl. wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q35 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M7 is -NR39CH2-, -NR39CH2CH2-, or -NR39CH(R40)-; and Q43 and Q44 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that at least one of Q43 and Q44 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
[0093] In one embodiment, further to any of the embodiments of Formula Hd above, each occurrence of R41 is R42 as defined for Formula Ig. [0094J In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure. Formula lie.
Figure imgf000051_0001
Formula He, all salts, prodrugs, tautomers, and isomers thereof, wherein:
A6 is selected from the group consisting Of -CR1V0-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)-,
-NR21-, and -O-;
Q is selected from the group consisting of hydrogen, halogen, optionally substituted lower alky], optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NII2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NIIR23, -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R21, -C(O)NHR23, -C(O)NR21R21, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R21, -NHC(O)R23, -NR^1C(O)R21, -NHC(S)R23, -NR21C(S)R21, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR21C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R13, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR21, -NHC(S)NR23R23, -NR21C(S)NR23R23, -NHS(O)2NHR23, -NR21S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R21, and -NR23S(O)2NR21R2';
M8, Q4!, Q52 and Q54 are as defined in Formula II; and R19, R20, R21, R23, R24, and R25 are as defined for Formula Ib;
provided, however, that the compound is not
Figure imgf000051_0002
Figure imgf000051_0003
Figure imgf000052_0001
[0095J In one embodiment of compounds of Formula He, Mg is -(CR19R20)rC(O)NR2(1-(CR19R20)s-, preferably -C(O)NR26-(CR19R20)s-, more preferably -C(O)NR39-CRSV°- or -C(O)NR39-(CR80R80)2-> wherein R39 is hydrogen or lower alkyl and R is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, Λb is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Q41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substitucnts selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR2\ -NR23R23, -OR23 and -S(O)2R23 and Q45 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR2\ -NR23R23, -OR23 and -S(O)2R2'. Further to any of the above embodiments, Q52 and QS4 are independently hydrogen, fluoro, chloro, methyl, or -CFv
[0096] In one embodiment of compounds of Formula He, M8 is -(CRl9R20)t-C(O)NR2h-(CR'9R20)s-, preferably -C(O)NR26-(CRI9R20)s-, more preferably -C(O)NR39-CR80RS0- or -C(O)NR19-(CRR80)2-, and A6 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, M8 is -(CR!9R20)t-C(O)NR26-(CRl5R20)s-, preferably -C(O)NR26-(CRl 9R20)s-, more preferably -C(O)NR39-CRs0R80- or -C(O)NR3<3-(CR8V°)2-; A6 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR21, -NR21R"1, -OR21 and -S(O)2R2'; and Q45 is hydrogen, -OR21, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl. aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR21R21, -OR21 and -S(O)2R:\ In one embodiment, Ms is -(CRl9R20)rC(O)NR26-(CR' V),-, preferably -C(O)NR26-(CR' 9R20X-, more preferably -C(O)NR19-CR80R80- or -C(O)NR?9-(CR80R80)2-, A6 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substitucnts selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl. -NHR23, -NR23R23, -OR23 and -S(O)2R23; Q45 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R2\ -OR23 and -S(O)2R23; and Q52 and Q54 are independently hydrogen, fluoro, ehloro, methyl, or -CF3.
[0097] In one embodiment of compounds of Formula He, M8 is -C(O)NR39-CH2-, -C(O)NR39CH(CH3)-, or -C(O)NR39-(CH2)2-; A6 is -CH2- or -C(OV, preferably -CH2-; Q41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; Q45 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41 , -OR41 and -S(O)2R41 ; and Q52 and Q54 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably Q52 and Q/4 are independently fluoro, chloro, methyl, or -CF3, wherein R41 is as defined in Formula Ig,
[0098] In one embodiment of compounds of Formula He, A6 is -CH2- or -C(O)-, preferably -CH2-; Q41 is aiyl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q4i, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q45 is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)7R41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alky], -NHR41, -NR41R41, and -OR41; Ms is -C(O)NR1OI,-, -C(O)NR3l)CH(R4<1)-, or -C(O)NR39CH2CH2-; and Q52 and Q54 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alky], -NR44R*4. -OR44, or -SR44. provided, however, that at least one of Q" and Q54 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R39, R40, R41, R42 and R44 are as defined for Formula II.
[0099] In one embodiment of compounds of Formula lie, Ag is -CH2-; Q41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q45 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; Mg is -C(O)NR19CH:-, -C(O)NR39CH(R40)-, or -C(O)NR39CH2CH2-; and Q52 and Q54 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that at least one of Q52 and Q54 is hydrogen, fluυro, chloro, lower alkyl or fluoro substituted lower alkyl.
[0100] In one embodiment, further to any of the embodiments of Formula He above, each occurrence of R41 is R42 as defined for Formula Ig.
[0101] In one embodiment of compounds of Formula lie, M8 is -C(O)NHCH2-, -C(O)NH-CH(CH3)- or -C(O)NH-(CH2)2-; A6 is -CH2- or -C(O)-, preferably -CII2-; Q4' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, fluoro substituted methyl, methoxy, and fluoro substituted methoxy; Q45 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably hydrogen or chloro; and Q52 and Q14 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, preferably Q52 and Q5'' are methyl.
(0102] In one embodiment of compounds of Formula lie, the compound is selected from the group consisting of:
3-(l -Benzyl-3,5-dimethyl-lH-pyrazol-4-ylmethyl)-lH-pyrrolo[2,3-bJpyτidine (P-0133),
2-[3,5-Dimethyl-4-(lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyrazol-l -yl]-l -phenyl-ethanone
(P-0134),
3,5-Dimethyl-4-(lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxyhc acid 4-methoxy- benzylamide (P-Ol 35).
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 2-chloro- benzylamide (P-0136),
3,5-Dimethyl-4-(lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 2-fluoro- benzylamide (P-0137),
3-[3,5-Dimethyl-l -(5-trifluoromelhyl-furan-2-ylmethyl)-lH-pyrazol-4-ylmethyl]-lH-pyrrolo[2.3- bjpyridine (P-0138),
3-[3,5-Dimethyl-l -(5-methyl-isoxazol-3-ylmethyl)-l H-pyrazol-4-ylmethyl]-lH-pyττolo[2,3- b]pyridine (P-0139),
3,5-Dimethyl-4-(l H-p}τrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 4-chloro- benzylamide (P-0140),
3,5-Dimethyl-4-(lH-pyrrolof2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid [2-(4-methoxy- phenyl)-ethyl]-amide (P-0141),
3,5-Dimethyl-4-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l-carboxylic acid 3-methoxy- benzylamide (P-0142),
3-{3,5-Dimethyl-l -[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-l H-pyrazol-4- ylmethyl}-lH-pyrrolo[2,3-b]pyridiπe (P-0143),
3-[3,5-Dimethyl-l -(4-mcthyl-2-phcnyl-thiazol-5-ylmcthyl)-lH-pyrazol-4-ylmethyl]-lH- pyrrolo[2,3-b]pyridine (P-0144),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 2-methoxy- benzylamide (P-0145),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-bJpyridin-3-ylmcthyl)-pyrazole-l-carboxylic acid [2-(2,4- dichloro-phenyl)-ethyl]-amide (P-0146),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid [2-(4-fluoro- phenyl)-ethyl]-amide (P-0147),
3,5-Dimethyl-4-(lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid [2-(2-fluoro- phenyl)-ethyll -amide (P-0148),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid ((S)-I -phenyl- ethyl)-amide (P-0149),
3, 5-Dimcthyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 3-fluoro- benzylamide (P-0150),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 4-fluoro- benzylamide (P-0151),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 4-methyl- benzylamide (P-Ol 52),
3,5-Dimcthyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 2-methyl- benzylamide (P-0153),
4-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-l -carboxylic acid [2-(4- fluoro-phenyl)-ethyl]-amide (P-0157),
4-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-l -carboxylic acid A- fluoro-benzylamide (P-0158),
4-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-p\τazole-l -carboxylic acid 4- chloro-benzylamide (P-Ot 59),
4-(5-Chloro-lH-pyrrolo[2.3-b]pyridin-3-ylmcthyl)-3,5-dimcthyl-pyrazolc-l -carboxylic acid [(S)- l-(4-fluoro-phenyl)-ethyl]-amide (P-0160) , and all salts, prodrugs, tautomers, and isomers thereof.
[0103] In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula Hf,
Figure imgf000056_0001
Formula Hf, all salts, prodrugs, tautomers, and isomers thereof, wherein:
A7, is selected from the group consisting Of -CR19R20-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)2-,
-NR21-, and -O-;
Q55 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted hctcrocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR23, -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR23R23, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R23, -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR21C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R", -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR23C(S)NR23R23, -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R23, and -NR23S(O)2NR23R23;
M9, Q51. Qfi2, and Q64 are as defined for Formula II; and R19, R20, R21, R23, R24, and R25 are as defined for Formula Ib.
[0104] In one embodiment of compounds of Formula Hf, M9 is -(CRI9R20)t-NR2(i-(CRI 9R20),- or -(CRI 9R20)rNR26C(O)-(CRll)R2V, preferably -NR26-(CR19R20)s- or -NR26C(O)-(CR19R20X-, more preferably -NR39CR80R80- or -NR39(CR80R80)r, wherein R39 is hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, A-, is -CR19R'0- or -C(O)-, preferably -CH2- or -C(O)-, In one embodiment, Q51 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R21 and Q55 is hydrogen, -OR21, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, hcterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR21R23, -OR23 and -S(O)2R23. Further to any of the above embodiments, Q62 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
[0105] In one embodiment of compounds of Formula Hf, M9 is -(CR1?R20)rNR26-(CRl<)R20),- or -(CR19R2VNR26C(O)-(CR19R2V, preferably -NR26-(CR 19R2V or -NR26C(O)-(CR1 V V, more preferably -NR34CR80R80- or -NR^(CR80R80)-,-, and A7 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, M9 is -(CR19R2G)rNR26-(CR! 5R2V or
-(CR19R20VNR26C(O)-(CR19R2V, preferably -NR26-(CR 19R2V or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR39(CR8OR8O)2-; A7 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q11 is optionally substituted lower alkyl, aryl or heteroaryl. wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR21 and -S(O)2R21; and Q55 is hydrogen, -OR", -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NIIR23, -NR23R23, -OR21 and -S(O)2R2'. In one embodiment, M9 is -(CR19R20)rNR26-(CR1C)R20)s- or -(CR19R20VNR26C(O)-(CR19R20X-, preferably -NR:6-(CR19R2V or -NR2fiC(O)-(CR19R20)s- more preferably -NR39CR80R80-, -NR19(CR8V0);-; Ai is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q51 is optionally substituted lower alkyl, aryl or heteroaryl. wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR21. -NR23R21, -OR21 and -S(O)2R23; Q55 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein aryl or heteroaiyl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR21R21. -OR23 and -S(O)2R23; and Q62 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl. [0106] In one embodiment of compounds of Formula Hf, M9 is -NR19CH2- or -NRiy-(CH2);-; A, is -CH2- or -C(O)-, preferably -CH2-; Q5' is aryl or hcteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41 , -NR4iR41, -OR41 and -S(O)2R41; Q55 is hydrogen, -CN, fluoro, chloro. lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or hcteroaryl, wherein aiyl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; and Q62 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R41 is as defined in Formula Ig.
[0107] In one embodiment of compounds of Formula Hf, A7 is -CH2- or -C(O)-, preferably -CH2-; Q5' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R4', -NHR41, -NR41R41, -NR39C(O)R41, -NR19S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di -alky lam ino, cycloalkyl, heterocycloalkyl. aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q51, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2. -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino: Q55 is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NIIR41, -NR41R4'', -NR39C(O)R41, -NR19S(O)2R41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; M9 is a bond, -NR19-, -S-, -0-, -NR39CH2-, -NR39CH2CII2-, -NR39CH(R40)-, -SCH2-, -OCH2-, -C(O)NR19-, -S(O)2NR19-, -CH2NR39-, -CH(R40)NR39-. -NR39C(O)-, or -NR39S(O)2-; Q62 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44; and Q64 is hydrogen, lower alkyl. or fluoro substituted lower alkyl, wherein R'9, R40, R41, R42 and R44 are as defined for Formula II.
[0108] In one embodiment of compounds of Formula Hf, A? is -CH2-; Q ' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q55 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M9 is -NR34CH2-, -NR39CH3CH2-, or -NR39CH(R40)-; Q62 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; and Q64 is hydrogen, lower alkyl, or fluoro substituted lower alkyl.
[0109| In one embodiment, further to any of the embodiments of Formula Hf above, each occurrence of R"" is R42 as defined for Formula Ig.
[0110] In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula Ug,
Figure imgf000059_0001
Formula Ilg, all salts, prodrugs, tautomers, and isomers thereof, wherein:
A8 is selected from the group consisting Of -CR19R20-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)2-,
-NR21-. and -O-;
Q65 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, - NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH7, -NR24R25, -NHR23, -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R", -C(O)NHR23, -C(O)NR21R23, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR21C(O)R2'. - NHC(S)R23, -NR21C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR21, -NR23C(O)NH2, -NR21C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NIIC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR2', -NHC(S)NR23R23, -NR23C(S)NR21R2', -NHS(O)2NHR21, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R23, and -NR23S(O)2NR23R23;
M10, Q61, Q72, Q74 are as defined for Formula II; and R19, R20, R21. R23, R24, and R25, R20 are as defined for Formula Ib.
[0111] In one embodiment of compounds of Foπnula Hg, M10 is -(CRI9R20)t-NR2tJ-(CRl 9R2ι)χ- or -(CR19R2VNR26C(O)-(CR19R20X-, preferably -NR26-(CR19R20)s- or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR39(CR80R80)2-, wherein R39 is hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, A8 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Q61 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, iluoro substituted lower alkyl. -NHR23, -NR23R23, -OR23 and -S(O)2R23 and QM is hydrogen, -OR21, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cyeloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23. Further to any of the above embodiments, Q74 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
[0112] In one embodiment of compounds of Formula Hg, M10 is -(CR1<)R:!0)rNR26-(CR19R20)i- or -(CR19R20)rNR26C(O)-(CR19R20)5-, preferably -NR26-(CR19R20)s- or -NR26C(O)-(CR19R20),-, more preferably -NR19CR80R80- or -NR39(CR80R80)2-, and A3 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment. M10 is -(CR19R20)rNR26-(CR19R20)s- or
-(CR19R20)t-NR26C(O)-(CR19R20)s-, preferably -NR26-(CR19R20)s- or -NR26C(O)-(CR19R20),-, more preferably -NK39CR80R80- or -NR3^(CR80R80)-,-; A8 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q61 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR2', -NR23R23, -OR23 and -S(O)2R23: and Q"5 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R21, -OR23 and -S(O)2R23. In one embodiment, M10 is -(CR19R20),-NR26-(CR19R20)s- or -(CR19R20VNR26C(O)-(CR19R20X-, preferably -NR2^(CR19R20),- or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR39(CR8OR8I1)2-; A8 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q61 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR2', -NR23R23, -OR23 and -S(O)2R23; Q65 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR11R2', -OR23 and -S(O)2R23; and Q74 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl. [0113] In one embodiment of compounds of Formula TTg, M10 is -NR39CH2- or -NR!I)-(CH2)2-; As is -CH;- or -C(O)-, preferably -CH2-; Q61 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; Q65 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; and Q74 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R41 is as defined for Formula Ig.
[0114] In one embodiment of compounds of Formula Hg, A8 is -CH2- or -C(O)-, preferably -CH?-; Q6' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR19C(O)R41, -NR19S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q61, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NII2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino: Q65 is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; M10 is a bond, -NR39-, -S-, -0-, -NR39CH2-, -NR39CH2CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, -C(O)NR3"-, -S(O)2NR39-, -CH2NR39-, -CH(R40)NR39-, -NR39C(O)-, or -NR39S(O)2-; Q74 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44; and Q72 is hydrogen, lower alkyl. or fluoro substituted lower alkyl, wherein R'9, R40, R41, R42 and R44 are as defined for Formula II.
|0115] In one embodiment of compounds of Formula Hg, Ag is -CH2-; Q61 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy. and fluoro substituted lower alkoxy; Q65 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M10 is -NR39CH2-, -NRigCH,CH2-( or -NR39CH(R*)-; Q74 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; and Q72 is hydrogen, lower alkyl, or fluoro substituted lower alkyl.
10116) In one embodiment, further to any of the embodiments of Formula Hg above, each occurrence of R41 is R42 as defined for Formula Ig.
[0117] In one embodiment of compounds of Formula Hg, M10 is -NHCH2-, A8 is -CH;-, Q0' is phenyl optionally substituted with 1 or 2 substituents selected from the group consisting of fluoro. chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromefhoxy, Q65 is hydrogen, fluoro, -CN, or l -methyl-pyrazol-4-yl, Q72 is lower alkyl or fluoro substituted lower alkyl, and Q74 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl. In one embodiment, M]0 is -NIICH2-, A8 is -CH2-, C/1 is 4-fluoro-phenyl, Q65 is hydrogen, chloro, -CN, or 1 -methyl - pyrazol-4-yl, Q72 is methyl or ethyl and Q74 is hydrogen or chloro.
[0118] In one embodiment, the compound of Formula Hg is selected from the group consisting of :
[l -Hthyl-5-(lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l H-pyrazol-3-yl]-(4-fluoro-bcnzyl)-amine
(P-Ol 65),
(4-Fluoro-benzyl)-[l -methyl-5-( lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-lH-pyrazol-3-yl]-amine
(P-Ol 69),
[5-(5-Chloro-lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l -methyl- lH-pyrazol-3-yl]-(4-fluoro-benzyl)- amine (P-0170),
(4-Fluoro-benzyl)-{l -methyl-5-[5-(l-methyl-lH-pyrazol-4-yl)-l H-pyrrolo[2,3-b]pyridin-3- ylmethyl]-] H-pyrazol-3-yl} -amine (P-0180),
(5-Chloro-lH-p>τrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]- methanone (P-0184),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-l -ethyl-l H-pyrazol-3-yl]-(4-fluoro-benzyl)- amine (P-Ol 85),
3-[5-(4-Fluoro-benzylamino)-2-methyl-2H-pyrazol-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5- carbonitrile (P-0191),
(3-Chloro-benzyl)-[5-(5-chloro-lH-p>ττolo[2,3-b]pyridin-3-ylmethyl)-l -methyl-lH-pyrazol-3-ylJ- amine (P-0410),
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l -methyl-l H-pyrazol-3-yl]-(2,5-difluoro- benzyl)-amine (P-0411),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l -methyl-lH-pyrazol-3-yl]-(2-fluoro-benzyl)- amine (P-0413), and all salts, prodrugs, tautomers, and isomers thereof.
[0119] In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula Ilh,
Figure imgf000063_0001
Formula Hh, all salts, prodrugs, tautomers, and isomers thereof, wherein:
A9 is selected from the group consisting Of -CR1V0-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)2-,
-NR21-, and -O-;
0 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NIIC(O)NH2, -NHC(S)NII2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR23, -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR21, -C(O)NR23R23, -C(S)NHR23, -C(S)NR23R13, -S(O)2NHR23, -S(O)2NR23R23, -NIIC(O)R23, -NR23C(O)R2', -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR23C(O)NII2, -NR23C(O)NHR23, -NHC(O)NR21R23, -NR23C(O)NR23R33, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR21C(S)NR23R25, -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R23, and -NR23S(O)2NR23R23;
MH, Q' ', and Q82 are as defined for Formula II; and R19, R20, R21, R23, R24, and R25 are as defined for Formula Ib.
[0120] In one embodiment of compounds of Formula Hh, Mn is
Figure imgf000063_0002
or -(CR19R20VNR26C(O)-(CR19R20X-, preferably -NR26-(CRl9R20)s- or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR39(CR80R%-, wherein R™ is hydrogen or lower alkyl and R is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, A9 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Q71 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR2', -NR23Rr3, -OR23 and -S(O)2R23 and Q75 is hydrogen,
Figure imgf000064_0001
-CN. fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl. fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23.
[0121] In one embodiment of compounds of Formula Hh, M1 1 is -(CRi9R20)t-NR26-(CR| l)R2U)5- or -(CR19R20VNR76C(O)-(CR19R2V, preferably -NR^-(CR19R20V or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR39(CRS0R8C)2-. and A9 is -CR19R20- or -C(O)-, preferably -CII2- or -C(O)-. In one embodiment, M1, is -(CR1 V0)t-NR26-(CRi αR20)s- or
-(CR19R20VNR26C(O)-(CR19R20X-, preferably -NR?6-(CR19R2°V or -NR26C(O)-(CR19R20V, more preferably -NR39CR80R80- or -NR3'( CR8V)2-; A9 is -CR19R20- or -C(O)-, preferably -CII2- or -C(O)-; Q71 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; and Q/5 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR21R23, -OR2' and -S(O)2R23.
(0122] In one embodiment of compounds of Formula Hh, M1 1 is -NR39CH2- or -NR39-(CH2)2-; A9 is -CH2- or -C(O)-, preferably -CH2-; Q71 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; Q75 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, helerocycloalkyl. aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41, wherein R41 is as defined for Formula Ig.
[0123] In one embodiment of compounds of Formula Hh, A9 is -CH2- or -C(O)-, preferably -CH2-; Q7' is aryl or heteroaryl. wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, hcterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl. aryl, and heteroaryl as a substituent of Q ', or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NII:, -C(O)NII2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylami.no; Q s is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NIIR41, -NR41R41, -NR(9C(O)R4\ -NR19S(O)2R41, fluoro, chloro. lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; Mn is a bond. -NR"-. .S-, -0-, -NR19CH2-, -NR39CH2CH2-, -NR19CH(R40)-, -SCH2-, -OCH2-, -C(O)NR19-, -S(O)2NR19-. -CH2NR39-, -CH(R4n)NR39-, -NR19C(O)-, or -NR19S(O)2-; and Q82 is hydrogen, lower alkyl, or fluoro substituted lower alkyl, wherein R39, R40, R41, R42 and R44 are as defined for Formula II.
[0124] In one embodiment of compounds of Formula Hh, Λ9 is -CH2-; Q71 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q7' is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl. lower alkoxy, or fluoro substituted lower alkoxy; Mn is -NR39CH2-, -NR39CH2CH2-, or -NR39CH(R40)-; and Q82 is hydrogen, lower alkyl, or fluoro substituted lower alkyl.
[0125] In one embodiment, further to any of the embodiments of Formula Hh above, each occurrence of R41 is R42 as defined for Formula Ig.
[0126] In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula Hi,
Figure imgf000065_0001
Formula Hi, all salts, prodrugs, tautomers, and isomers thereof, wherein:
Ai0 is selected from the group consisting Of -CR19R20-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O),-,
-NR21-, and -0-.
QH~ is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl. optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl. -OH, -NH2, -NO2, -CN. -NHC(O)NH;. - NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NII2, -S(O)2NH2, -NR24R25, -NHR2I -OR21, -SR21, -C(O)R21, -C(S)R21, -S(O)R23, -S(O)2R23, -C(O)NHR21, -C(O)NR21R21, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR2'. -S(O)2NR21R23, -NHC(O)R", -NR21C(O)R21, - NHC(S)R23, -NR21C(S)R23. -NIIS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR21, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR21, -NR21C(S)NH2. -NR23C(S)NHR23, -NHC(S)NR23R21, -NR23C(S)NR21R21, -NHS(O)2NIIR23, -NR23S(O)2NH2. -NR23S(O)2NHR21, -NHS(O)2NR21R23, and -NR23S(O)2NR23R23;
Mi2, Q81, and QM are as defined for Formula II; and
R19, R20, R21, R21, R24, and R25 are as defined for Formula Ib.
[0127] In one embodiment of compounds of Formula Hi. M12 is -(CR19R2 VNR26-(CR'"R2V or -(CR1V)1-NR26C(O)-(CR19R20V, preferably -NR26-(CR 19R20),- or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR19(CR80R80)r, wherein R19 is hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, A)0 is -CR19R20- or -C(O)-, preferably -CII2- or -C(O)-. In one embodiment, Q81 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, rluoro substituted lower alkyl, -NHR23, -NR23R23, -OR21 and -S(O)2R21 and Q85 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NIIR23, -NR23R23, -OR21 and -S(O)2R21.
[0128] In one embodiment of compounds of Formula Hi, M12 is
Figure imgf000066_0001
or -(CR19R20VNR26C(O)-(CR19R20X-, preferably -NR26-(CR!9R20)s- or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR39(CR80R80),-, and A10 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Mi2 is -(CR19R20)rNR26-(CR19R20)s- or
-(CR19R20VNR26C(O)-(CR19R2V, preferably -NR25-(CRI9R20)b- or -NR26C(O)-(CR19R20),-, more preferably -NR19CRRsu- or -NR39(CR80R80)2-; A10 is -CR19R20- or -C(O)-. preferably -CH2- or -C(O)-; Q81 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl aie optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR21R23, -OR23 and -S(O)2R21; and Q" is hydrogen, -OR21, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR". -NR21R21, -OR21 and -S(O)2R2 '.
[0129] In one embodiment of compounds of Formula Hi, M12 is -KR39CII2- or -NR39-(CII2)2-; Λ|0 is -CHj- or -C(O)-, preferably -CH7-; Q81 is aryl or heteroaryl. wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; Q85 is hydrogen, -CN, fluoro, chloro. lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy. cycloalkyl, heterocycloalkyl, aryl or heteroaryl. wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41, wherein R41 is as defined for Formula Ig.
[0130| In one embodiment of compounds of Formula Hi, A10 is -CH2- or -C(O)-, preferably -CH2-; Q81 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more subslituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy. lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl. heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q81, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42. -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q85 is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NH41R41, -NR19C(O)R41, -NR111S(O)2R41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alky], fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; M12 is a bond, -NR19-, -S-, -0-, -NR19CH2-, -NR19CH2CH2-, -NR19CH(R40)-, -SCH2-, -OCH2-, -C(O)NR'9-. -S(O)2NR19-, -CH2NR39-, -CH(R40)NR39-, -NR39C(O)-, or -NR39S(O)2-; and Q94 is hydrogen, lower alkyl, or fluoro substituted lower alkyl, wherein R39, R40, R41, R42 and R44 are as defined for Formula II,
[0131 | In one embodiment of compounds of Formula Hi, Ai0 is -CH2-; Q81 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q85 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M12 is -NR19CH2-, -NR19CH2CH2-, or -NR39CH(R40)-; and Q"4 is hydrogen, lower alkyl, or fluoro substituted lower alkyl.
[0132] In one embodiment, further to any of the embodiments of Formula Hi above, each occurrence of R41 is R42 as defined for Formula Ig.
[0133] In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula Hj,
Figure imgf000068_0001
Formula Hj , all salts, prodrugs, tautomers, and isomers thereof, wherein:
A1, is selected from the group consisting Of -CR19R20-, -C(O)-, -C(S)-, -S(O)-, and -S(O)2-; Q95 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR23, -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR23R21, -C(S)NIIR23, -C(S)NR23R23, -S(O)2NIIR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R2', -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR23C(S)NR23R23, -NIIS(O)2NIIR23, -NR23S(O)2NH2, -NR23S(O)2NlIR23, -NIIS(O)2NR23R23, and -NR23S(O)2NR23R23;
M13, Q"1, Q102 and Q104 are as defined for Formula II; and R19, R20, R23, R24, and R25 are as defined for Formula Ib,
[01341 In one embodiment of compounds of Formula Hj, M13 is -(CR19R20),-NR26-(CR|C>R2V or -(CR1VVNR26C(O)-(CR19R20X-, preferably -NR26-(CRl9R20)s- or -NR26C(O)-(CR19R20),-, more preferably -NR19CR80R8"- or -NR"(CR8I)R8())2-, wherein R39 is hydrogen or lower alkyl and Rsn is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, An is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Q91 is optionally substituted lower alkyl, aryl or hcteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR2', -NR23R23, -OR23 and -S(O)2R23 and Q95 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl. heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23. Further to any of the above embodiments, Q10" and Q104 are independently hydrogen, fluoro, chloro, methyl, or -CF3.
[0135] In one embodiment of compounds of Formula Hj, M13 is -(CR19R20)t-NR26-(CR19R20)s- or -(CR19R2VNR26C(O)-(CR111R20X-, preferably -NR26-(CR19R20)s- or -NR25C(O)-(CR19R20).,-, more preferably -NR39CR80R80- or -NR39(CRS0R8O)r, and A11 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, M13 is -(CR19R20)rNR26-(CR19R20)s- or
-(CRμ:)R20)rNR26C(O)-(CRl9R20V, preferably -NR26-(CR19R20)s- or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR39(CR80RS0)2-; An is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q91 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; and Q95 is hydrogen, -OR' , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23. In one embodiment, M13 is -(CR19R20),-NR26-(CR19R20)s- or -(CR19R20)rNR26C(O)-(CR19R20)s-, preferably -NR26-(CR19R2V or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR39(CRS0R80),-; A1 , is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q91 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; Q95 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; and Q102 and Q104 are independently hydrogen, fluoro, chloro, methyl, or -CF3.
[0136] In one embodiment of compounds of Formula Hj, M13 is -NR39CH2- or -NR3M-(CH2)2-; An is -CII2- or -C(O)-, preferably -CH2-; Q91 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; Q95 is hydrogen, -CN, fluoro, ehloro. lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl. wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41 ; and Q102 and Q104 are independently hydrogen, fluoro, ehloro, lower alkyl, or fluoro substituted lower alkyl, preferably Q102 and Q10'1 are independently hydrogen, fluoro, ehloro, methyl, or -CF3, wherein R41 is as defined for Formula Ig.
[0137] In one embodiment of compounds of Formula Uj, Au is -CH2- or -C(O)-, preferably -CH2-; Q ' is aryl or heteroaryl, wherein aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R4', -NHR41, -NR41R41, -NR39C(O)R41, -NR19S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q91, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q95 is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NIIR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, fluoro, ehloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; Mn is a bond, -NR39-, -S-, -0-, -NR39CH2-, -NR39CII2CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, -C(O)NR39-, -S(O)2NR39-, -CH2NR39-, -CH(R40)NR39-, -NR39C(O)-, or -NR39S(O)2-; and Q102 and Q104 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44, provided, however, that at least one of Q102 and Q104 is hydrogen, fluoro, ehloro, lower alkyl or fluoro substituted lower alkyl, wherein R39, R40, R41. R42 and R44 are as defined for Formula II.
|0138] In one embodiment of compounds of Formula Hj, An is -CH2-; Q91 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy: Q95 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M]3 is -NR CH2-, -NR39CH2CH2-, or -NR39CH(R40)-; and Q102 and Q104 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that at least one of QI(P and Q104 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
[0139] In one embodiment, further to any of the embodiments of Formula Hj above, each occurrence of R41 is R42 as defined for Formula Ig,
[0140] IQ one embodiment, a compound of Formula II has a structure according to the followiπ sub-gcncπc structure, Formula Hk,
Figure imgf000071_0001
Formula Ilk, all salts, prodrugs, tautomers, and isomers thereof, wherein:
A,, is selected from the group consisting Of -CR19R20-, -C(O)-, -C(S)-, -S(O)-, and -S(O)2-; Q105 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR21, -OR23, -SR23, -C(O)R21, -C(S)R21, -S(O)R21, -S(O)2R23, -C(O)NHR23, -C(O)NR21R21, -C(S)NHR23, -C(S)NR21R21, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R21, -NR21C(O)R-', -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23. -NIIC(O)NHR21, -NR23C(O)NH2, -NR21C(O)NHR23, -NHC(O)NR23R23, -NR21C(O)NR23R23, -NHC(S)NHR21, -NR21C(S)NH2, -NR21C(S)NHR23, -NHC(S)NR23R23, -NR21C(S)NR21R21. -NIIS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR21R23, and -NR23S(O)^NR23R23;
Mi4, Ql ϋ l, and Q1 12 are as defined for Formula II; and R19, R20, R23, R24, and R25 are as defined for Formula Ib.
10141] In one embodiment of compounds of Formula Ilk, M14 is -(CR19R20)rNR2()-(CRl 9R20)s- or -(CR19R2VNR26C(O)-(CR19R20V, preferably -NR25-(CR 19R2V or -NR26C(O)-(CR19R20),-, more preferably -NR19CR80R80- or -NR39(CR80R80)2-, wherein R39 is hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, Ai2 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Q101 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alk\ l. fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23 and Q105 is hydrogen, -OR2\ -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23. Further to any of the above embodiments, Q1 12 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
[0142] In one embodiment of compounds of Formula Hk, M14 is -(CR19R20),-NR26-(CR19R:o)s- or -(CRI 9R20)ΓNR26C(O)-(CR19R20)S-, preferably -NR26-(CR19R20)s- or -NR26C(O)-(CR1V1V. more preferably -NR39CR80R80- or -NR39(CR80R80)2-, and A12 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, M14 is -(CR19R20)rNR26-(CR19R2V or
-(CR19R2VNR26C(O)-(CR19R20X-, preferably -NR26 -(CR19R20),- or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR39(CRis0R80)2-; An is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q101 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; and Q105 is hydrogen, -OR"" , -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23. In one embodiment, M14 is -(CRI 9R20),-NR26-(CR19R20)s- or -(CR19R20)rNR26C(O)-(CRl9R20)s-, preferably -NR26-(CR' 9R20X- or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR3g(CR8OR8O)2-; A12 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q101 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; Q105 is hydrogen, -OR23, -CN, fluoro, chloro. lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; and Q112 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
[0143] In one embodiment of compounds of Formula Ilk, M14 is -NR39CH2- or -NR19-(CH;):-; A17 is -CH2- or -C(O)-, preferably -CH2-; Q101 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41.; Q1"5 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy. cyeloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl. aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41 , -NR41R4', -OR41 and -S(O)2R41; and Q112 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R41 is as defined for Formula Ig.
[0144] In one embodiment of compounds of Formula Hk, A12 is -CH2- or -C(O)-, preferably -CH2-; Q101 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR"11, -S(O)R41, -S(O)2R4' , -NHR", -NR41R41, -NR39C(O)R41, -NR59S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q101, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2. -S(O)2NH2, -C(O)NH2, -OR41, -SR42, -NHR42, -NR42R42, -NR3yC(O)R42, -NR39S(O)2R''3, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl , and cycloalkylamino; Qm is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41. -NR39S(O)2R41, fluoro, chlυro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41, M14 is a bond, -NR1"-, -S-, -0-, -NR39CH2-. -NR39CH2CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, -C(O)NR19-, -S(O)2NR1'-, -CH2NR39-. -CH(R4O)NRV'-, -NR39C(O)-, or -NR39S(O)2-; and Q112 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44, wherein R39. R40, R41, R4: and R44 are as defined for Formula II.
[014Sj In one embodiment of compounds of Formula Uk, A12 is -CII2-; Q101 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q105 is hydrogen, -CN, fluoro, chloro. lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; Mi4 is -NR39CH2-, -NR39CH2CH2-, or -NR39CH(R4")-; and Q1 12 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy. [0146] In one embodiment, further to any of the embodiments of Formula Ilk above, each occurrence of R41 is R4" as defined for Formula Ig.
[0147) In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula Hm, "
Figure imgf000074_0001
Formula Hm, all salts, prodrugs, tautomers, and isomers thereof, wherein:
An is selected from the group consisting Of -CR19R20-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)2-,
-NR21-, and -O-;
Ql b is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR21, -OR23. -SR23, -C(O)R23. -C(S)R23. -S(O)R23, -S(O)2R23, -C(O)NHR21, -C(O)NR23R21, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R2', -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR21. -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NIIC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR23C(S)NR21R23, -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R23, and -NR23S(O)2NR23R23;
Mi5, Q1 ". and Q124 are as defined for Formula IT: and R19, R20, R21, R23, R24, and R25 are as defined for Formula Ib,
10148] In one embodiment of compounds of Formula Hm, M15 is -(CR19R20)rNR26-(CR|gR20),- or -(CRll)R20)rNR2(lC(O)-(CRlvR20)s-, preferably -NR26-(CR19R2O)S- or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR39(CR8OR80)2-, wherein R39 is hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen, In one embodiment, An is -CR19R20- or -C(O)-. preferably -CH2- or -C(O)-, In one embodiment, Q1 " is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)3R23 and Q1 15 is hydrogen,
-OR23, -CN, fluoro, chloro. lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, hcterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR21, -NR23R2', -OR23 and -S(O)2R23, Further to any of the above embodiments. Q124 is hydrogen, fluoro, chloro. lower alkyl or fluoro substituted lower alkyl.
(0149] In one embodiment of compounds of Formula Hm, M13- is -(CR19R20)t-NR2<)-(CR'9R20)i- or -(CR1V)1-NR26C(O)-(CR19R20),-, preferably -NR26-(CR19R20)4- or -NR26C(O)-(CR19R20),-. more preferably -NR39CR80R80- or -NR39(CR80R80)2-, and A13 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, M15 is -(CR19R20)rNR2o-(CR'9R20)s- or -(CR19R20VNR26C(O)-(CR19R20X-, preferably -NR26-(CR1 SR2O)S- or -NR26C(O)-(CR 19R2V, more preferably -NR39CR80R80- or -NR39(CR80R80),-; A1, is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q11 1 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; and Q1 15 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O),R23. In one embodiment, M15 is -(CR19R20)rNR26-(CR1<)R20)s- or -(CR19R20)t-NR26C(O)-(CR19R20)r, preferably -NR76-(CR'VV or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR39(CR80R80)2-, An is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q1" is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23, Q115 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R21. -OR23 and -S(O)2R23; and Q124 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
[0150] In one embodiment of compounds of Formula Ilm, Mn is -NR39CH2- or -NR19-(CH2)2-; An is -CH2- or -C(O)-, preferably -CH2-; Q1 " is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41. -NR41R41, -OR41 and -S(O)2R41; Q115 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR42, -NR42R42, -OR42 and -S(O)2R42; and Q124 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R41 is as defined for Formula Ig,
[0151] In one embodiment of compounds of Formula Hm, A13 is -CH2- or -C(O)-, preferably -CH2-; Q1 " is aryl or heteroaryl, wherein aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q11 1, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NH39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cyeloalkylamino; Q1 15 is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NIlR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41 , fluoro, chloro, lower alkyl. fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; M15 is a bond, -NR39-, -S-, -0-, -NR39CII2-, -NR39CII2CII2-, -NR39CH(R40)-, -SCH2-, -OCH2-, -C(O)NR39-, -S(O)2NR19-. -CH2NR39-, -CH(R40JNR3"-, -NR39C(O)-, or -NR30S(O)2-; and Q124 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44, wherein R39, R40, R41, R42 and R44 are as defined for Formula II.
[0152] In one embodiment of compounds of Formula Hm, An is -CH2-; Q " is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl. lower alkoxy, and fluoro substituted lower alkoxy; Q115 is hydrogen, -CN. fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy. or fluoro substituted lower alkoxy; Mn is -NR39CH2-, -NR39CHpCH2-, or -NR39CH(R40)-; and Q124 is hydrogen, fluoro. chloro. lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
[0153] In one embodiment, further to any of the embodiments of Formula Hm above, each occurrence of R41 is R42 as defined for Formula Ig. [0154] In one embodiment, a compound of Formula Il has a structure according to the following sub-generic structure, Formula Hn,
Figure imgf000077_0001
Formula . [In, all salts, prodrugs, tautomers, and isomers thereof, wherein:
A14 is selected from the group consisting Of -CR19R20-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)2-, -NR21-, and -0-;
Q125 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alky], optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25. -NHR2', -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR23R21, -C(S)NHR23, -C(S)NR23R2I -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR21C(O)R23, -NIIC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR23C(S)NR23R23, -NHS(O)2NHR", -NR23S(O)2NH2, -NR23S(O)2NHR23, -NlIS(O)2NR23R23, and -NR23S(O)2NR23R23;
M)6, Q121, and Q132 are as defined for Formula II; and
R19, R2", R21, R23, R24, and R25 are as defined for Formula Ib.
[0155] In one embodiment of compounds of Formula Hn, M16 is -(CR19R20)rNR:6-(CR19R2u)s- or -(CR19R21YNR26C(O)-(CR19R20V, preferably -NR26-(CRI9R2°V or -NR26C(O)-(CR19R20),-, more preferably -NR39CR8V0- or -NR39(CR80R80)2-, wherein R39 is hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment, Ai4 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Q121 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23 and Q125 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23. Further to any of the above embodiments, Qm is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
|0156] In one embodiment of compounds of Formula Hn, M16 is -(CR19R20)rNR26-(CR19R20)b- or -(CR19R20JrNR26C(O)-(CR 19R20X-, preferably -NR^-(CR19R2"),- or -NR25C(O)-(CR19R20),-, more preferably -NR39CR80R80- or -NR39(CRS0Rso)2-. and A14 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, M16 is -(CR1 V°),-NR26-(CR19R2O)S- or
-(CR19R2VNR26C(O)-(CR19R2V, preferably -NR26-(CR19R20)5- or -NR26C(O)-(CR19R20),-, more preferably -NR19CR80R80- or -NR39(CR80R80)2-; A14 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q1 ' is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR2\ -NR21R23, -OR23 and -S(O)7R23; and Q125 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, hctcrocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R21, -OR23 and -S(O)2R23. In one embodiment, M15 is -(CR19R20),-NR26-(CR19R20)s- or -(CRl9R20)rNRMC(O)-(CRigR;V, preferably -NR26-(CRI9RI0)s- or -NR26C(O)-(CR19R20),-, more preferably -NR39CR30R80- or -NR19(CR80R8l%-; A14 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q121 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R21, -OR21 and -S(O)2R23; Q125 is hydrogen, -OR23. -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR21 and -S(O)2R23; and Q132 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
[0157] In one embodiment of compounds of Formula Hn, Mi6 is -NR19CH2- or -NR19-(CH2)2-; A]4 is -CH2- or -C(O)-, preferably -CH2-; Q121 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR42, -NR42R42, -OR42 and -S(O)2R42; Q125 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; and QI3: is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl, wherein R41 is as defined for Formula Ig.
[0158] In one embodiment of compounds of Formula Hn, A14 is -CII2- or -C(O)-, preferably -CH2-; Q13' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R4'. -NIIR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of O'2', or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl. and cycloalkylamino; Q125 is hydrogen, -CN1 -OR41. -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, fluoro, chloro. lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl. fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; M16 is a bond, -NR19-, -S-, -0-, -NR39CH2-, -NR39CH2CH2-, -NR35CH(R40)-, -SCH2-, -OCH2-. -C(O)NR39-, -S(O)2NR39-, -CH2NR39-, -CH(R40)NR39-, -NR39C(O)-, or -NR39S(O)2-; and Qm is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44, wherein R39, R40, R41, R42 and R44 are as defined for Formula II.
[0159] In one embodiment of compounds of Formula Hn, A14 is -CH2-; Q121 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q125 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; Mi6 is -NR39CH2-, -NR39CH2CH2-, or -NR39CH(R40)-; and Q132 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
|0160) In one embodiment, further to any of the embodiments of Formula Hn above, each occurrence of R41 is R4' as defined for Formula Ig.
[0161] In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula Ho,
Figure imgf000080_0001
Foπnula Ho, all salts, prodrugs, tautomers, and isomers thereof, wherein:
A15 is selected from the group consisting Of -CR19R20-. -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)2-,
-NR31-, and -O-;
Q115 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25,
Figure imgf000080_0002
-OR23, -SR23, -C(O)R21, -C(S)R21, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR23R21, -C(S)NIIR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR21R23, -NHC(O)R23, -NR21C(O)R21, -NHC(S)R23, -NR23C(S)R21, -NHS(O)2R21. -NR23S(O)2R23, -NIIC(O)NHR21,
-NR21C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR21, -NHC(S)NR23R23, -NR23C -NHS(O)2NHR23, -NR23S(O)2NII2, -NR21S(O)2NHR23, -NHS(O)2NR21R23, and -NR23S(O)2NR23R23; Mn, Q111, and Q144 are as defined for Foπnula II; and
R19, R20, R21, R23, R24, and R25 are as defined for Formula Ib.
[0162] In one embodiment of compounds of Formula Ho, M17 is -(CR19R20)rNR26-(CRl9R2V or -(CR1V)1-NR26C(OXCR19R20),-, preferably -NR26-(CR19R20)s- or -NR26C(O)-(CR19R20),-, more preferably -NR19CR80R80- or -NR39(CR80R80)2-, wherein R39 is hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen. In one embodiment. A15 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Q131 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23 and Q115 is hydrogen, -OR21, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alky], -NHR23, -NR23R23, -OR23 and -S(O)2R23. Further to any of the above embodiments, Q144 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl. [0163] In one embodiment of compounds of Formula Ho, M 7 is -(CR19RM)rNR26-(CRl 9R:V or -(CR1V0X-NR26C(O)-(CR11V0X-, preferably -NR26-(CR' V°)S- or -NR26C(O)-(CR19R20),-, more preferably -NR39CR8V1-, -NR39(CR8V°)2~. and A15 is -CR1V0- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Mn is -(CR1 Vϋ)rNR26-(CR' V0),- or
-(CR1V)1-NR26C(O)-(CR1V0),-, preferably -NR:6-(CR! V°)S- or -NR26C(O)-(CR1V0),-, more preferably -NR19CR80R*0-, -NR39(CR8V°)2-; A15 is -CR1V0- or -C(O)-, preferably -CH2- or -C(O)-; Q™ is optionally substituted lower alkyl, aryl or heteroaryl, w herein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR21, -NR2V. -OR2' and -S(O)2R"; and Qn< is hydrogen,
Figure imgf000081_0001
-CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR2V\ -OR11 and -S(O)2R23. In one embodiment, M17 is -(CR'VVNVHCR'VX- or -(CR1 V0X-NR26C(O)-(CR1 V0),-, preferably -NR26-(CR' V0X- or -NR26C(O)-(CR1V0X-, more preferably -NR39CR80R80-, -NR'9(CR8Vϋ)2-; Ai5 is -CR1V0- or -C(O)-, preferably -CH2- ur -C(O)-; Q111 is optionally substituted lower alkyl. aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR2V3, -OR23 and -S(O)2R21, Q135 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl. fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; and Q144 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl.
[0164] In one embodiment of compounds of Formula Ho, Mi7 is -NR19CH2- or -NR39-(CH2)2-; Ai5 is -CH2- or -C(O)-, preferably -CH2-; Q'3' is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR42, -NR42R42, -OR42 and -S(O)2R12; Q115 is hydrogen. -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl. fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; and Q!44 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, wherein R41 is as defined for Formula Ig. |01651 In oπe embodiment of compounds of Formula Ho, Ai5 is -CH3- or -C(O)-, preferably -CH2-; QH1 is aryl or heteroaryl, wherein aryl or hcteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR19S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl. heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q131, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH;., -C(O)NH2. -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR19S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q135 is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR19S(O)2R4', fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41 ; M, , is a bond, -NR39-, -S-, -0-, -NR19CH2-, -NR39CH2CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, -C(O)NR39-, -S(O)2NR"-. -CH2NR39-, -CH(R40)NR39-, -NR39C(O)-, or -NR39S(O)2-; and Q144 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44, wherein R39, R40, R41, R4: and R44 are as defined for Formula II.
[Ol 66] In one embodiment of compounds of Formula Ho, Ais is -CH2-; Qn i is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q135 is hydrogen, -CN, fluoro. chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M15 is -NR19CH2-, -NR39CH2CII2-, or -NR39CH(R40)-; and Q144 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
|0167] In one embodiment, further to any of the embodiments of Formula Ho above, each occurrence of R41 is R42 as defined for Formula Ig.
10168] In one embodiment, a compound of Formula II has a structure according to the following sub-generic structure, Formula lip,
Figure imgf000083_0001
Formula Up, all salts, prodrugs, tautomers, and isomers thereof, wherein:
A16 is selected from the group consisling Of -CR19R20-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)2-,
-NR21-, and -0-;
Q145 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, - NHC(S)NH2, -NHS(O)2NH,, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR23, -OR21, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR21R21, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR2^C(O)R23, - NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR21C(O)NR23R23, -NIIC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NIIC(S)NR23R23. -NR21C(S)NR21R2', -NIIS(O)2NHR23, -NR23S(O)2NH2, -NR21S(O)2NHR23, -NHS(O)2NR23R23, and -NR23S(O)2NR23R23;
M13, QH1, and Q1" are as defined for Formula II; and R19, R20, R21, R21, R24, and R25 are as defined for Formula Ib;
provided, however, that the compound is not
Figure imgf000083_0002
H or
Figure imgf000083_0003
10169) In one embodiment of compounds of Formula Up, M,s is -(CR19R20)rNR2t)-(CR19R20)s- or -(CR19R2VNR26C(O)-(CR19R20V, preferably -NR26-(CR|gR20)r or -NR26C(O)-(CR10R20),-, more preferably -NR19CR80R80- or -NRM(CR80RS0)r, wherein R39 is hydrogen or lower alkyl and R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl, preferably hydrogen, In one embodiment, A1, is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Q141 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR13R23, -OR23 and -S(O)2R21 and Q143 is hydrogen, -0R:\ -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23. Further to any of the abo\e embodiments, Q152 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl.
|0170] In one embodiment of compounds of Formula Hp, M18 is -(CR1V0)rNR26~(CR19R20)s- or -(CR19R2VNR26C(O)-(CR19R2V, preferably -NR26-(CR19R2O)S- or -NR26C(O)-(CR19R2V, more preferably -NR39CR80R80- or -NR39(CR80R)2-, and A,6 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-. In one embodiment, Mj8 is -(CRI9R20)rNR26-(CRllJR20)i- or
-(CR19R2U),-NR26C(O)-(CR19R2V, preferably -NR26-(CR19R20)s- or -NR26C(O)-(CR19R20),-, more preferably -NR39CR80R8"- or -NR39(CR80RS0)2-; A16 is -CR19R20- or -C(O)-, preferably -CH2- or -C(O)-; Q141 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR21 and -S(O)2R2'; and Q145 is hydrogen, -0R/3, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl. aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23. -NR23R23, -OR23 and -S(O)2R23. In one embodiment, M18 is -(CR! 9R20)rNR25-(CR19R20)r or -(CR19R2VNR26C(O)-(CR19R20X-, preferably -NR26-(CRl9R20)s- or -NR26C(O)-(CR19R20).,-, more preferably -NR39CR80R80- or -NRw(CR8V0)2-; A16 is -CR10R20- or -C(O)-, preferably -CH2- or -C(O)-; Q141 is optionally substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; Q14' is hydrogen, -OR23, -CN, fluoro. chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocyeloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; and Q1'2 is hydrogen, fluoro, chloro, lower alkyl. or fluoro substituted lower alkyl.
[0171 ] In one embodiment of compounds of Formula Up. M18 is -NR39CH2- or -NR39-(CH2)2-; A16 is -CH2- or -C(O)-, preferably -CH2-; Q141 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41; QH5 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy. fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or hctcroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR4' and -S(O)2R41; and Q152 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl, wherein R4' is as defined for Formula Ig.
[0172] In one embodiment of compounds of Formula Up, A]6 is -CH2- or -C(O)-, preferably -CH2-; Q141 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino. cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q 4 , or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2. -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; Q145 is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)1R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; M18 is a bond, -NR19-, -S-, -0-, -NR39CH2-, -NR19CH2CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, -C(O)NR1'-, -S(O)2NR39-, -CH2NR39-, -CH(R4U)NR39-. -NR39C(O)-, or -NR39S(O)2-; and Q152 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44, wherein R19, R40, R41, R4: and R44 are as defined for Formula TT.
[0173] In one embodiment of compounds of Formula Up, Ais is -CH2-; Q141 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro. chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy; Q145 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; M18 is -NR CH2-, -NR19CH2CH2-, or -NR111CH(R40)-; and Q152 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy. |0174] In one embodiment, further to any of the embodiments of Formula Up above, each occurrence of R41 is R42 as defined for Formula Ig.
[0175] In one embodiment of compounds of Formula Up, M18 is -NH-CH2- or -NH-(CH^)2-, preferably -NH-CH2-; A]6 is -CH2- or -C(O)-, preferably -CH2-; Q'41 is aiyl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, and heterocyc Io alkyl; Q145 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably hydrogen, -CN, or chloro; and Q152 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl. preferably hydrogen or chloro, more preferably chloro.
J0176] In one embodiment, the compound of Formula 111 is selected from the group consisting of
[4-Chloro-5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-ben7yl)-amine
(P-0156),
[4-Ethyl-5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine (P-0162),
(4-Fluoro-benzyl)-[4-methyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine
(P-0163),
^-Chloro-S-ClH-pyrrolotZ.S-bjpyridin-S-ylmethylJ-thiazol-l-ylj-pyridin-S-ylmetliyl-aminc
(P-Ol 64),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-2-ylmethyl-amine
(P-Ol 67),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amine
(P-0168),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2-ylmethyl)- amine (P-0171),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(l ,5-dimethyl-lH-pyrazol-3- ylmethyl)-amine (P-0172),
[4-Chloro-5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl-pyridin-3- ylmethyl)-aminc (P-Ol 73),
[4-Chloro-5-(lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-2H-pyrazol-3- ylmethyl)-amine(P-0175),
[2-(4-Fluoro-benzylamino)-thiazol-5-yl]-(lH-pyrrolo[2,3-b]pyndin-3-yl)-methanone (P-0177),
{2-[(4-Chloro-benzyl)-mcthyl-amino]-thiazol-5-yl}-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methanone
(P-0178),
[4-Chloro-5-(5-chloro-lH-pyrrolo[253-b]pyridin-3-ylmcthyl)-thiazol-2-yl]-thia/ol-2-ylmethyl- amine (P-0189), [4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylraethyl)-thiazol-2-yl]-(6-methoxy-p\ridin-3- ylmethyl)-amine (P-0190),
Benzyl-[4-chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine (P-0192), [4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-metho.κy-benzyl)- amine (P-0193),
(4-Chloro-benzyl)-[4-chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]- amine (P-Ol 94),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoiO-benzyl)- amine (P-0195),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5- ylmethyl)-amine (P-0196),
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H- imidazol-4-ylmethyl)-amine (P-0197),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-lhiazol-2-yl]-(2-ethyl-2H-pyrazol-3- ylmethyl)-amine (P-0198),
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-ylJ-(6-methoxy-pyridin-2- ylmethyl)-amine (P-0199),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-4- ylmethyl)-aminc (P-0200),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-thiazol-4- ylmethyl)-amine (P-0201),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-methyl-thiazol-5- ylmcthyl)-amine (P-0202),
[4-Chloro-5-(5-chloro-l II-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-chloro-pyridin-2- yl methyl) -amine (P-O 203),
[4-Chloro-5-(lH-pyrrolo[2,3-blpyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5- ylmcthyl)-amine (P-0204),
[4-Chloro-5-( lH-pyrτolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-imidazol- 4-ylmethyl)-amine (P-0205),
[4-Chloro-5-(lH-pyirolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2-ylmethyl)- amine (P-0206),
[4-Chloro-5-(lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3-ylmcthyl)- amine (P-0207),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-ylJ-(4,5-dimethyl-thiophen-2- ylmethyl)-amine (P-0208), [4-Chloro-5-( lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-thiophen-3- ylmethyl)-amine (P-0209),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thia2ol-2-yl]-(5-fluoro-pyπdin-3- ylmethyl)-amine (P-0231),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-y]]-pyridin-3-ylmethyl- amine (P-0236),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl- amine (P-0237),
[4-Ch]oro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-ylJ-(3-chloro-pyridin-4- ylmethyl)-aminc (P-0238),
^-Chloro-S-CS-chloro-lH-pyrrolop^-bJpyridin^-ylmethyO-thiazoW-ylJ^l -ethyl-lH-pyrazol^- ylmethyl)-amine (P-0239),
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2- ylmethyl)-amme (P-0240),
[4-Ch]oro-5-(5-chloro-lH-pyrrolo[2,3-b]ρyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3- ylmethyl)-amine (P-0241),
[4-Chloro-5-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl- pyridin-3-ylmethy])-aminc (P-0242),
[4-Chloro-5-(5-ch]oro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-6-fluoro- benzyl)-amine (P-0243),
[4-Chloro-5-(5-chloro-lII-pyiτolo[2,3-b]pyridiπ-3-ylnieth.yl)-thiazol-2-yl]-phenethyl -amine (P-0244),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-y]methyl)-thiazol-2-yl]-(2,4-difluoro-benzyl)- amine (P-024S),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-fluoro-benzy])- amine (P-0246),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methoxy-pyridin-3- ylmethyl)-amine (P-0247),
(2-Chloro-benzyl)-[4-ch]oro-5-(5-chloro-lH-pyrrulo[2,3-b]p>τidin-3-ylmethyl)-thiazo]-2-yl]- amine (P-0248),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]ρyridin-3-ylmethyl)-thiazol-2-yl]-(2 -methyl-benzyl)- amine (P-0249),
[4-Chloro-5-C5-chloro-lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-4-fluoiO- benzyl)-amine (P-0250),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)4hiazol-2-yl]-(3-fluoro-pyridin-2- ylmcthyl)-amine (P-0251), [4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmt:thyl)-thiazol-2-yl]-(6-morpholin-4-yl- pyridin-2-ylmethyl)-amine (P-0252),
[4-Chlϋro-5-(5-chloro-lH-pyrrolof2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3.5-diϋhlϋro-p>τidin-4- ylmethyl)-amme (P-0253),
[4-Chloro-5-(5-chloro-lII-pyπOlo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-trifluoromethyl- benzyl)-amine (P-0254).
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-thiazol-2-yI]-(6-methyl-pyridin-2- ylmethyl)-amine (P-0255),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-atnine
(P-0290) , and all salts, prodrugs, tautomers, and isomers thereof.
10177] In one embodiment, a compound of Formula I has a structure according to the following sub-generic structure, Formula III,
Figure imgf000089_0001
Formula III, all salts, prodrugs, tautomers, and isomers thereof, wherein:
L4 is -CH2-, -CH2CH2-, -CH(R40)-, -C(O)-, or -C(O)NH-;
R81 is selected from the group consisting of hydrogen, -OR41, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR41 and -S(O)2R41;
RH1 is selected from the group consisting of hydrogen, CV3 alkyl, fluoro substituted C2.?alkyl, OH, C1.3 alkoxy, and fluoro substituted Cu alkoxy;
R83 is heterocycloalkyl, heteroaryl, or
Figure imgf000089_0002
^ _ jn which ? indicates the attachment point of R^ to L4 of Formula III, wherein heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NIIR41, -NR41R41. -OR41 and -S(O)2R41;
RQZ, R1", Rt)4, R95, and R96 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NHS(O)2R41, -NHC(O)R41, -NIIR41, -NR41R41, -OR41 and -S(O)2R41; and
R and R41 are as defined for Formula Ig;
Figure imgf000090_0001
Figure imgf000091_0001
[0178] In one embodiment of compounds of Formula III, L4 is -CH2-, -CH2CH2-, -CH(CH3)- or -C(O)-, R81 is hydrogen, fiuoro, chloro, -CN, lower alkyl, fluoro substituted lower alkyl, lower
alkoxy, or fluoro substituted lower alkoxy, R82 is hydrogen, R83 is
Figure imgf000091_0002
f wherein R9*,
R91, R94, R93. and R96 are independently hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that when RM is fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, at least one of R92, R93, R9>, and R96 is fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
[0179] In one embodiment of compounds of Formula III, L4 is -CH2-, -CH2CH2-, -CH(CH3)- or -C(O)-, R81 is hydrogen, fluoro, chloro, -CN, methyl, or methoxy, preferably hydrogen, chloro,
-CN, or methyl, R8' is hydrogen, R" is
Figure imgf000091_0003
, wherein R92, R9\ R94, R9\ and R96 are independently hydrogen, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy, preferably hydrogen, chloro, methyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy, provided, however, that when R94 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy, at least one of R9:. R*3, R93, and R96 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
[0180] In one embodiment of compounds of Formula III, L4 is -CIL-, R81 is fluoro, chloro, -CN.
methyl, or methoxy, preferably chloro, -CN. or methyl, R82 is hydrogen, R83 is
Figure imgf000092_0001
wherein R94 is hydrogen and R92, R93, R95, and R96 are independently hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy or trifluoromethoxy.
10181] In one embodiment of compounds of Formula III, L4 is -CH2-, -CH2CH2-, -C(O)-, or -CII(CII3)-, preferably -CII2- or -C(O)-, R8' is hydrogen, flouro, R82 is hydrogen, R83 is
, wherein R92 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, methyl, or trifluoromethyl, and R93, R91, R95. and R96 are independently hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, or trifluoromethoxy, preferably hydrogen or fluoro. In one embodiment, L4 is -CH2-, -C(O)-, or -CH(CH3)-, R8' is hydrogen, R82 is hydrogen, R92 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, methyl, or trifluoromethyl, and R93, R94, R95, and R96 are hydrogen. In one embodiment, L4 is -CH2-, -C(O)-, or -CH(CH3)-, RS1 is hydrogen, R82 is hydrogen, R92 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, methyl, or trifluoromethyl, R 4, R \ and R are hydrogen, and R93 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, trifluoromethyl or methoxy, more preferably fluoro. In one embodiment, L4 is -CH2-, -C(O)-, or -CH(CH3)-, R81 is hydrogen, R82 is hydrogen, R92 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, methyl, or trifluoromethyl, R93, R95, and R96 are hydrogen, and R94 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, methyl or trifluoromethyl, more preferably fluoro. In one embodiment, L4 is -ClLCIL- or -C(O)-, R81 is hydrogen, R82 is hydrogen, R92, R95, and R96 are hydrogen, R93 is hydrogen, fluoro. chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, or trifluoromethoxy, more preferably fluoro, chloro, trifluoromethyl or methoxy, and R94 is hydrogen, fluoro. or chloro, provided, however, that when L4 is -C(O)- and R94 is fluoro or chloro, R*3 is not hydrogen, In one embodiment, L4 is -CH2CH2-, R81 is hydrogen. R82 is hydrogen, R92, R"4, R*\ and R"" are hydrogen, and R9 * is hydrogen, fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably hydrogen or fluoro. In one embodiment, L4 is -C(O)-, Rni is hydrogen, R82 is hydrogen, R92, R95, and R96 are hydrogen, R93 is fluoro, chloro, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, difluoromethoxy, or trifluoromethoxy, preferably fluoro, chloro, trifluoromethyl or methoxy, and R94 is hydrogen, fluoro, or chloro.
[0182] In one embodiment of compounds of Formula III, R83 is pyrrolidine, morpholine. pyridine, pyrimidine, pyrazine, pyrazole, isoxazole, imidazol, or benzimidazole, wherein R8' is optionally substituted with one or more substituents independently selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NHR41, -NR41R41, -OR41 and -S(O)2R41, preferably wherein R83 is optionally substituted with 1 or 2 substituents independently selected from fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, or cycloalkylamino, more preferably Ωuoro, chloro, methyl, trifluoromethyl, methoxy or morpholine.
[0183] In one embodiment of compounds of Formula III, L4 is -CH2-, -CH2CH2-, -CH(CH1)- or -C(O)-, preferably -CH2-, -CH2CH2-, or -C(O)-, R81 is hydrogen, fluoro, chloro, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, preferably hydrogen, chloro, methyl or -CN, R82 is hydrogen, and R83 is pyrrolidine, morpholine, pyridine, pyrimidine, pyrazine, pyrazole, isoxazole, imidazole, or benzimidazole, wherein R83 is optionally substituted with 1 or 2 substituents independently selected from fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, or cycloalkylamino, preferably fluoro, chloro, methyl, trifluoromethyl, methoxy or morpholine.
[0184] In one embodiment of compounds of Formula III, the compound is selected from the group consisting of:
Pyridin-3-ylmethyl-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p\τidin-2-yl]-amine (P-0094), (5-Methyl-isoxazol-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0095),
(2-Pyrrolidin-l -yl-ethyl)-[5-( l H-p>τrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0096), [l -(4-Methanesulfonyl-phenyl)-ethyl]-[5-(lH-pyrrolo[2,3-b]pyπdin-3-ylmcthyl)-pyridin-2-yl]- amine (P-0097),
(2-Morpholin-4-yl-ethyl)-[5-(lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0099), 3,4-Dichloro-N-[5-(lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide (P-OlOO), 2-Chloro-4-fluoro-N-[5-(l H-pyrrolo[2!3-b]pyπdin-3-ylmethyl)-pyndm-2->l]-benzdmide (P-OlOI)
2,5-Dimeth>l-2H-pyrazole-3-cdrboxylic acid [5-(lH-pyττolo[2.3-b]pyiidm-3-ylmethyl)-pyridin-2- yl]-amide (P-0102), l hiophene-2-carbox>hc acid [5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyπdin-2-yl]-amide
(P-0103),
2-Methoxy-N-[5-(l H-p>rrolo[2,3-b]pyπdin-3-ylmethyl)-pyridin-2-yl]-isonicotinamidc (P-0104)
N-[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyπdin-2-yl]-isonicotinamide (P-0105)
Pyrazine-2-carboxylic acid [5-( lH-pyrrolo[2,3-b]pyπdm-3-ylmethyl)-pyπdm-2-yl] -amide
(P-0106),
Pyπdme-2-carboxylic acid [5-(l H-pyrrolo[2,3-b]pyndm-3-ylmethyl)-pyridin-2-yl]-amide
(P-0107),
6-Methyl-N-[5-( lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-pyridm-2-yl]-nicotindmide (P-0108),
4-Fluoro-3-methyl-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyπdin-2-yl]-benzamidc
(P-Ol 09),
5-Mcthyl-pyrazme-2-carboxylic acid [5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyπdm-2-yl]- amide (P-OIlO),
3-Chloro-N-[5-(lH-pyrrolo[2,3-b]pyπdin-3-ylmethyl)-pyndin-2-yl]-bcnzamide (P-OlI l),
4-Fluoro-N-[5-(lH-pyπ"olo[2,3-b]pyπdm-3-ylmethyl)-pyridm-2-yl]-3-tπfluoromethyl-benzamide
(P-Ol 12),
N-[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridm-2-yl]-3-tπfluoromethoxy-benzamide
(P-Ol 13),
N-[5-(l H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridm-2-yl]-3-trifluoromethyl-benzamide (P-Ol 14),
3-Chloro-4-fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyπdin-2-yl]-benzamide (P-0115),
3,4-Difluoro-N-[5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyπdin-2-yl]-benzamide (P-0116),
2-Chloro-N-[5-(lH-pyπolo[2,3-b]pyπdm-3-ylmethyl)-pyridin-2-yl]-benzamide (P-0117),
5-riuoro-2-methyl-N-[5-(l H-pyrrolo[2,3-b]pyπdm-3-ylmethyl)-pyπdin-2-yl]-benzamide
(P-Ol 18),
2-Fluoro-N-[5-(l H-pyπ"olo[2,3-b]pyridm-3-ylmethyl)-pyπdin-2-yl]-benzamide (P-Ol 19),
3-Methoxy-N-[5-(lH-pyrrolo[2,3-b]pyπdm-3-ylmethyl)-pyπdm-2-yl]-benzamide (P-0120),
3-Fluoro-N-[5-(l H-pyrrolo[2>3-b]pyπdm-3-ylmethyl)-pyridin-2-yl]-benzamide (P-0121),
3-Methyl-N-[5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyπdm-2-yl]-benzamide (P-0122),
2-Chloro-N-[5-(lH-pyrrolo[2,3-b]pyπdin-3-ylmethyl)-pyridin-2-yl]-isonicotinamidc (P-0123),
((R)-l -Phenyl-ethyl)-[5-(lH-pyrrolo[2,3-b]pyπdm-3-ylmethyl)-pyπdin-2-yl]-amine (P-0125),
(3-Morpholm-4-yl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyπdin-3-ylmeth>l)-pyridm-2-yl]-amine
(P-0126),
[l -(2-Fluoro-pheiiyl)-ethyl]-[5-(lH-pynolo[2,3-b]p>ridm-3-ylmethyl)-pyridin-2-yl]-amme (P-0127),
[2-(3-Fluoro-phenyl)-ethyl]-[5-(lH-pyπ"olo[2,3-b]pyridin-3-ylmeth) l)-pyπdin-2-yl]-amme
(P-0128),
(3-ChIoro-benz>l)-[5-(lH-pyrrolo[2,3-b]pyπdm-3-ylmethyl)-p>πdm-2-yl]-amme (P-0129),
(l-Meth>l-lH-imidazol-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyπdm-3-vlmeth>l)-pyπdm-2-vl]- amine (P-0130),
(l ,5-DimethyI-l H-pyrazol-3-ylmethyl)-[5-(l H-pyrrolo[2 3-b]ρyπdin-3-ylmethyl)-p>πdin-2-yl]- amine (P-0131),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyπdm-3-ylmethyl)-pyndm-2-yl]-(6-tπfluoromethyl-pyπdin-3- ylmethyl)-amme (P-0181),
[5-(l H-PyrroIo[2,3-b]pyπdm-3-ylmethyl)-pyπdm-2-yl]-(6-tπfluoromethyl-pyπdm-3-ylmethyl)- amine (P-0182),
(3-Chloro-pyπdin-4-ylmethy])-[5-( lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyridin-2-yl]-amine
(P-0183),
(2-ChIoro-6-fluoro-bcnzyl)-[5-(lH-pyrrolo[2,3-b]pyπdin-3-ylmethyl)-pyridin-2-yl]-amme
(P-0210),
Phenethyl-[5-(lH-pyπOlo[2,3-b]pyπdin-3-ylmethyl)-pyridin-2-yl]-amme (P-0211),
(2 4-Difluoro-ben7yl)-[5-(l H-pyπolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0212),
(2-FIuoro-benzyI)-[5-(lH-pyrrolo[2,3-b]pyndm-3-ylmethyl)-pyπdin-2-yl]-aminc (P-0213),
(3-Bromo-pyπdm-4-ylmethyl)-[5-(lH-pyrrolor2,3-b]pyridin-3-ylmethyl)-pyπdin-2-yl] -amine
(P-0214),
(2-Methoxy-pyπdin-3-ylmethyl)-[5-(lII-pyrrolo[2,3-b]pyπdm-3-ylmethyl)-pyπdiπ-2-yl]-amme
(P-0215),
(2-Chloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyπdm-3-ylmethyl)-pyπdin-2-yl]-amme (P-0216),
(2-Meth>]-benzyl)-[5-(lH-pyπolo[2,3-b]pyridin-3-ylmethyl)-pyπdm-2-yl]-dmme (P-0217),
(l -Meth>l-l II-benzoimidazol-2-ylmethyl)-[5-(lII-pyrrolo[2,3-b]pyπdm-3-ylmcthy])-pyπdm-2- yl]-amme (P-0218),
(6-Methoxy-pyπdin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyπdin-2-yl]-amine
(P-0219),
( l H-Bcnzoimidazol-2-ylmethyl)-[5-(iπ-p>iτolo[2,3-b]pyπdin-3-ylmethyl)-pyπdin-2-yl]-amine
(P-0220).
(2-ChIoro-4-fluoro-benzyl)-[5-(lH-pyπ"olo[2,3-b]pyridm-3-ylmethyl)-pyridin-2-yl]-amine
(P-0221),
(5-Methoxy-pyπdin-3-yImcthyl)-[5-(lH-pyrrolo[2,3-b]pyπdin-3-ylmcthy])-pyπdin-2-yl]-ammc
(P-0222),
(3-FIuoro-pyndin-4-^Imethyl)-[5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyridin-2-yl]-amme (P-0223),
(6-Methoxy-pyπdin-2-ylmethyl)-[5-(l H-pyiτolo[2,3-b]pyπdin-3-ylmeth>l)-pyπdin-2-ylJ-ammc
(P-0224).
(4-Fluoro-2 -tπ fluoromethyl-benzyl)-[5 -( 1 H-pyrrolo[2,3 -b]pyπdin-3 -> lmethy l)-pyπdm-2-yl] - amine (P-0225),
[5-(l H-Pyπ olo[2,3-b]pyπdin-3-ylmethyl)-pyridin-2-yl]-(2-tπfluoromethyl-bcnzyl)-ammc
(P-0226),
(3.5-Dichloro-pyndin-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyπdin-3-ylmethyl)-pyπdm-2-yl]-amine
(P-0227),
(6-Moφholin-4-yl-pyπdin-2-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyndin-3-ylmethyl)-pyπdin-2-yl]- amine (P-0228),
(3-Fluoro-pyπdin-2-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyπdm-3-ylmethyl)-pyπdiπ-2-yl] -amine
(P-0229),
(5-Fluoro-pyridin-3-ylmethyl)-[5-(l H-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyπdin-2-yl] -amine
(P-0230),
(3-Chloro-pyridin-4-ylmethyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyπdin-3-ylmethyl)-pyridin-2->l]- amine (P-0235),
3-{6-[(3-Chloro-p>τidm-4-ylmethyl)-amino]-pyridm-3-ylmethyl}-l H-p>rrolo[2,3-b]pyπdine-5- carbomtπle (P-O 256),
3-[6-(4-Chloro-benzylamino)-pyπdiπ-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitπle
(P-02S7),
Propane-1 -sulfonic acid (2,4-difluoro-3- {[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2- ylamino] -methyl } -phenyl)-amide (P-0258) ,
Propane-1 -sulfonic acid (3-{ [5-(5-chloro-lH-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyπdin-2- ylammo]-methyl}-2,4-difluoro-phenyl)-amidc (P-0259),
3-[6-(4- I πfluoromethyl-benzylammo)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5- carbomtπle (P-0269),
[5-(5-Chloro-lH-pyrτolo[2,3-b]pyπdin-3-yliτiethyl)-pyπdin-2-yl]-(2-fluoro-benzyl)-amine
(P-0270),
3-[6-(2-Fluoro-benz\lamino)-pyπdm-3-ylmethyl]-lH-p}'rrolo[2,3-b]pyridine-5-carbonitπle
(P-0271),
(2-Fluoro-benzyl)-[5-C5-methyl-l H-pyπo]o[2,3-b]pyridm-3-ylmethyl)-pyπdin-2-yl]-amine
(P-0272),
3-{6-[(6-Trifluoromethyl-pyτidin-3-ylmethyl)-amino]-pyπdm-3-ylmethyl}-lH-pyrrolo[2,3- b]pyπdme-5-carbonitπlc (P-0273),
3-[6-(2-Tiifluoromethyl-ben7ylamino)-pyπdin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyπdine-5- carbonitrile (P-0274),
[5-(5-Chloro-lH-p>τrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-beπzyl)- amine (P-0275),
[5-(5-Methyl-lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)- amine (P-0276),
3-[6-(2,6-Difluoro-benzylamino)-pyridin-3-ylmethyl]-1 H-p>τrolo[2,3-b]pyridine-5-carbonitrilc
(P-0277),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,6-difluoro-benzyl)-amine
(P-0278),
(2-Chloro-benzyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-y]]-aminc
(P-0279),
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0280),
3-[6-(2-Chloro-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-bJpyridine-5-carbonitrile
(P-0281),
(6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2- yl] -amine (P-0282),
[5-(5-Chloro-1 H-ρyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3- ylmcthyl)-amine (P-0283),
3-{6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-lH-pyiτolo[2,3-b]pyridine-5- carbonitrile (P-0284),
(2-Methoxy-pyridin-3-ylmethyl)-[5-(5-mcthyl-lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-pyridin-2- yl] -amine (P-0285),
[5 -(5 -Chloro- 1 H-pyrrolo [2 ,3 -b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2 -methoxy-pyridin-3 - ylmethyl)-amine (P-0286),
3-{6-[(2-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl} -lH-pyrrolo[2,3-b]pyridine-5- carbonitrile (P-0287),
(2-Ethoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0288),
(2,5-Difluoro-benzyl)-[5-(lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-aminc (P-0296),
(2,5-Difluoro-benzyl)-[5-(5-mcthyl-lH-pyiTolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl] -amine
(P-0297),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,5-difluoro-benzyl)-amine
(P-0298),
3-[6-(2,5-Difluoro-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile
(P-0299),
3-[6-(2-TrifluoiOmethoxy-benzylamino)-pyridin-3-ylπiethyl]-lH-pyrrolo[2,3-b]pyridiαe-5- carbomtrile (P-0321),
[5-(lH-P>τrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trilluoromethoxy-benzyl)-amine
(P-0322),
3-[6-(2-Ethoxy-ben7ylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridinc-5-carbonitriIe
(P-0323),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-nuoro-pyridin-3-ylmethyl)- amine (P-0324),
[5-(5-Fluoro-lII-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoroincthyl-benzyI)- amine (P-0325),
[5-(5-Methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridiπ-2-yl]-(2-trifluoromethyl-benzyl)- amine (P-0326),
(2-Chloro-bcnzyl)-[5-(5-fluoro-lH-pyrrolϋ[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0327),
(2-Chloro-benzyl)-[5-(5-methoxy-lH-pyrrolo[2,3-bJp>τidin-3-ylmethyl)-pyridin-2-yl] -amine
(P-0328),
(2,5-Difluoro-bcnzyl)-[5-(5-fluoτo-l H-pyrτolo[2,3-b]pyτidin-3-ylmethyl)-pyridin-2-ylJ-aminc
(P-0329),
(2,5-Difluoro-benzyl)-[5-(5-methoxy-lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyridin-2-y]]-amine
(P-0330),
[5-(5-Fluoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)- amine (P-0331),
(6-Methoxy-pyridin-3-ylmethyl)-[5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2- yl]-amine (P-0332),
(2,6-Difluoro-benzyl)-[5-(5-fluoro-lII-pyiτolo[2,3-b]pyridin-3-ylmethyI)-pyridin-2-yl]-amine
(P-0333),
(2,6-Difluoro-benzyl)-[5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-amine
(P-0334),
(2-Methoxy-bcnzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0336),
3-[6-(2-Methoxy-benzy]amino)-pyridin-3-ylmcthyl]-lII-pyrrolo[2,3-b]pyridine-5-carbonitrile
(P-0337),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-difluoromethoxy-benzyl)- amine (P-0338),
3-[6-(2-Difluoromethoxy-benzylamino)-pyridin-3-ylmcthyl]-lII-pyπolo[2,3-b]pyridinc-5- carbonitrile (P-0339),
(2)6-Difluoro-benzyl)-[5-(lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]-amine (P-0340),
(2,6-Difluoro-benzyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0341),
(2.4-Dichloro-ben2yl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-aminc (P-0342),
(3-Fluoro-benzyl)-[5-(lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0343),
(2-Fluoro-4-trifluoromethyl-benzyl)-[5-(lH-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylJ- amine (P-0344),
(4-Ch]oro-2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyπdin-2-yl]-arπine
(P-0345),
(3-Fluoro-5-triΩuoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0346),
(2-Morpholin-4-yl-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0347),
(4-Chloro-3-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0348),
(2-Chloro-5-trifluoromethyl-benzyl)-[5-(lH-pyrτolo[2,3-bJpyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0349),
(2-Fluoro-5-tπfluoromethyl-benzyl)-[5-(l H-pyrrolo[2,3-b]pyτidin-3-ylmethyl)-pyridin-2-yl]- amine (P-0350),
(2,3-Dichloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0351).
(2-Fluoro-3-methoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0352),
Dimethyl-(5-{[5-(l H-pyrrolo[2)3-bJpyridm-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyrimidin-2- yl)-amine (P-0353),
(3-Chloro-2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0354),
(5-F]uoro-pyridin-2-ylmethyl)-[5-(l H-pyrrolo[2,3-bJpyridin-3-y]methyl)-pyridin-2-yl]-amine
(P-0355),
(3,5-Difluϋro-benzyl)-[5-(lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0356),
(2-Propoxy-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-y]]-amine (P-0357),
(2-Morpholin-4-yl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0358),
(2-Chloro-3-methoxy-benzy])-[5-(l H-pyrro]o[2,3-b]pyridin-3-ylmethyl)-pyridin-2-y]]-amine
(P-0359),
(2-Fluoro-6-trifluoromethyl-benzyl)-[5-(lH-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0360),
[2-(2-N4oi-pholin-4-yl-ethoxy)-benzyl]-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0361), (2.3-Difluoro-bcnzyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridm-2-yl]-amine (P-0362).
(2-Chloro-3-trifluoromethyl-bcnzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0363),
(2-Chloro-5-fluoro-ben/yl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-ρyridin-2-yl]-amine
(P-0364),
(2-Fluoro-3-trifluoromethyl-benzyl)-[5-(lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0365),
(5-Fluoro-2-methoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridiii-2-yl]-amir\e
(P-0366),
(2-Difluoromethoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0367),
(2-Fluoro-4-mcthyl-benzyl)-[5-(lH-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylJ -amine
(P-0368),
[2-(3-Dimethylamino-propoxy)-benzyl]-[5-(lH-pyrTolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0369),
(2,6-Diraethoxy-pyridin-3-ylmethyl)-[5-(lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-pyridm-2-yl]- amine (P-0370),
(2-Fluoro-5-methoxy-benzyl)-[5-(lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0371),
(4-Fluoro-2-methyl-bcnzyl)-[5-(lH-pyrrolo[2,3-b]p>Tidin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0372),
(3-Chloro-5-fluϋro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-amine
(P-0373),
(6-Cyclopentyloxy-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0374),
(5-Fluoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0375),
[5-( l H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[2-(2,2,2-trifluoro-ethoxy)-pyridin-3- ylmethyl]-amine (P-0376),
Propane-1 -sulfonic acid (2-fluoro-3-{[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2- ylamino]-mcthyl} -phcnyl)-amide (P-0377),
(2,5-Dichloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-y]]-amine (P-0380),
Pyrimidin-5-ylmethyl-[5-(lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0381).
(5-Chloro-2-fluoro-benzyl)-[5-(lH-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0382),
(2-Ethyl-benzyl)-[5-nH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0383), 2,2-Dimethy]-N-(3- {[5-(l H-pyrrolϋ[2,3-b]pyridin-3-ylmethyl)-pyridin-2->iamino]-methyl} - pyridin-2-yl)-propionamide (P-0384),
Methyl-(3-{[5-(l H-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyridin-2-ylamino]-methylj -pyπdin-2-ylj- amine (P-0385),
Methyl-(5-{[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylarnino]-rnethyl} -pyrimidin-2- yl)-amine (P-0386),
(2-Chloro-4-melhanesulfonyl-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridiπ-3-ylmethyl)-pyridin-2-yl]- amine (P-0387),
{5-[l-( lH-Pyrτolo[2,3-b]pyridin-3-yl)-ethyl]-pyridin-2-yl} -(4-trifluoromcthyl-ben7yl)-amine (P-
0388),
(5-Fluoro-2-metliyl-benzyl)-[5-(lH-pyrrolo[2.3-bJpyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0397),
Dimethyl-(3-{[5-(lH-pyrrol o[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-methyl}-pyridin-2-yl)-amine (P-0399),
(5-Chloro-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl] -amine
(P-0400),
(2-Methoxy-pyrimidin-5-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethy])-pyridin-2-yl]-amine
(P-0401),
[5-(5-Chloro-l II-pyiτolo[2,3-b]pyridin-3-ylmethyl)-pyπdin-2-yl]-[6-(2.2,2-trifluoro-ethoxy)- pyridin-3-ylmethy IJ -amine (P-0409) , l -(3-Fluoro-phenyl)-3-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-urea (P-0412) , and all salts, prodrugs, tautomers. and isomers thereof.
[0185] In one embodiment, a compound of the invention is:
(4-Chloro-benzyl)-[6-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridazm-3-yl]-amine (P-0092),
(4-Morpholin-4-ylmethyl-benzyl)-[5-( lII-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0093),
(2-Methoxy-ethyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0098),
[4-Chloro-l -ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l H-pyrazol-3-ylJ-Ll -(4-fluoro- phenyl)-meth-(E)-ylidene]-amine (P-0166),
( (2,2-Difluoro-benzo[l ,3]dioxol-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyτidin-3-ylmethyl)-pyridin-2- yl]-amine (P-0398); or all salts, prodrugs, tautomers, and isomers thereof.
(0186) In certain embodiments of the above compounds, compounds are excluded where N (except where N is a heteroaryl ring atom), O, or S is bound to a carbon that is also bound to N (except where N is a heteroaryl ring atom), O, or S, except where the carbon forms a double bond with one of the heteroatoms. such as in an amide, carboxylic acid, and the like; or where N (except where N is a heteroaryl ring atom), O, C(S). C(O). or S(O)n (n is 0-2) is bound to an alkene carbon of an alkenyl group or bound to an alkyne carbon of an alkynyl group; accordingly, in certain embodiments compounds which include linkages such as the following are excluded from the present invention: -NR-CH2-NR-, -0-CH2-NR-. -S-CH2-NR-, -NR-CH2-O-, -0-CH2-O-. -S-CH2-O- -NR-CH2-S-, ^0-CH2-S-, -S-CH2-S-, -NR-CH=CH-, -CH=CH-NR-, -NR-C =€-, - C -C-NR-, -0-CH=CH-, -CH=CH-O-, -0-C =C-, -C ≡C-0-. -S(O)0 2-CH=CH-, -CH=CH-S(O)0 2-, -S(O)0J-C ΞC-, -C S-C-S(O)0-2-, -C(O)-CH=CH-, -CH=CH-C(O)-, -C ≡€-C(O)-, or -C(O)-C ≡C-. C(S)-CH=CH-, -CH=CH-C(S)-, -C ≡C-C(S)-, or -C(S)-C ≡C-.
[0187] In reference to compounds herein, specification of a compound or group of compounds includes pharmaceutically acceptable salts of such compound(s), prodrug(s), and all stereoisomers, unless clearly indicated to the contrary. In reference to compounds of Formula II, unless clearly indicated to the contrary, it is understood that such reference includes compounds of Formulae Ha, Hb, Hc, Hd, He, Hf, Hg, Hh, Hi, Hj, Ilk, Ilm, Hn, and Hp, and all sub-embodiments thereof.
|0188] In another aspect, the invention provides methods for treating a c-kit-mediated disease or condition in an animal subject (e.g. a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e g., a disease or condition characterized by abnormal c-kit activity (e.g. kinase activity). Invention methods involve administering to the subject suffering from or at risk of a c-kit- mediated disease or condition an effective amount of a compound of Formula II or Formula III, and all sub-embodiments thereof. In one embodiment, the c-kit mediated disease is selected from the group consisting of malignancies, including, but not limited to. mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canine mast cell tumors, and inflammatory diseases, including, but not limited to, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and hypereosinophilia.
[0189] In a related aspect, compounds of Formula II or Formula III. and all sub-embodiments thereof, can be used in the preparation of a medicament for the treatment of a c-kit-mediated disease or condition selected from the group consisting of malignancies, including, but not limited to, mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic leukemia chronic myelogenous leukemia, mastocytosis, melanoma, and canme mast cell tumors and inflammatory diseases, including, but not limited to, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bow el syndrome, transplant rejection, and hypereosmophilia
[0190] In a further aspect, the invention provides methods for treating a c-fms-mediated disease or condition in an animal subject (e g a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e g , a disease or condition characterized by abnormal c-fms activity (e g kinase activity) Invention methods mvolve administering to the subject suffering from or at risk of a c- fms-mcdiated disease or condition an effective amount of compound of Formula II or Formula III, and all sub-embodiments thereof In one embodiment, the c-fhib mediated disease is selected from the group consisting of immune disorders, including, but not limited to, rheumatoid arthritis, systemic lupus erythematosa (SLE), and transplant rejection, inflammatory diseases including, but not limited to, osteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric rcticulohistiocytosis, and atherosclerosis, metabolic disorders, including, but not limited to, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, and hpolysis, disorders of bone structure, mineralization and bone formation and resorption, including but not limited to, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e g osteomyelitis), pen-prosthetic or wear-debπs-mediated osteolysis, and metastasis of cancer to bone kidney and genitourinary diseases, including, but not limited to, endometriosis, nephritis (e g glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes- dssocidted renal complications (e g diabetic nephropathy), and renal hypertrophy, disorders of the central nervous system, including, but not limited to, multiple sclerosis, stroke, Alzheimer's disease and Parkinson s disease, inflammatory and chronic pain, including, but not limited to, bone pain, and cancers, including, but not limited to, multiple myeloma, acute myeloid leukemia (AML), chronic myeloid leukemia (CML), prostate cancer, breast cancer, ovarian cancer, melanoma, glioblastoma multiforme, metastasis of tumors to other tissues, and other chronic myeloproliferative diseases such as myelofibrosis
[0191] In a related aspect, compounds of Formula II or Formula III. and all sub-embodiments thereof, can be used m the preparation of a medicament for the treatment of a c-fms-mediated disease or condition selected from the group consisting of immune disorders, including, but not limited to rheumatoid arthritis, systemic lupus erythematosa (SLE), and transplant rejection inflammatory' diseases including, but not limited to, osteoarthritis, inflammatory bow el syndrome, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD) emphv sema, Kawasaki's Disease, hemophagυcvtic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis, metabolic disorders, including, but not limited to, I ype I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesitv, and hpolysis, disorders of bone structure, mineralization and bone formation and resorption, including, but not limited to, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e g osteomyelitis), pcπ-prosthctic or wear-dcbπs-mcdiated osteolysis, and metastasis of cancer to bone, kidney and genitourinary diseases, including, but not limited to, endometriosis, nephritis (e g glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis diabetes-associated renal complications (e g diabetic nephropathy), and renal hypertrophy, disorders of the central nervous system, including, but not limited to, multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease, inflammatory and chronic pain, including, but not limited to, bone pain, and cancers, including, but not limited to, multiple myeloma, acute myeloid leukemia (AML), chionic myeloid leukemia (CML), prostate cancer breast cancer, ovarian cancer, melanoma, glioblastoma multiforme, metastasis of tumors to other tissues, and other chronic myeloproliferative diseases such as myelofibrosis
[0192] In a further aspect, the invention provides methods for treating a c-fms-mediated disease or condition in an animal subject (e g a mammal such as a human, other primates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), e g , a disease or condition characterized by abnormal c-fms activity (e g kinase activity) Invention methods involve administering to the subject suffering from or at risk of a c- fms-mediated disease or condition an effective amount of compound of formula 1, Formula Ia, Formula Ib, or Formula Ig, and all sub -embodiments thereof In one embodiment, the c-fms mediated disease is selected from the group consisting of osteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, l ype I diabetes, T ype II diabetes, obesity, Paget's disease, infection-mediated osteolysis (e g osteomyelitis), peπ- prosthetic or wear-debπs-mediated osteolysis, endometriosis, diabetic nephropathy, multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease, inflammatory pam chronic pam, bone pam, prostate cancer, melanoma, glioblastoma multiforme, and metastasis of tumors to tissues other than bone, preferably the c-fms mediated disease is selected from the group consisting of inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, Type I diabetes. Type IT diabetes Paget's disease, diabetic nephropathy, multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease, inflammatory pam, chronic pain, bone pain, prostate cancer, metastasis of tumors to tissues other than bone, and other chronic myeloproliferative diseases such as myelofibrosis
|0193] In a related aspect, compounds of Formula I, Formula Ia, Formula Ib, or Formula Ig, and all sub-embodiments thereof, can be used in the preparation of a medicament for the treatment of a c-fms-mediated disease or condition selected from the group consisting of osteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, Type I diabetes, I ype II diabetes, obesity, Paget's disease, infection-mediated osteolysis (e g osteomyelitis), pen-prosthetic or wear-debπs-mediated osteolysis, endometriosis, diabetic nephropathy, multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease, inflammatory pain chronic pain, bone pain, prostate cancer, melanoma, glioblastoma multiforme, and metastasis of tumors to tissues other than bone, preferably the c-fms mediated disease is selected from the group consisting of inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, Type I diabetes, Type II diabetes, Paget's disease, diabetic nephropathy, multiple scleiosis, stroke, Alzheimer's disease and Parkinson's disease, inflammatory pam, chronic pam, bone pain, prostate cancer, metastasis of tumors to tissues other than bone, and other chronic myeloproliferative diseases such as myelofibrosis
[0194] In a further aspect, the invention provides methods for treating, in an animal subject (e g a mammal such as a human, other pπmates, sports animals, animals of commercial interest such as cattle, farm animals such as horses, or pets such as dogs and cats), a disease or condition mediated by c-fms and c-kit, e g , a disease or condition characterized by abnormal c-fms activity and/or c- kit activity (e g kinase activity) Invention methods involve administering to the subject suffering from or at risk of a disease or condition mediated by c-fms and c-kit an effective amount of compound of Formula II or Formula III, and all sub-embodiments thereof In one embodiment, the condition mediated by c-fms and c-kit is selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors, glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma, breast cancer, ovarian cancer, prostate cancer, canine mast cell tumors, metastasis of cancer to bone or other tissues, chronic myeloproliferative diseases such as myelofibrosis, renal hypertrophy, asthma rheumatoid arthritis, allergic rhinitis, multiple sclerosis, osteoarthritis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosis, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease, emphysema, Kawasaki's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, atherosclerosis, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, lipolysis, hypereosmophilia. osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, mtcction-mediated osteolysis (e g osteomyelitis), peπ-prosthctic or wear-debπs-mediated osteolysis, endometriosis, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, stroke, Alzheimer's disease, Parkinson's disease, inflammatory pain, chrome pam, and bone pain
[0195] In a related aspect, compounds of Formula II or Formula III, and all sub-embodiments thereof, can be used m the preparation of a medicament tor the treatment of a c-fms-mediated and/or c-kit mediated disease or condition selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer gastrointestinal stromal tumors, glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasm associated with neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma, breast cancer, ovarian cancer, prostate cancer, canme mast cell tumors, metastasis of cancer to bone or other tissues, chronic myelopiohferatrve diseases such as myelofibrosis, renal hypertrophy, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, osteoarthritis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosa, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease, emphysema, Kawasaki 's Disease, hemophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, atherosclerosis, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, lipolysis, hypereosmophilia, osteoporosis, increased risk of fracture Paget's disease, hypercalcemia, infection-mediated osteolysis (e g osteomyelitis), pen-prosthetic or wear-debπs-mediated osteolysis, endometriosis, glomerulonephritis, interstitial nephritis, Lupus nephritis, tubular necrosis, diabetic nephropathy, stroke, Alzheimer's disease, Parkinson's disease, inflammatory pam, chronic pam, and bone pam
[0196] In particular embodiments, the compound has an ICso of less than 100 nM, less than 50 tiM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay In certain embodiments, the selectivity of the compound is such that the compound is at least 2-fold, 5-fold, 10-fold, or 100-fold more active on c-kit than on Ret, PDGF, or both Ret and PDGF In certain embodiments, the selectivity of the compound is such that the compound is at least 2-fold, 5-fold, 10-fold, or 100-fold more active on c-kit than on c-ftns In certain embodiments, the selectivity of the compound is such that the compound is at least 2-fold, 5-fold, 10-fold, or 100-fold moie active on c-fms than on c-kit In certain embodiments, the compound has in combination each pairing of activity (e g IC\0) and/or selectivity as specified in this paragraph
[0197] In particular embodiments, the compound has an IC50 of less than 100 nM, lesb than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay for c-kit, c-fms, or both c-kit and c-fms kinase activity In certain embodiments, the selectivity of the compound is such that the compound is at least 2-fold, 5-fold, 10- fold, or 100-fold more active on c-kit, c-fms, or both c-kit and c-fms than on Ret, PDGF, or both Ret and PDGf
[0198] In particular embodiments, the compound has an IC50 of less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay for c-kit, c-fms, or both c-kit and c-fms kinase activity, and further has an IC50 of less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, or less than 5 nM as determined in a generally accepted kinase activity assay for at least one of HGK, TrkA, or l rkB kinase activity
[0199] An additional aspect of this invention relates to compositions that include a therapeutically effective amount of a compound of Formula II or Formula IIIand all sub- embodiments thereof and at least one pharmaceutically acceptable carπei, excipient, and or diluent, including combinations of any two or more compounds of Formula II or Formula III The composition can further include one or more different pharmacologically active compounds, which can include one or more compounds of Formula I (including Formula Ia, Ib, and Ig, and all sub- embodiments thereof), Formula II or Formula III
[0200] In one aspect, the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including a compound of Formula II or Formula 111, in combination with one or more other therapies or medical procedures effective in treating the cancer Other therapies or medical procedures include suitable anticancer therapy (e g drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedure (e g surgery, radiation treatment, hyperthermia heating, bone marrow or stem cell transplant) In one aspect the one or more suitable anticancer therapies or medical procedures is selected from treatment with a chemotherapeutic agent (e g chemolherapeutic drug), radiation treatment (c g x-ray, 7-ray, or electron, proton, neutron, or a particle beam), hyperthermia heating (e g microwav e, ultrasound, radiofrequcncy ablation), Vaccine therapy (e g AFP gene hepatocellulai carcinoma vaccine, AFP adenoviral vector vaccine, AG-858. allogeneic GM-CSF-secretion breast cancer vaccine, dendritic cell peptide vaccines), gene therapy (e g Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (c g aminolevulinic acid motexafm lutetium), surgery, and bone marrow and stem cell transplantation
[0201] In one aspect, the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including a compound of Formula II or Formula III, in combination with one or more suitable chemothcrapcutic agents In one aspect, the one or more suitable chemotherapeutic agents is selected from an alkylating agent, including, but not limited to, adozelesm, altretamme, bizelesm, busulfan, carboplatm, carboquone, carmushne, chlorambucil, cisplatm cyclophosphamide dacarbazme, estramustme fotemustme, hepsulfam, lfosfamide, improsulfan, irofulven, lomustinc, mechlorethamme, melphalan, oxaliplatm, piposulfan, semustme, streptozocm, temozolomide, thiotepa, and treosulfan an antibiotic, including, but not limited to, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicm, ldarubiun, menogaπl, mitomycin, mitoxantrone, neocarzmostatm, pentostatin, and phcam>cm, an antimetabolite, including, but not limited to, azacitidme, capecitabme cladπbme, clofarabme, cytarabine, decitabme, floxuπdme, fludarabme, 5-fluorouracil ftorafur, gemcitabme, hydroxyurea, mercaptopuπne, methotrexate, nelarabme, pemetrexed, raltitrexed, thioguamne, and tπmetrexate, an immunotherapy, including, but not limited to, alemtuzumab, bcvacizumab, cetuximab, gahximab, gcmtuzumab, pamtumumab, pertuzumab, πtuximab, tositumomab, trastuzumab, and 90 Y ibritumomab tiuxetan, a hormone or hormone antagonist, including, but not limited to, anastrozole, androgens, buserelm, diethylstilbestrol, exemestane, flutamide, fulvestrant, goscrelm, ldoxifene, leti ozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene, a taxane, including, but not limited to, DJ-927, docetaxel, TPI 287, pachtaxel and DHA-paclitaxel, a retinoid, including, but not limited to, alitretmom, bexarotene, fenretinide, isotretinoin, and tretinoin, an alkaloid, including, but not limited to, etoposide, homoharrmgtonme, temposide, vinblastine, vincristine, vmdesme, and vmorelbme, an antiangiogenic agent, including, but not limited to, AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenahdomide, and thalidomide, a topoisomerase inhibitor, including, but not limited to, amsacπne, edotecarm, exatecan, irinotecan (also active metabolite SN-38 (7-ethyl-lO-hydroxy-camptothccin)), rubitecan, topotecan, and 9-aminocamptothecm, a kinase inhibitor, including, but not limited to erlotimb, gcfitimb, fla\opiπdol, imatimb mesylate, lapatmib, sorafenib, sunitimb malate, AEE-788, AG- 013736, AMG 706, ΛMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosponne) and vatalanib, a targeted signal transduction inhibitor including, but not limited to bortezomib, geldanamycin, and rapamycm, a biological response modifier, including but not limited to, lmiquimod, lnterferon-α, and mterleukm-2, and other chemotherapeutics, including, but not limited to 3-AP (3-ammo-2-carboxyaldehyde thiosemicarbazone), ammoglutethimide, asparaginase, bryostatin-1 cilengitide E7389, lxabepilone, procarbazine, sulmdac, temsirohmus, tipifarnib Preferably, the method of treating a cancer involves administering to the subject an effectrv e amount of a composition of Formula II, Formula III or Formula IV in combination w ith a chemo therapeutic agent selected from 5-fluorouracil, carboplatm dacarbazmc, gefitinib, oxahplatin, paclitaxel, SN-38, temozolomide, vinblastine, be\acizumab, cetuximab, or erlotmib
|0202| In another aspect, the invention provides a method of treating or prophylaxis of a disease or condition m a mammal, by administering to the mammal a therapeutically effective amount ot a compound of Formula II or Formula ITI, a prodrug of such compound, or a pharmaceutically acceptable salt of such compound or prodrug The compound can be alone or can be part of a composition
|0203] In a related aspect, the invention provides kits that include a composition as described herein In particular embodiments, the composition is packaged, e g , in a vial, bottle, flask, which may be further packaged, e g , within a box, envelope, or bag, the composition is approved by the U S Food and Drug Administration or similar regulatory agency for administration to a mammal, e g , a human, the composition is approved for administration to a mammal, e g , a human, for a c-kit- and^or c-fms-mediated disease or condition, the kit of the invention includes written instructions on use and/ or other indication that the composition is suitable or approved for administration to a mammal, e g , a human, for a c-kit- and/or c-fms-mediated disease or condition, the composition is packaged in unit dose or single dose form, c g , single dose pills, capsules, or the like
[0204] In another aspect, the present invention also provides a method for modulating c-kit or c-fms activity by contacting c-kit or c-fms with an effective amount of a compound of Formula Il or Formula IIIand all sub-embodiments thereof active on c-kit and/or c-fms (such as compounds developed using methods described herein) The compound is preferably provided at a level sufficient to modulate the activity of the c-kit or c-fms by at least 10%, more preferably at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or greater than 90% In many embodiments, the compound will be at a concentration of about 1 μM, 100 μM, or 1 mM, or in a range of 1-100 nM, 100-500 nM, 500-1000 nM, 1-100 μM, 100-500 μM, or 500-1000 μM In particular embodiments, the contacting is carried out in vitro
[0205] Additional aspects and embodiments will be apparent from the following Detailed Description and from the claims DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0206] Λs used herein the following definitions apply:
[0207] "Halo" and "'halogen" refer to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br). or iodo (I).
[02081 "Hydroxyl" and "hydroxy" refer to the group -OH.
[0209] "Thiol" refers to the group -SH.
[0210] "Lower alkyl" alone or in combination means an alkane-derived radical containing from 1 to 6 carbon atoms (unless specifically defined) that includes a straight chain alkyl or branched alkyl. The straight chain or branched alkyl group is attached at any available point to produce a stable compound. In many embodiments, a lower alkyl is a straight or branched alkyl group containing from 1-6, 1 -4, or 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t- butyl, and the like. "Optionally substituted lower alkyl" denotes lower alkyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of -F, -OH, -NHj, -NOT, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR", -SRa, -OC(O)R3, -OC(S)R", -C(O)Ra, -C(S)Ra, -C(O)OR3, -C(S)OR3, -S(O)R", -S(O)2R3, -C(O)NHR", -C(S)NHR3, -C(O)NRaRa, -C(S)NR3R", -S(O)2NHR3, -S(O)2NR0R3, -C(NH)NHR1, -C(NH)NR1TT, -NHC(O)R3, -NHC(S)R3, -NRaC(0)R\ -NRaC(S)R\ -NHS(O)2R3, -NRaS(O)2Ra. -NHC(O)NHR3, -NHC(S)NHR3, -NR3C(O)NH2, -NR3C(S)NH2, -NR3C(O)NHR3. -NR3C(S)NHR3, -NHC(O)NR3R3, -NHC(S)NR3R3, -NR3C(O)NR3R3, -NR3C(S)NR3R3, -NHS(O)2NHR3, -NR3S(O)2NH2, -NR3S(O)2NHR", -NHS(O)2NR3R", -NR3S(O)2NR3R9, -NHR\ -NRaRa, -Re, -Rf, and -R". Further, possible substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula I (including Formulae Ia, Ib, Ig and all sub-embodiments thereof), attached at any available atom to produce a stable compound. For example "fluoro substituted lower alkyl" denotes a lower alkyl group substituted with one or more fluoro atoms, such as perfluoro alkyl, where preferably the lower alkyl is substituted with 1 , 2, 3, 4 or 5 fluoro atoms, also 1 , 2, or 3 fluoro atoms. While it is understood that substitutions are attached at any available atom to produce a stable compound, when optionally substituted alkyl is an R group of a moiety such as -OR, -NHR, -C(O)NHR, and the like, substitution of the alkyl R group is such that substitution of the alkyl carbon bound to any -O-, -S-. or -N- of the moiety (except where -N- is a heteroaryl ring atom) excludes substituents that would result in any -0-, -S-, or -N- of the substituent (except where -N- is a heteroaryl ring atom) being bound to the alkyl carbon bound to any -O-, -S-, or -N- of the moiety.
[0211] "Lower alkylene" refers to a divalent alkane-derived radical containing 1-6 carbon atoms, straight chain or branched, from which two hydrogen atoms are taken from the same carbon atom or from different carbon atoms. Examples of lower alkylene include, but are not limited Iu, methylene -CH2-, ethylene - CH2CH2-, propylene -CH2CH2CH2-, isopropylene -CH(CH3)CH-, and the like. "Optionally substituted lower alkylene" denotes lower alkylene that is independently substituted, unless indicated otherwise, with one or more, preferably 1 , 2, 3, 4 or 5, also 1. 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of -F, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR", -SRa, -OC(O)R3, -OC(S)R3, -C(O)R3, -C(S)R3, -C(O)OR3, -C(S)ORa, -S(O)R3, -S(O)2R3, -C(O)NHR3, -C(S)NHR3, -C(O)NR3R3, -C(S)NR3R3, -S(O)2NHR3, -S(O)2NR3R3, -C(NH)NHRa, -C(NH)NR^, -NHC(0)Ra, -NHC(S)R3, -NRaC(0)Ra, -NR3C(S)R3, -NHS(O)2R", -NRaS(O)2Ra, -NHC(O)NHR3, -NHC(S)NHR3, -NR3C(O)NHR3, -NR3C(O)NH2, -NR3C(S)NH2, -NR3C(S)NHR3, -NHC(0)NRaR3, -NHC(S)NR8R3, -NRaC(0)NRaR3, -NR3C(S)NR3R3, -NHS(O)2NHR3, -NR3S(O)2NH2, -NR3S(O)2NHR3, -NHS(O)2NR3R3, -NR3S(O)2NR3R3, -NHRa, -NRaRa, -Re, -Rf, and -RE, or two substituents on any one carbon or a substituent on each of any two carbons in the alkylene chain may join to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di- alkylamino, and cycloalkylamino.
[0212] "Lower alkenyl" alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) and at least one, preferably 1-3, more preferably 1-2, most preferably one, carbon to carbon double bond. Carbon to carbon double bonds may be either contained within a straight chain or branched portion. Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like. "Substituted lower alkenyl" denotes lower alkenyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of -F, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NII2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -0Ra, -SRa, -OC(O)R\ -OC(S)R3, -C(O)R\ -C(S)Ra, -C(O)OR3, -C(S)OR3, -S(O)R8, -S(O)2R3, -C(O)NHR3, -C(S)NHR3, -C(O)NR3R", -C(S)NR3R3, -S(O)2NHR3, -S(O)2NR3R3, -C(NH)NHR3, -C(NH)NR13R', -NHC(O)R3, -NHC(S)Ra, -NR3C(O)R3, -NRaC(S)Ra, -NHS(O)2R3, -NR3S(O)2R'1, -NHC(O)NHR3, -NHC(S)NHR3, -NR3C(O)NH2, -NR3C(S)NH2, -NR3C(O)NHR3, -NRaC(S)NHRa, -NIIC(O)NR3R3, -NHC(S)NR0R8, -NR3C(O)NR0R3, -NRaC(S)NRaRa, -NHS(O)2NHR8, -NR8S(O)2NH2, -NR8S(O)2NHR", -NHS(0)2NRaRa, -NR8S(O)2NR3R3, -NHRa, -NRaRa, -Rd, -R', and -Rg. Further, possible substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula I (including Formulae Ia, Ib, Ig and all sub-embodiments thereof), attached at any available atom to produce a stable compound. For example "fluoro substituted lower alkenyl" denotes a lower alkenyl group substituted with one or more fluoro atoms, where preferably the lower alkenyl is substituted with 1 , 2, 3, 4 or 5 fluoro atoms, also 1 , 2, or 3 fluoro atoms. While it is understood that substitutions are attached at any available atom to produce a stable compound, substitution of alkenyl groups are such that -F, -C(O)-, -C(S)-, - C(NH)-, -S(O)-, -S(O)2-, -O-, -S-, or -N- (except where -N- is a heteroaryl ring atom), are not bound to an alkene carbon thereof. Further, where alkenyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, -C(O)R, and the like, substitution of the moiety is such that any -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -O-, -S-, or -N- thereof (except where -N- is a heteroaryl ring atom) are not bound to an alkene carbon of the alkenyl substituent or R group. Further, where alkenyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, -C(O)NHR, and the like, substitution of the alkenyl R group is such that substitution of the alkenyl carbon bound to any -O-, -S-, or -N- of the moiety (except where -N- is a heteroaryl ring atom) excludes substituents that would result in any -0-, -S-, or -N- of the substituent (except where -N- is a heteroaryl ring atom) being bound to the alkenyl carbon bound to any -0-, -S-, or -N- of the moiety. An "alkcnyl carbon" refers to any carbon within an alkenyl group, whether saturated or part of the carbon to carbon double bond. An "alkene carbon" refers to a carbon within an alkenyl group that is part of a carbon to carbon double bond.
[0213] "Lower alkynyl" alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) containing at least one, preferably one, carbon to carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl, and the like. "Substituted lower alkynyl" denotes lower alkynyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of -F, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH. -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NfH)NH2, -0R\ ~SRa, -OC(O)R3, -OC(S)R3, -C(O)Ra, -C(S)R3, -C(O)OR", -C(S)ORa, -S(O)R", -S(O)2R8, -C(O)NHR", -C(S)NHR11, -C(O)NR8R3, -C(S)NRaRa, -S(O)2NHR3, -S(O)2NR3R", -C(NH)NHR3, -C(NH)NRbR\ -NHC(O)R3, -NHC(S)R3, -NR3C(O)R", -NR3C(S)R3, -NHS(O)2R\ -NR8S(O)2R3, -NHC(O)NHR3, -NHC(S)NHR3, -NRaC(O)NH2) -NR3C(S)NH2, -NR3C(O)NHR8, -NR3C(S)NHR3, -NHC(O)NRaRa, -NHC(S)NR3R', -NR3C(O)NR3R8, -NR3C(S)NR3R1. -NHS(O)2NlIR3, -NR4S(O)2NH2, -NR3S(O)2NHR3, -NHS(0)2NRaRa, -NRaS(0)2NRaRa. -NHRa, -NRaR\ -Rd, -Re, and -Rs, Further, possible substitutions include subsets of these substitutions, such as are indicated herein, for example, in the description of compounds of Formula I (including Formulae Ia, Ib, Ig and all sub- embodiments thereof), attached at any available atom to produce a stable compound. For example "fluoro substituted lower alkynyP denotes a lower alkynyl group substituted with one or more fluoro atoms, where preferably the lower alkynyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions are attached at any available atom to produce a stable compound, substitution of alkynyl groups are such that -F, -C(O)-, -C(S)-, -C(NII)-, -S(O)-, -S(O)2-, -0-, -S-, or N- (except where -N- is a heteroaryl ring atom), are not bound to an alkyne carbon thereof. Further, where alkynyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, -C(O)R, and the like, substitution of the moiety is such that any -C(O)-, -C(S)-,-S(O)-, -S(O)2-, -0-, -S-, or -N- thereof (except where -N- is a heteroaryl ring atom) are not bound to an alkyne carbon of the alkynyl substituent or R group. Further, where alkynyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, - C(O)NHR, and the like, substitution of the alkynyl R group is such that substitution of the alkynyl carbon bound to any -0-, -S-, or -N- of the moiety (except where -N- is a heteroaryl ring atom) excludes substituents that would result in any -0-. -S-, or -N- of the substituent (except where -N- is a heteroaryl ring atom) being bound to the alkynyl carbon bound to any -0-, -S-, or -N- of the moiety. An "alkynyl carbon" refers to any carbon within an alkynyl group, whether saturated or part of the carbon to carbon triple bond. An "alkyne carbon" refers to a carbon within an alkynyl group that is part of a carbon to carbon triple bond.
[0214] "Cycloalkyl" refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like. "Cycloalkylene" is a divalent cycloalkyl. Λ "substituted cycloalkyl" is a cycloalkyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN. -C(O)OH, -C(S)OH. -C(O)NH2, -C(S)NH,, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR", -SR'1, -OC(O)R3, -OC(S)R3, -C(0)Ra, -C(S)Ra, -C(O)OR3, -C(S)OR3, -S(O)Ra, -S(O)2R3, -C(O)NHR0, -C(S)NHR3, -C(O)NR-R3, -C(S)NR3R3, -S(O)2NHR3, -S(O)2NR3R3, -C(NH)NHR3, -C(NH)NRbRc, -NIIC(O)R', -NHC(S)R3, -NR0C(O)R3, -NR8C(S)R3, -NHS(O)2R3, -NRaS(O)2Ra, -NHC(O)NHR9, -NHC(S)NHR'1, -NR3C(O)NH2, -NR3C(S)NH2, -NR3C(O)NHR3, -NRaC(S)NHR3, -NHC(O)NR3R", -NHC(S)NRaRa, -NR3C(O)NR3R3, -NR3C(S)NR3R3, -NHS(O)2NHR3, -NR3S(O)2NH2, -NRaS(0)2NHRa, -NHS(0)2NRdR\ -NR3S(O)2NR3R3, -NHRa, -NRaR\ -Rd, -Re, -Rf, and -Rg, "Substituted cycloalkylene" is a divalent substituted cycloalkyl.
[0215] "Heterocycloalkyl" refers to a saturated or unsaturated non-aromatic cycloalkyl group having from 5 to 10 atoms in which from 1 to 3 carbon atoms in the ring are replaced by heteroatoms of O, S or N, and are optionally fused with benzo or heteroaryl of 5-6 ring members. Heterocycloalkyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N- oxide of a tertiary ring nitrogen. Heterocycloalkyl is also intended to include compounds in which one of the ring carbons is oxo substituted, i.e. the ring carbon is a carbonyl group, such as lactones and lactams. The point of attachment of the heterocycloalkyl ring is at a carbon or nitrogen atom such that a stable ring is retained. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl. "Heterocycloalkylene" is a divalent heterocycloalkyl. A "substituted heterocycloalkyl" is a heterocycloalkyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH3, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -0Ra, -SR3, -OC(O)R3, -OC(S)R3, -C(0)Ra, -C(S)R3, -C(O)OR3, -C(S)0R\ -S(O)Ra, -S(O)2R3, -C(0)NHRa, -C(S)NHR8, -C(0)NRaRa, -C(S)NRaR\ -S(O)2NHR3, -S(O)2NR3R3, -C(NH)NHR\ -C(NH)NR1Tl0, -NHC(O)R8, -NHC(S)Ra, -NR3C(O)R3, -NR3C(S)R3, -NHS(O)2R3, -NR3S(O)2R3, -NHC(O)NHR3, -NHC(S)NHR3, -NR3C(O)NH2, -NR3C(S)NH2, -NR3C(O)NHR3, -NR3C(S)NHR3, -NHC(O)NR3R3, -NHC(S)NR3R", -NRaC(O)NR"Ra, -NR3C(S )NRaR", - NHS(O)2NHR3, -NR3S(O)2NH2, -NR3S(O)2NHR3, -NHS(O)2NR3R3, -NR3S(O)2NR3R", -NHR3, -NR3R", -Rd, -Rc, -Rf, and -RA "Substituted heterocycloalkylene" is a divalent substituted heterocycloalkyl .
[0216] "Aryl" alone or in combination refers to a monocyclic or bicyclic ring system containing aromatic hydrocarbons such as phenyl or naphthyl, which may be optionally fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members. "Arylene" is a divalent aryl. A "substituted aryl" is an aryl that is independently substituted, unless indicated otherwise, with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents are selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -OR3, -SR3, -OC(O)R3, -OC(S)R3, -C(O)R3, -C(S)R3, -C(O)OR3, -C(S)OR", -S(O)R3, -S(O)2R3, -C(O)NHR2, -C(S)NHR3, -C(O)NR3R2, -C(S)NRaRa, -S(O)2NHR", -S(O)2NR3R3, -C(NH)NHR3, -C(NH)NRbRc, -NHC(0)Ra, -NHC(S)R', -NRaC(0)Ra, -NR3C(S)R8, -NHS(O)2R3, -NR8S(O)2R3, -NHC(O)NHR8, -NIIC(S)NHRa, -NR3C(O)NH2, -NR3C(S)NH2, -NR3C(O)NHR3, -NR4C(S)NHR8, -NHC(O)NR3R*, -NHC(S)NRaRa, -NRaC(0)NRaR\ -NRaC(S)NRaRa, -NHS(O)2NHR3, -NR3S(O)2NH2, -NR3S(O)2NHR", -NHS(O)2NR3R3, -NR8S(O)2NR3R3, -NHRa, -NRaRa, -Rd, -Re, -Rf, and -Rg. A "substituted arylene" is a divalent substituted aryl.
10217] "Heteroaryl" alone or in combination refers to a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1 -4, more preferably 1 -3, even more preferably 1 -2. heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, such as sulfmyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triaziπyl, furanyl, benzofuryl, and indolyl. "Nitrogen containing heteroaryl" refers to heteroaryl wherein any heteroatoms arc N. "Heteroarylene" is a divalent heteroaryl, A "substituted heteroaryl" is a heteroaryl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, wherein the substituents arc selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -0Ra, -SRa, -OC(O)R3, -OC(S)R3, -C(O)R3, -C(S)R", -C(0)0Ra, -C(S)OR3, -S(O)Ra, -S(O)2Ra, -C(O)NHR8, -C(S)NHR3, -C(O)NR3R8, -C(S)NRaRa, -S(O)2NHR3, -S(O)2NR3R3, -C(NH)NHRa, -C(NH)NRbRc, -NHC(O)R8, -NHC(S)Ra, -NRaC(0)Ra, -NRaC(S)Ra, -NHS(O)2R0, -NR8S(O)2R3, -NHC(O)NHR3, -NHC(S)NHR", -NR3C(O)NH2, -NR3C(S)NH2, -NRaC(0)NHRa, -NR3C(S)NHR3, -NHC(O)NR3R3, -NHC(S)NR3R", -NR3C(O)NR3R3, -NR3C(S)NR3R3, -NHS(O)2NHR4, -NR3S(O)2NH2, -NR3S(O)2NHR3, -NHS(O)2NR3R3, -NRaS(O)2NRaRa, -NIIR3, -NR8R3, -Rd, -Re, -Rf, and -R8. "Substituted heteroarylene" is a divalent substituted heteroaryl.
[021 SJ The variables R3, Rb, Rc, -Rd, -Re, -Rf and -RB as used in the description of optional substituents for alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are defined as follows: each R\ Rb. and Rc are independently selected from the group consisting of -Rd. -Re, -R1, and -RF, or Rb and Rc combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of halogen, -NO2, -CN, -OH, -NH2, -OR11, -SRU, -NHR", -NRURU, -R\ and ^Ry;
each -Rd is independently lower alkyl, wherein lower alkyl is optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2 or 3 substituents selected from the group consisting of fluoro, -OH, -NH2. -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -0Rk, -SRk, -OC(O)Rk, -OC(S)Rk, -C(O )R\ -C(S)R\ -C(0)0R\ -C(S)OR\ -S(O)R\ -S(O)2Rk, -C(O)NHRk, -C(S)NHRk, -C(O)NRV, -C(S)NRkRk, -S(O)2NHRk, -S(O)2NRkRk, -C(NH)NHRk, -C(NH)NR111R", -NHC(0)Rk, -NHC(S)Rk, -NRkC(0)Rk, -NRkC(S)Rk, -NHS(0)2Rk, -NRkS(0)2Rk, -NHC(0)NHR\ -NHC(S)NHR\ -NRkC(0)NH2, -NRkC(S)NH2, -NRkC(O)NHRk, -NRkC(S)NHRk, -NHC(0)NRkR\ -NHC(S)NRkRk, -NRkC(0)NRkRk, -NRkC(S)NRkRk, -NHS(0)2NHRk, -NRkS(O)2NH2, -NRkS(0)2NHRk, -NHS(0)2NRkRk, -NRkS(O)2NRkRk, -NHRk, -NRkRk, -R', and -R1;
each -~Re is independently lower alkenyl, wherein lower alkenyl is optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2 or 3 substituents selected from the group consisting of fluoro, -OH, -NH2, -NO2. -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -ORk, -SRk, -OC(O)Rk, -OC(S)Rk, -C(O)R", -C(S)R",
Figure imgf000116_0001
-C(S)OR\ -S(O)Rk, -S(O)2Rk, -C(O)NHRk, -C(S)NHRk, -C(0)NRkRk, -C(S)NRkRk, -S(0)2NHRk, -S(O)2NRkRk, -C(NH)NHRk, -C(NH)NR111R", -NHC(O)R", -NHC(S)Rk, -NRkC(0)Rk, -NRkC(S)Rk, -NHS(O)2R", -NRkS(O)2Rk, -NHC(O)NHR", -NHC(S)NHR", -NRkC(0)NH2, -NRkC(S)NH2, -NR"C(O)NHR", -NRkC(S)NIIRk, -NHC(0)NR"Rk, -NHC(S)NRkR", -NRkC(0)NRkRk, -NRkC(S)NRkRk, -NHS(0)2NHRk, -NRkS(O)2NH2, -NRkS(0)2NHRk, -NHS(0)2NRkRk, -NR"S(O)2NR"Rk, -NHR", -NRkRk, -Rh, and
-RJ;
each -Rf is independently lower alkynyl, wherein lower alkynyl is optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2 or 3 substituents selected from the group consisting of fluoro, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -ORk, -SR". -OC(O)Rk, -OC(S)R", -C(O)R", -C(S)R", -C(O)OR", -C(S)OR\ -S(O)Rk, -S(O)2R", -C(O)NIIR\ -C(S)NHRk. -C(O)NRkRk, -C(S)NRkRk, -S(O)2NHRk, -S(O)2NRkRk, -C(NH)NHR", -C(NH)NR111R", -NHC(O)Rk, -NHC(S)R", -NRkC(O)Rk, -NRkC(S)Rk, -NHS(O)2R", -NRkS(O)2Rk, -NHC(O)NHRk, -NHC(S)NHRk, -NRkC(O)NH2, -NRkC(S)NH2, -NRkC(O)NHRk, -NRkC(S)NHRk, -NHC(O)NRV1 -NHC(S)NRkRk, -NRkC(O)NRkRk, -NRkC(S)NRkRk, -NHS(O)2NHRk, ~NRkS(O)2NH2) -NRkS(O);NHRk, -NHS(O)2NRkRk, -NRkS(O)2NRkRk, -NHRk, -NRkRk, -Rh, and -RJ;
each -Rg is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and hcteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2 or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NIIC(O)NH2, -NIIC(S)NII2, -NHS(O)2NII2, -C(NH)NH2, -0Rk, -SRk, -OC(O)Rk, -OC(S)R\ -C(0)Rk, -C(S)Rk, -C(0)0Rk, -C(S)ORk, -S(O)Rk, -S(O)2Rk, -C(0)NHRk, -C(S)NHRk, -C(O)NRkRk, -C(S)NRV, -S(0)2NHRk, -S(0)2NRkRk, -C(NH)NHRk, -C(NH)NRmRn, -NHC(O)Rk, -NHC(S)Rk, -NRkC(0)Rk, -NRkC(S)Rk, -NHS(0)2Rk, -NRkS(0)2RK, -NIIC(O)NIIRk, -NIIC(S)NHRk, -NRkC(0)NH2, -NRkC(S)NH2, -NRkC(0)NHRk, -NRkC(S)NHRk, -NHC(O)NRkRk, -NHC(S)NRkRk, -NRkC(0)NRkRk, -NRkC(S)NRkRk, -NHS(0)2NHRk, -NRkS(O)2NH2, -NRkS(0)2NHRk, -NHS(O)2NRV, -NRkS(O)2NRkRk, -NHRk, -NRkRk, -Rh, -R1, and -V;
wherein Rk, Rra, and Rn at each occurrence are independently selected from the group consisting of V1, -R', and -R', or Rm and R" combine with the nitrogen to which they are attached form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, -NO2, -CN, -OH, -NH2, OR", -SRU, -NHRU, -NRV, V, and -Ry;
wherein each -R1' is independently lower alkyl optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of fluoro, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -0Rr, -SRr, -OC(O)R', -OC(S)R', -C(O)R', -C(S)R', -C(0)0Rr, -C(S)ORr, -S(O)Rr, -S(O)V, -C(O)NHRr, -C(S)NHR', -C(O)NRrRr, -C(S)NRrRr, -S(O)2NHR', -S(0)2NR'R', -C(NH)NHR', -C(NH)NRSR!, -NHC(O)R', -NHC(S)R', -NR'C(0)R', -NR'C(S)R', -NHS(O)2R', -NR1S(O)2R', -NHC(0)NHRr, -NHC(S)NHR', -NR'C(0)NH2, -NRrC(S)NH2, -NR'C(0)NIIR', -NRrC(S)NIIRr, -NHC(O)NR'Rr, -NHC(S)NRrR', -NR'C(0)NR'R', -NR'C(S)NR'Rr, -NHS(O)2NHRr, -NR1S(O)2NH2, -NR1S(O)2NHR/, -NHS(O)2NR1R', -NRrS(O)2NRrRr, -NHRr, -NRrRr, -R'. and -R1;
wherein each -R1 is independently selected from the group consisting of lower alkenyl and lower alkynyl, wherein lower alkenyl or lower alkynyl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2 or 3 substituents selected from the group consisting of fluoro, -OH, -NH2, -NO2, -CN, -C(O)OII, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(NH)NH2, -ORr, -SRr, -OC(O)Rr, -OC(S)R', -C(O)Rr, -C(S)Rr, -C(O)ORr, -C(S)ORr, -S(O)R', -S(O)2R', -C(O)NHRr, -C(S)NHRr, -C(0)NRrRr, -C(S)NRrRr, -S(0)2NHRr, -S(O)2NRrRr, -C(NH)NHRr, -C(NH)NR8R', -NIIC(O)R', -NHC(S)Rr, -NR'C(0)Rr, -NRrC(S)Rr, -NHS(O)2R', -NRrS(0)2Rr, -NHC(O)NHR', -NHC(S)NHR', -NR'C(0)NH2) -NR'C(S)NH2, -NRrC(O)NHRr, -NRrC(S)NHRr, -NHC(0)NR'Rr. -NHC(S)NR^', -NRrC(0)NRrR', -NRrC(S)NRrRr, -NHS(O)2NHR', -NR1S(O)2NH2, -NR'S(0)2NHRr, -NHS(0)2NRrR', -NRrS(0)2NR'Rr, -NHR', -NR'Rr. and -R1;
wherein each -RJ is independently selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2 or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, -C(O)OH, -C(S)OH, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NHC(O)NH2, -NHC(S)NH2, -XHS(O)2NH2, -C(NH)NH2, -OR', -SRr, -OC(O)Rr, -OC(S)R', -C(O)Rr, -C(S)R', -C(O)OR', -C(S)OR', -S(O)Rr, -S(O)2Rr, -C(O)NIIR', -C(S)NHR', -C(0)NR'R', -C(S)NR'Rr, -S(O)2NHR', -S(O)2NR'R', -C(NH)NHR', -C(NH)NR5R1, -NHC(O)R', -NHC(S)Rr, -NR'C(0)Rr, -NR'C(S)R', -NHS(O)2R', -NR'S(0)2Rr, -NHC(O)NHR', -NHC(S)NHR1, -NR'C(0)NH2, -NR'C(S)NH2, -NR'C(0)NHRr, -NRrC(S)NHRr, -NHC(O)NRrRr, -NHC(S)NR1R', -NR'C(0)NR'Rr, -NR'C(S)NRrR', -NHS(0)2NHRr, -NR'S(O)2NH2, -NRrS(0)2NHR', -NHS(0),NR'R', -NR'S(0)2NR'R', -NHR', -NRrRr, cycloalkylamino, and -R";
wherein each Rr, Rs, and R1 at each occurrence are independently selected from the group consisting of lower alkyl, C3^ alkenyl, C3 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more, preferably 1. 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of ~Ry, fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided that any substitution of the lower alkyl carbon bound to any -0-, -S-, or N-, of -OR', -SR', -C(O)OR', -C(S)OR', -C(0)NHRr, -C(S)NHR', -C(0)NRrRr, -C(S)NR'Rr, -S(O)2NHR1; -S(O)2NRrRr, -C(NH)NHRr, -NRrC(O)Rr, -NRrC(S)Rr, -NR'S(O)2Rr, -NHC(0)NIIRr, -NIIC(S)NlIR1, -NRrC(O)NH2, -NR'C(S)NH2, -NRrC(O)NIIRr, -NR'C(S)NHRr, -NHC(O)NR1R', -NHC(S)NR1R', -NRrC(O)NRrRr, -NRrC(S)NRrRr, -NHS(O)2NHR', -NRrS(O)2NH2, -NRrS(O)2NHR'5 -NHS(O)2NR1R", -NRrS(0)2NRrRr, -NHRr, or -NRrRr is selected from the group consisting of fluoro and -R*, and wherein C3^ alkcnyl or C3^6 alkynyl arc optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of-Ry, fluoro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, provided that any substitution of the CM alkenyl or Cv6 alkynyl carbon bound to any -0-, -S-, or -N-, of -0Rr, -SRr, -C(O)OR', -C(S)ORr, -C(0)NHRr, -C(S)NHR', -C(O)NR1R', -C(S)NR1R', -S(O)2NHR', -S(0)2NRrRr, -C(NH)NHR', - NRrC(0)R', -NRrC(S)Rr, -NRrS(O)2R', -NIIC(O)NIIR', -NIIC(S)NIIR', -NRrC(0)NII2, -NR'C(S)NH2, -NR'C(0)NHRr, -NR'C(S)NHR', -NHC(O)NRTl'. -NHC(S)NRrRr, -NRrC(0)NR'Rr, -NR'C(S)NR'Rr, -NHS(O)2NHR', -NIfS(O)2NH2, -NR'S(O)2NHRr, -NHS(0)2NR'Rr, -NR'S(O)2NR'Rr, -NHR', or -NRrRr is selected from the group consisting of fluoro, lower alkyl, fluoro substituted lower alkyl, or -Ry, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkyl amino, di-alkyl amino, and cycloalkylamino, or Rs and R1 combine with the nitrogen to which they are attached form a 5-7 membered heterocycloalkyl or a 5 or 7 membered nitrogen containing heteroaryl, wherein the 5-7 membered heterocycloalkyl or 5 or 7 membered nitrogen containing heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of halogen, -NO2, -CN, -OH, -NH2, OR", -SRU, -NHRU, -NRURU, -Rx, and ^Ry;
wherein each Ru is independently selected from the group consisting of lower alkyl, C3.6 alkenyl, C3^6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein lower alkyl is optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of -Ry, fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, and cycloalkylamino, provided that any substitution of the lower alkyl carbon bound to the -O- of -OR11, -S- of ^SR", or -N- of -NHR11 is fluoro or -Rv, and wherein C3.g alkenyl or C3^ alkynyl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of -Ry, fluoro, -OH, -NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio. mono- alkylamino, di-alkylamino, and cycloalkylamino, provided that any substitution of the C3.6 alkenyl or C3_6 alkynyl carbon bound to the the -O- of -OR", -S- of -SR", or -N- of -NHR" is fluoro, lower alkyl, fluoro substituted lower alkyl, or -RJ, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkyl amino, di-alkyl amino, and cycloalkylamino;
wherein each -Rκ is selected from the group consisting of lower alkyl, lower alkenyl and lower alkynyl, wherein lower alkyl is optionally substituted with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of - Ry, fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkyl amino, di-alkyl amino, and cycloalkylamino, and wherein lower alkenyl or lower alkynyl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1 , 2, or 3 substituents selected from the group consisting of -R*, fluoro, -OH, -NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkyl amino, di-alkyl amino, and cycloalkylamino;
wherein each -Ry is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally substituted with one or more, preferably 1 , 2, 3, 4 or 5, also 1, 2, or 3 substituents selected from the group consisting of halogen, -OH, -NH2, -NO2, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkyl amino, di-alkyl amino, and cycloalkylamino.
[0219] "Lower alkoxy" denotes the group -ORZ, where Rz is lower alkyl. "Substituted lower alkoxy" denotes lower alkoxy in which R2 is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I (including Formulae Ia, Ib, Ig and all sub-embodiments thereof), including descriptions of substituted cycloalkyl, cycloheteroalkyl, aryl and heteroaryl, attached at any available atom to produce a stable compound. Preferably, substitution of lower alkoxy is with 1, 2, 3. 4, or 5 substituents, also 1, 2. or 3 substituents. For example "fluoro substituted lower alkoxy" denotes lower alkoxy in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkoxy is substituted with 1 , 2. 3, 4 or 5 fluoro atoms, also 1 , 2, or 3 fluoro atoms. While it is understood that substitutions on alkoxy are attached at any available atom to produce a stable compound, substitution of alkoxy is such that -O-, -S-, or -N- (except where N is a heteroaryl ring atom), are not bound to the alkyl carbon bound to the alkoxy -O-. Further, where alkoxy is described as a substituent of another moiety, the alkoxy oxygen is not bound to a carbon atom that is bound to an — O-, -S-, or -N- of the other moiety (except where N is a heteroaryl ring atom), or to an alkene or alkyne carbon of the other moiety.
[0220] "'Lower alkylthio" denotes the group -SRad, where Rda is lower alkyl. "Substituted lower alkylthio" denotes lower alkylthio in which Raa is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I (including Formulae Ia, Ib, Ig and all sub-embodiments thereof), including descriptions of substituted cycloalkyl, cyclohctcroalkyl, aryl and heteroaryl, attached at any available atom to produce a stable compound. Preferably, substitution of lower alkylthio is with 1, 2, 3, 4, or 5 substituents, also 1 , 2, or 3 substituents. For example "fluoro substituted lower alkylthio" denotes lower alkylthio in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkylthio is substituted with 1 , 2, 3, 4 or 5 fluoro atoms, also 1 , 2, or 3 fluoro atoms. While it is understood that substitutions on alkylthio are attached at any available atom to produce a stable compound, substitution of alkylthio is such that -O-, -S-, or -N- (except where N is a heteroaryl ring atom), are not bound to the alkyl carbon bound to the alkyllhio -S-. Further, where alkylthio is described as a substituent of another moiety, the alkylthio sulfur is not bound to a carbon atom that is bound to an -O-, -S-, or -N- of the other moiety (except where N is a heteroaryl ring atom), or to an alkene or alkyne carbon of the other moiety.
[0221] "Amino" or "amine" denotes the group -NH2. "Mono-alkylamino" denotes the group -NHRbb where Rbb is lower alkyl. "Di-alkylamino" denotes the group -NRbbRDC, where Rbb and Rcc are independently lower alkyl. "Cycloalkylamino" denotes the group -NRddRee, where Rdd and Ree combine with the nitrogen to form a 5-7 membered heterocycloalkyl, where the heterocycloalkyl may contain an additional heteroatom within the ring, such as — O-, -N-, or -S-, and may also be further substituted with lower alkyl. Examples of 5-7 membered heterocycloalkyl include, but are not limited to, piperidine, piperazine, 4-methylpiperazine, morpholine, and thiomorpholine. While it is understood that when mono-alkylamino, di-alkylamino, or cycloalkylamino are substituents on other moieties that are attached at any available atom to produce a stable compound, the nitrogen of mono-alkylamino, di-alkylamino, or cycloalkylamino as substituents is not bound to a carbon alom that is bound to an -O-, -S-, or -N- of the other moiety. [0222] As used herein, the term c-kit-mediated disease or condition refers to a disease or condition in which the biological function of c-kit affects the de\ elopment and or course of the disease or condition, and or in which modulation of c-kit alters the development, course, and/or symptoms For example, mutations m the c-kit gene such as the W42, Wv, and W41 mutations reported by Herbst et al al (J Biol Chem , 1992, 267 13210-13216) confer severe, intermediate, and mild phenotypic characteristics, respectively These mutations attenuate the intrinsic tyrosine kinase activity of the receptor to different degrees and are models for the effect of modulation of c-kit activity A c-kit mediated disease or condition includes a disease or condition for which c-kit inhibition provides a therapeutic benefit, e g wherein treatment with c-kit inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition
[0223] As used herein, the teπn c-fms-mediated disease or condition refers to a disease or condition in which the biological function of c-fms affects the development and/or course of the disease or condition, and/or m which modulation of c-fms alters the development, course, and -Or symptoms For example the C 'sf Ir /CsJ Ir mutant mouse of Dai et al (Blood, 2002, 99 1 1 1 -120) which lacks c-fms is an animal model for diseases or conditions wherein c-fms activity has been abolished A c-fms mediated disease or condition includes a disease or condition for which c-fms inhibition provides a therapeutic benefit, e g wherein treatment with c-fms inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition
[0224] As used herein, the term "composition" refers to a formulation suitable for administration to an intended animal subject for therapeutic purposes that contains at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipicnt
[0225] The term "pharmaceutically acceptable' indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration For example, it is commonly required that such a material be essentially sterile, e g , for mjectibles
[0226] In the present context, the terms "therapeutically effective" and "effectrve amount" indicate that the mateπals or amount of material is effective to prevent, alle\iate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated [0227] Reference to particular amino acid residues m human c-kit polypeptide is defined by the numbering corresponding to the Kit sequence in GenBank NP_000213 (SEQ ID NO 1) Reference to particular nucleotide positions in a nucleotide sequence encoding all or a portion of c-kit ts defined by the numbeπng corresponding to the sequence provided in GenBank NM_000222 (StQ ID NO 2) Reference to particular amino acid residues in human c-fms polypeptide is defined by the numbering corresponding to the FMS precursor sequence in GenBank NP 005202 (SEQ ID NO 3) Reference to particular nucleotide positions m a nucleotide sequence encoding all or a portion of c-fms is defined by the numbering corresponding to the sequence provided in GenBank NM 00521 1 (SEQ ID NO 4)
[U228] The terms "kit", "c-kit", and "c-Kit" mean an enzymatically active kinase that contains a portion with greater than 90% ammo acid sequence identity to ammo acid residues including the ATP binding site of full-length c-kit (e g , human c-kit, e g , the sequence NP_000213, SEQ ID NO 1 ), for a maximal alignment over an equal length segment, or that contains a portion with greater than 90% ammo acid sequence identity to at least 200 contiguous ammo acids of native c-kit and retains kinase activity Preferably the sequence identity is at least 95, 97, 98, 99, or even 100% Preferably the specified level of sequence identity is over a sequence at least 100-500, at least 200-400, or at least 300 contiguous amino acid residues in length Unless indicated to the contrary, the term includes reterencc to wild-type c-kit, allelic variants, and mutated forms (e g having activating mutations)
|0229] The terms "fms", "c-fms", "FMS", and "c-Fms" mean an enzymatically active kinase that contains a portion with greater than 90% ammo acid sequence identity to amino acid residues including the ΛTP binding site of full-length c-fms (e g human c-fms, c g residues 20-972 of GenBank sequence NP 005202, SEQ ID NO 3), for a maximal alignment over an equal length segment, or that contains a portion with greater than 90% amino acid sequence identity to at least 200 contiguous ammo acids of native c-fms and retains kinase activity Preferably the sequence identity is at least 95, 97, 98, 99, or 100% Preferably the specified level of sequence identity is over a sequence at least 100-150, at least 200-400, or at least 300 contiguous ammo acid residues in length Unless indicated to the contrary, the term includes wild-type c-fms, allelic variants, and mutated forms (e g having activating mutations) The term "pFMS" refers to phosphorylated c-fms The term "c-fms activity" refers to a biological activity of c-fms. particularly including kinase activity The abbreviation "M-CSF" refers to the ligand for the c-fms RPTK, and the abbreviation "SCF" refers to the ligand for the c-Kit RPTK
I023UJ I he term "c-kit kinase domain" refers to a reduced length c-kit (ι e shorter than a full-length c-kit by at least 100 ammo acids) that includes the kinase catalytic region in c-kit lhe term 'c-fms kinase domain" refers to a c-fms of reduced length (i e shorter than a full-length c-fms b} at least 100 amino acids) that includes the kinase catalytic region of c-fms Highly pretcrably for use in this invention, the kinase domain retains kinase activity, prefeiably at least 60, 70, 80, 90, or 100% of the native c-fms kinase activity ihe term "the kinase ' or terms of similar import relate to either c-kit or c-fms
[0231] As used herein, the terms "hgand" and "modulator" are used equivalently to refer to a compound that changes (i e , increases or decreases) the activity of a target biomolecule, e g an enzyme such as a kinase or kinase Generally a ligand or modulator will be a small molecule, where "small molecule" refers to a compound with a molecular weight of 1500 daltons or less, or preferably 1000 daltons or less, 800 daltons or less, or 600 daltons or less
[0232] In the context of compounds binding to a target the term "greater affinity" indicates that the compound binds more tightly than a reference compound, or than the same compound in a reference condition, ; e , with a lower dissociation constant In particular embodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50 100, 200, 400, 500, 1000, or 10,000-fold greater affinity
[0233] Also in the context of compounds binding to a biomolccular target, the term "greater specificity" indicates that a compound binds to a specified target to a greater extent than to another biomolecule or biomolecules that may be present under relevant binding conditions, where binding to such other biomolecules produces a different biological activity than binding to the specified target Typically, the specificity is with reference to a limited set of other biomolecules, e g in the case of c-kit or c-fms, other tyrosine kinases or even other type of enzymes In particular embodiments, the greater specificity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, or 1000- fold greater specificity
[0234] As used herein in connection with binding compounds or hgands, the term "specific for c-kit kinase", "specific for c-kit", and terms of like import mean that a particular compound binds to c-kit to a statistically greater extent than to other kinases that may be present in a particular sample Also, where biological activity other than binding is indicated, the term "specific for c-kit" indicates that a particular compound has greater biological effect associated with binding c-kit than to other tyrosine kinases, e g , kmase activity inhibition Preferably, the specificity is also with respect to other biomolecules (not limited to tyrosine kinases) that may be present in a particular sample I he term "specific for c-fms kmase", 'specific for c-fms*', and terms of like import mean that a particular compound binds to c-fms to a statistically greater extent than to other kinases that iω> be present in a particular sample Also, where biological activity other than binding is indicated, the term 'specific for c-fms" indicates that a particular compound has greater biological effect associated with binding c fms than to other tyrosine kinases, e g kinase activity inhibition. Preferably, the specificity is also with respect to other biomolecules (not limited to tyrosine kinases) that may be present in a particular sample.
[0235] As used herein in connection with lest compounds, binding compounds, and modulators (ligands), the term "synthesizing" and like terms means chemical synthesis from one or more precursor materials.
[0236] By "assaying" is meant the creation of experimental conditions and the gathering of data regarding a particular result of the experimental conditions. For example, enzymes can be assayed based on their ability to act upon a detectable substrate. Λ compound or ligand can be assayed based on its ability to bind to a particular target molecule or molecules.
[0237] Λs used herein, the term "modulating'* or "modulate" refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as c-kit or c-fms. For example, an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e.g. , an enzyme.
[0238] The term "c-kit activity" refers to a biological activity of c-kit, particularly including kinase activity. The term "c-fms activity" refers to a biological activity of c-fms, particularly including kinase activity.
[0239] In the context of the use, testing, or screening of compounds that are or may be modulators, the term "contacting" means that the compound(s) are caused to be in sufficient proximity to a particular molecule, complex, cell, tissue, organism, or other specified material that potential binding interactions and/or chemical reaction between the compound and other specified material can occur.
[0240] Λs used herein in connection with amino acid or nucleic acid sequence, the term "isolate" indicates that the sequence is separated from at least a portion of the amino acid and/or nucleic acid sequences with which it would normally be associated,
[0241] In connection with amino acid or nucleic sequences, the term "purified" indicates that the particular molecule constitutes a significantly greater proportion of the biomolecules in a composition than in a prior composition, e.g., in a cell culture. The greater proportion can be 2- fold, 5-fold, 10-fold or more greater.
I. General [0242] In one aspect, the present invention concerns compounds of Pormula 1, 1 ormula Ia, Formula Ib, Formula Ig, Formula II, Formula Ila, Formula lib, Formula lie, Formula lid Formula He, Formula Hf. Formula Hg, Formula Hh, Formula Ih, Formula IIj, Formula Ilk, Formula Hm, Formula Hn, Formula Ho, Formula Up, or 1- ormula III and all sub-embodiments thereof, that are inhibitors of c-kit, c-fms, or both c-kit and c-fms, and the use of the compounds in treating diseases that are mediated b> c-kit, e-fms, or both c-kit and c-fms
Exemplary Diseases Associated with c-Kit.
[0243] The compounds described herein are useful for treating disorders related to c-kit e g , diseases related to unregulated kinase signal transduction, including cell proliferative disorders, fibrotic disorders and metabolic disorders, among others As described in more detail below and in Lipson et al , U S 20040002534 (U S application 10/600, 868, filed June 23, 2003) which is incorporated herein by reference in its entirety cell proliferative disorders which can be treated by the present invention include cancers, and mast cell proliferative disorders
[0244] The presence of c-kit has also been associated with a number of different types of cancers, as described below In addition, the association between abnormalities in c-kit and disease are not restricted to cancer As such, c-kit has been associated with malignancies, including mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors (GISTs), glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myelocytic leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, mastocytosis, melanoma, and canine mast cell tumors, and inflammatory diseases, including asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, inflammatory bowel syndrome, transplant rejection, and hypereosmophiha
Exemplary malignant diseases associated with c-kit
[0245] Abeπ ant expression and/or activation of c-kit has been implicated in a variety of cancers lividcnce for a contribution of c-kit to neoplastic pathology includes its association with leukemias and mast cell tumors small cell lung cancer, testicular cancer, and some cancers of the gastrointestinal tract and central nervous system In addition, c-kit has been implicated in playing a role in carcinogenesis of the female genital tract (Inoue, et al , 1994, Cancer Res 54(1 1) 3049- 3053), sarcomas of neuroectodermal oπgm (Ricotti, et al , 1998, Blood 91 2397-2405), and Schwann cell neoplasia associated with neurofibromatosis (Ryan, et al , 1994, J Neuro Res 37 415-432) It was found that mast cells are involved in modifying the tumor microem ironment and enhancing tumor growth (Yang et al 2003, J Clin Invest 1 12 1851 -1 861, Viskochil, 2003, J Clin Invest. 1 12: 1791 -1793). Thus, c-kit is a useful target in treating neurofibromatosis as well as malignant tumors.
|0246] Small cell lung carcinoma: c-kit kinase receptor has been found to be aberrantly expressed in many cases of small cell lung carcinoma (SCLC) cells (Hibi, et al., 1991 , Oncogene 6:2291-2296). Thus, as an example, inhibition of c-kit kinase can be beneficial in treatment of SCLC, e.g., to improve the long term survival of patients with SCLC.
[0247] Leukemias: SCF binding to the c-kit protects hematopoietic stem and progenitor cells from apoptosis (Lee, et al., 1997, J. Immunol. 159:321 1 -3219), thereby contributing to colony foπnation and hematopoiesis. Expression of c-kit is frequently observed in acute myelocytic leukemia (AML), and in some cases of acute lymphocytic leukemia (ALL) (for reviews, see Sperling, et al., 1997, Haemat 82:617-621 ; Escribano, et al., 1998, Leuk. Lymph. 30:459-466). Although c-kit is expressed in the majority of AML cells, its expression docs not appear to be prognostic of disease progression (Sperling, et al, 1997, Haemat 82:617-621). However, SCF protected AML cells from apoptosis induced by chemotherapeutic agents (Hassan, et al , 1996, Acta. Hem. 95:257-262). Inhibition of c-kit by the present invention will enhance the efficacy of these agents and can induce apoptosis of AML cells.
[0248] The clonal growth of cells from patients with myelodysplastic syndrome (Sawada, et al., 1996, Blood 88:319-327) or chronic myelogenous leukemia (CML) (Sawai, et al., 1996, Exp. Hem. 2: 1 16-122) was found to be significantly enhanced by SCF in combination with other cytokines. CML is characterized by expansion of Philadelphia chromosome positive cells of the marrow (Verfaillie, et al., Leuk. 1998, 12: 136-138). which appears to primarily result from inhibition of apoptotic death (Jones, Curr. Opin. One. 1997, 9:3-7). The product of the Philadelphia chromosome, p210DCR"ΛBL, has been reported to mediate inhibition of apoptosis (Bedi. et al.. Blood 1995, 86:1 148-1 158). Since p210DCR"ABL and c-kit both inhibit apoptosis and p62dok has been suggested as a substrate (Carpino, et al., Cell 1997, 88:197-204), clonal expansion mediated by these kinases may occur through a common signaling pathway. However, c-kit has also been reported to interact directly with p210DCR"ADL (Hallek, et al., Brit. J Hacm. 1996, 94:5- 16), which suggests that c-kit has a more causative role in CML pathology. Therefore, inhibition of c-kit will be useful in the treatment of the above disorders.
[02491 Gastrointestinal cancers: Normal colorectal mucosa does not express c-kit (Bellone, et al., 1997, J. Cell Physiol. 172: 1 -1 1). However, c-kit is frequently expressed in colorectal carcinoma (Bellone, et al., 1997, J. Cell Physiol. 172: 1-11), and autocrine loops of SCF and c-kit have been observed in several colon carcinoma cell lines (Toyota, et al., 1993, Turn Biol 14:295-302; Lahm, et al., 1995, Cell Growth &Differ 6: 11 11-1 118; Bellone, et al., 1997, J. Cell Physiol. 172:1-1 1 ). Furthermore, disruption of the autocrine loop by the use of neutralizing antibodies (Lahm, et al 1995, Cell Growth & Differ 6 1 1 1 1 -1 1 1 8) and downregulation of c-kit and/or SCT significantly inhibits cell proliferation (Lahm, et al , 1995, Cell Growth & Differ 6 1 1 1 1-1 1 1 8, Bellone, et al ,
1997, J Cell Physiol 172 1-1 1 )
[0250J SCF'c-kit autocrine loops have been observed in gastric carcinoma cell lines (Turner, et al , 1992, Blood 80 374-381 , Hassan, et al , 1998 Digest Dis Science 43 8-14), and constitutive c-kit acti\ ation also appears to be important for gastrointestinal stromal tumors (GISl s) GIS 1 s are the most common mesenchymal tumor of the digestive system More than 90% of GISTs express c-kit which is consistent with the putative origin of these tumor cells from interstitial cells of Cajal (ICCs) (Hirota, et al , 1998, Science 279 577-580) ICCs are thought to regulate contraction of the gastrointestinal tract, and patients lacking c-kit m their ICCs exhibited a myopathic form of chronic idiopathic intestinal pseudo-obstruction (Isozaki, et al , 1997, Amer J of Gast 9 332- 334) lhe c-kit expressed in GTS Fs from several different patients was observed to have mutations in the intracellular juxtamembrane domain leading to constitutive activation of c-kit (Hirota, et al ,
1998, Science 279 577-580) Hence, inhibition of c-kit kinase will be an efficacious means for the treatment of these cancers
[0251] 1 esticular cancers Male germ cell tumors have been histologically categorized into seminomas, which retain germ cell characteristics, and nonseminomas which can display characteristics of embryonal differentiation Both seminomas and nonseminomas are thought to initiate from a preinv asive stage designated carcinoma in situ (CIS) (Murty, et al , 1998, Sem Oncol 25 133-144) Both c-kit and SCI4 have been reported to be essential tor normal gonadal development during embryogenesis (Loveland, et al , 1997, J Endocrinol 153 337-344) Loss of either the receptor or the hgand resulted in animals devoid of germ cells In postnatal testes, c-kit has been found to be expressed in Leydig cells and spermatogonia, while SCF was expressed in Sertoli cells (Loveland, et al , 1997, J Endocπnol 153 337-344) l esticular tumors develop from Leydig cells with high frequency in transgenic mice expressing human papilloma virus 16 (HPV16) E6 and E7 oncogenes (Kondoh, et al , 1991 , J Virol 65 3335-3339, Kondoh, et al , 1994, J Urol 152 2151-2154) lhese tumors express both c-kit and SCF, and an autocrine loop may contribute to the tumoπgenesis (Kondoh, ct al , 1995, Oncogene 10 341-347) associated with cellular loss of functional p53 and the retinoblastoma gene product by association with E6 and E7 (Dyson, et al , 1989, Science 243 934-937, Wemess, et al , 1990, Science 248 76-79, Scheffner et al , 1990, Cell 63 1 129-1 136) Defective signaling mutants of SCF (Kondoh, et al , 1995, Oncogene 10 341-347) or c-kit (Li, et al , 1996, Cane Res 56 4343-4346) inhibited formation of testicular tumors in mice expressing HPV 16 E6 and E7 lhe c-kit kinase activation is pivotal to tumoπgeneMs in these animals and thus modulation of the c-kit kinase pathway
Figure imgf000129_0001
the present m\ention will prevent or treat such disorders
[0252] Expression of c-kit in germ cell tumors shows that the receptor is expressed by the majority of carcinomas in situ and seminomas, but c-kit is expressed in only a rmnont) of πonsemmomas (Strohrπeyer, et al , 1991, Cane Res 51 181 1-1816, Rajpert-de Mevts, et al , 1994, Int J Λndrol 17 85-92, Izquierdo, et al , 1995, J Pathol 177 253-258 Strohrπeyer, et al 1995 J Urol 153 511-515, Bokenmeyer, et al 1996, J Cancer Res CIm Oncol 122 301 306, Sandlow , et al , 1996, J Androl 17 403-408) Therefore, inhibition of c-kit kinase provides a means for treating these disorders
[0253] CNS cancers SCF and c-kit are expressed throughout the CNS of developing rodents, and the pattern of expression indicates a role in growth, migration and differentiation of neuroectodermal cells Fxpression of both receptor and hgand have also been reported in the adult brain (Hamel, et al , 1997, J Neuro-Onc 35 327-333) Expression of c-kit has also been observed in normal human brain tissue (Tada, et al 1994, J Neuro 80 1063-1073) Glioblastoma and astrocytoma, which define the majority of intracranial tumors, arise from neoplastic transformation of astrocytes (I evin, et al , 1997, Principles & Practice of Oncology 2022-2082) Expression of c-kit has been observed in glioblastoma cell lines and tissues (Berdel et al , 1992, Cane Res 52 3498-3502, Tada, et al 1994, J Neuro 80 1063-1073, Stanulla, ct al , 1995, Act Neuropath 89 158-165)
[0254] Cohen, et al , 1994, Blood 84 3465-3472 reported that all 14 neuroblastoma cell lines examined contained c-kit/SCF autocrine loops, and expression of both the receptor and hgand were observed in 45% of tumor samples examined In two cell lines, anti-c-kit antibodies inhibited cell proliferation, suggesting that the SClVc-kit autocrine loop contnbuted to growth (w ill Cohen et al , 1994, Blood 84 3465-3472) Hence, c-kit kinase inhibitors can be used to treat these cancers
Exemplary Mast Cell Diseases Involving c-kit
[0255] Excessive activation of c-kit is also associated with diseases resulting from an overabundance of mast cells Mastocytosis is the term used to describe a heterogeneous group ot disorders characterized bv excessive mast cell proliferation (Metcalfe, 1991 , J Invest Derm 93 2S-4S, Golkar, et al , 1997, Lantet 349 1379-1385) Elevated c-kit expression was reported on mast cells from patients with aggressive mastocytosis (Nagata, et al , 1998, Leukemia 12 175- 1 81) [0256] Additionally, mast cells and eosinophils represent key cells involved in allergy, inflammation and asthma (Thomas, et al , 1996 Gen Pharmacol 27 593-597 Metcalfe, et al , 1997, Physiol Rev 77 1033-1079, Nacleπo, et al , 1997. JAMA 278 1842-1848, Costa, et al , 1997, JAMA 278 1815-1822) SCT, and hence c-kit, directly and indirectly regulates activation of both mast cells and eosinophils, thereby influencing the primary cells involved in allergy and asthma through multiple mechanisms Because of this mutual regulation of mast cell and eosinophil function, and the role that SCF can play in this regulation, inhibition of c-kit can be used to treat allergy-associated chronic rhinitis, inflammation and asthma
[0257J Mastocytosis SCF (also known as mast cell growth factor) stimulation of c-kit has been reported to be essential for the growth and development of mast cells (Ilamel, et al , 1997, J Neuro-Onc 35 327-333, Kitamura, ct al , 1995, lnt Arch Aller Immunol 107 54-56) Mice with mutations of c-kit that attenuate its signaling activity have exhibited significantly fewer mast cells in their skm (Tsujimura, 1996, Pathol lnt 46 933-938) Excessive activation of c-kit can be associated with diseases resulting from an over abundance ot mast cells
|0258| Mastocytosis is limited to the skin in the majority of patients, but can involve other organs in 15-20% of patients (Valent, 1996, Wein/Klin Wochenschr 108 385-397, Golkar, et al , 1997, Lancet 349 1379-1385) E\ en among patients with systemic mastocytosis, the disease can range from having a relatively benign prognosis to aggressive mastocytosis and mast cell leukemia (Valent, 1996, Wein/Klin Wochenschr 108 385-397, Golkar, et al , 1997 Lancet 349 1379-1385) c-kit has been observed on malignant mast cells from canine mast cell tumors (London et al , 1996, J Coinpar Pathol 115 399-414), as well as on mast cells from patients with aggressive systemic mastocytosis (Baghestaman, ct al , 1996, Leuk 1 16-122, Castells, et al , 1996, J Aller Clin Immunol 98 831-840)
[0259] SCF has been shown to be expressed on stromal cells as a membrane-bound protein, and its expression can be induced by fibrogenic growth factors such as PDGF It has also been shown to be expressed on keratinocytes as a membrane-bound protein in normal skm However, in the skin of patients with mastocytosis, an increased amount of soluble SCF has been observed (Longley, et al , 1993, New Engl J Med 328 1302-1307)
[0260] Mast cell chymase has been reported to cleave membrane-associated SCF to a soluble and biologically active form 1 his mast cell-mediated process can generate a feedback loop to enhance mast cell proliferation and function (Longley, et al , 1997, Proc Natl Acad Sci 94 9017- 9021), and may be important for the etiology of mastocytosis Transgenic mice overexpressmg a form of SCF that could not be proteolytically released from keratinocytes did not develop mastocytosis, while similar animals expressing normal SCF in keratinocytes exhibited a phenotype resembling human cutaneous mastocytosis (Kumsada, et al , 1998, J Exp Med 187 1565-1573) Formation of large amounts of soluble SCF can contribute to the pathology associated w ith mastocytosis in some patients and the present invention can treat or prevent such disorders by modulating the interaction between SCF and c-kit kinase Several different mutations of c-kit that resulted in constitutive kinase activity have been found in human and rodent mast cell tumor cell lines (Fuπtsu et al 1993, J CIm Invest 92 1736-1744, I sujimura et al , 1994, Blood 9 2619- 2626, lsujimura, et al , 1995, Int Arch Λller Immunol 106 377-385 Tsuμmura, 1996, Pathol Int 46 933-938) In addition, activating mutations of the c-kit gene have been observed in peπpheral mononuclear cells isolated from patients with mastocytosis and associated hematologic disorders (Nagata, et al , 1998, Mastocytosis Lcuk 12 175-181), and in mast cells from a patient with urticaria pigmentosa and aggressive mastocytosis (Longley, et al , 1996, Ts at Gen 12 312-314) Inhibition of c-kit kinase will therefore prove to ha\ e an excellent therapeutic role in the treatment of these disorders
[0261] In some patients, activating mutations of c-kit may be responsible for the pathogenesis ot the disease and these patients can be treated, or their diseases prevented, by modulation of the SCF interaction with c-kit kinase SCF activation of c-kit as been shown to prevent mast cell apoptosis which may be critical for maintaining cutaneous mast cell homeostasis (lemura, et al , 1994, Amer J Pathol 144 321-328, Yee, et al , 1994, J Exp Med 179 1777-1787, Mekoπ, et al , 1994, J Immunol 153 2194-2203, Mekoπ, et al , 1995, Int Arch Allergy Immunol 107 137-138) Inhibition of mast cell apoptosis can lead to the mast cell accumulation associated with mastocytosis Thus, observation ot c-kit activation resulting from overexpression ot the receptor, excessive formation of soluble SCF, or mutations of the c-kit gene that constitutively activate its kinase, provides a rationale that inhibition of the kinase activity of c-kit will decrease the number of mast cells and provide benefit for patients with mastocytosis
[0262] For cells with activating c-kit mutations, it w as found that inhibitors of c kit inhibit or even kill the cells (Ma et al 2000, J Invest Dermatol 114 392-394), particularly tor mutations in the regulatory region (Ma et al , 2002, Blood 99 1741 -1744) Ma et al , 2002 also showed that for mutations in the catalytic region, inhibitors STI571 (Gleevec) and SU9529 did not inhibit the cells, such that additional types of c-kit inhibitors are useful Thus, c kit inhibitors can be used against both wild-type c-kit as well as c-kit having mutations, e g , activating mutations m the regulatory region and/or catalytic region
[0263] Asthma & Allergy Mast cells and eosinophils represent key cells in parasitic infection, allergy, inflammation, and asthma (Thomas, et al , 1996, Gen Pharmacol 27 593-597, Metcalfe. et al , 1997, Physiol Rev 77 1033-1079, Holgate, 1997, ClBA Found Symp , Nacleπo, et al, 1997 JΛMΛ 278: 1842-1848; Costa, et al,, 1997, JAMA 778; 1815-1822). SCF has been shown to be essential for mast cell development, survival and growth (Kitamura, et al., 1995, Int. Arch. Λller, Immunol. 107:54-56; Metcalfe, et al., 1997, Physiol Rev 77:1033-1079). In addition, SCF cooperates with the eosinophil-specific regulator, IL-5, to increase the development of eosinophil progenitors (Metcalf, et al., 1998, Proc. Natl. Acad. Sci, USA 95:6408-6412). SCF has also been reported to induce mast cells to secrete factors (Okayama, et al., 1997, Int. Arch. Aller. Immunol. 1 14:75-77; Okayama, et al., 1998, Eur. J. Immunol. 28:708-715) that promote the survival of eosinophils (.Kay, et al., 1997, Int. Arch. Λller. Immunol. 113:196-199), which may contribute to chronic, eosinophil-mediated inflammation (Okayama, et al., 1 997, Int. Arch. Aller. Immunol. 114:75-77; Okayama, et al., 1998, Eur. J. Immunol. 28:708-715). In this regard, SCF directly and indirectly regulates activation of both mast cells and eosinophils.
|0264J SCF induces mediator release from mast cells, as well as priming these cells for IgE- induced degranulatioπ (Columbo, et al., 1 992, J, Immunol 149:599-602) and sensitizing their responsiveness to eosinophil-derived granule major basic protein (Furuta. et al., 1998, Blood 92: 1055-1061 ). Among the factors released by activated mast cells are IL-5, GM-CSF and TNF-α, which influence eosinophil protein secretion (Okayama, et al., 1997, Int. Arch. Aller. Immunol. 1 14:75-77; Okayama, et al., 1998, Eur. J. Immunol. 28:708-715). In addition to inducing histamine release from mast cells (Luckacs, et al., 1 996, J. Immunol. 156:3945-3951 ; Hogaboam, et al., 1998, J. Immunol. 160:6166-6171 ), SCF promotes the mast cell production of the eosinophil chcmotactic factor, eotaxin (Hogaboam, et al., 1998, J. Immunol, 160:6166-6171), and eosinophil infiltration (Luckacs, et al.. 1996, J. Immunol. 156:3945-3951 ).
10265] SCF also directly influences the adhesion of both mast cells (Oastych, et al., 1994, J. Immunol. 152:213-219; Kinashi, ct al., 1994, Blood 83: 1033-1038) and eosinophils (Yuan, et al., 1997, J. Exp. Med. 186:313-323), which in turn, regulates tissue infiltration. Thus, SCF can influence the primary cells involved in allergy and asthma through multiple mechanisms. Currently, corticosteroids are the most effective treatment for chronic rhinitis and inflammation associated with allergy (Naclerio, et al., 1997, JAMA 278: 1842-1848; Meltzer, 1997, Aller. 52:33- 40). These agents work through multiple mechanisms including reduction of circulating and infiltrating mast cells and eosinophils, and diminished survival of eosinophils associated with inhibition of cytokine production (Meltzer, 1997, Aller. 52:33-40). Steroids have also been reported to inhibit the expression of SCF by fibroblasts and resident connective tissue cells, which leads to diminished mast cell survival (Finotto, et al., 1997, J. Clin. Invest. 99 1721 -1728). Because of the mutual regulation of mast cell and eosinophil function, and the role that SCF can play in this regulation, inhibition of c-kit kinase will provide a means to treat allergy-associated chronic rhinitis, inflammation and asthma. [0266] Inflammatory arthritis (eg rheumatoid arthritis) Due to the association of mast cells with the arthritic process (Lee et al , 2002, Science 297:1689-1692), c-kit provides a useful target for prevention, delay, and/or treatment of inflammatory arthritis, such as rheumatoid arthritis,
|0267] Multiple sclerosis: Mast cells have been shown to play an extensive role in autoimmune diseases, as demonstrated in the mouse model of multiple sclerosis (MS), experimental allergic encephalomyelitis (EAE) Mast cells were indicated to be required for full manifestation of the disease, Secor et al , 2000, J Exp Med 191 :813-821. Thus, c-kit also provides a useful target for the prevention, delay, and/or treatment of multiple sclerosis.
Exemplary' diseases associated with c-fms
[0268] The presence of c-fms has been associated with a number of different types of diseases. As such, c-fms has been associated with immune disorders, including rheumatoid arthritis, systemic lupus erythematosis (SLE), and transplant rejection, inflammatory diseases including, but not limited to, osteoarthritis, inflammatory bowel syndrome, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease (COPD), emphysema, Kawasaki's Disease, hcmophagocytic syndrome (macrophage activation syndrome), multicentric reticulohistiocytosis, and atherosclerosis; metabolic disorders, including, but not limited to, Type I diabetes, Type Il diabetes, insulin resistance, hypoglycemia, obesity, and hpolysis; disorders of bone structure, mineralization and bone formation and resorption, including, but not limited to, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, infection-mediated osteolysis (e g , osteomyelitis), pen-prosthetic or wear-debris-mediated osteolysis, and metastasis of cancer to bone, kidney and genitourinary diseases, including, but not limited to,endometnosis, nephritis (e.g. glomerulonephritis, interstitial nephritis, Lupus nephritis), tubular necrosis, diabetes- associated renal complications (e.g diapetic nephropathy), and renal hypertrophy, disorders of the central nervous system, including, but not limited to, multiple sclerosis, stroke, Alzheimer's disease and Parkinson's disease; inflammatory and chronic pam, including, but not limited to bone pain; and cancers, including, but not limited to, multiple myeloma, acute myeloid leukemia (AML), chrome myeloid leukemia (CML). prostate cancer, breast cancer, ovarian cancer, melanoma, glioblastoma multiforme, metastasis of tumors to other tissues, and other chronic myeloproliferative diseases such as myelofibrosis
[0269] Aberrant expression and/or activation of c-fms has been implicated in acute myeloid leukemia, AML (Ridge et al, Proc. Nat. Acad. Sci., 1990, 87 1377-1380) Mutations at codon 301 are believed to lead to neoplastic transforation by ligand independence and constitutive tyrosine kinase activity of the receptor The tyrosine residue at codon 969 has been shown to be involved in a negative regulatory activity, which is disrupted by amino acid substitutions. Accordingly, c-fms mutations are most prevalent (20%) in chronic myelomonocytic leukemia and AML type M4 (23%), both of which are characterized by monocytic differentiation.
[0270] A condition related to AML is chronic myeloid leukemia (CML). During the myeloid blast crisis (BC) of CML, non-random additional chromosome abnormalities occur in over 80% of patients. However, these cytogenetic changes have been reported to precede the clinical signs of CML-BC by several months to years suggesting that other biological events may participate in the multistep process of acute transformation of CML. The autocrine production of growth factors has been shown to occur in several hematological malignancies and particularly in AML. Specchia et al [Br J Haematol. 1992 Mar; 8O(3):310-6] have demonstrated that TL-I beta gene is expressed in almost all cases of CML in myeloid blast crisis, and that a high proportion of cases showed constitutive expression of the M-CSF gene. Many of the same patients in the Specchia et al study demonstrated simultaneous co-expression of c-fms. After exposure of leukemic cells to phorbol myristate acetate (PMA), release of M-CSF protein was documented in three of five patients studied; however, no significant interleukin-3 (1L-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) or granulocyte colony-stimulating factor (G-CSF), was detected in these patients. This demonstrates that different patterns of growth factors secretion exist in AML and CML, and that distinct molecular events are likely involved in the control of leukemic proliferation.
[0271] The observation that production of M-CSF, the major macrophage growth factor, is increased in tissues during inflammation (Le Meur et al, J. Leukocyte Biology. 2002;72:530-537) provides a role for c-fms in certain diseases. For example, COPD is characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. The chronic inflammation of COPD is observed through the airways, parenchyma, and pulmonary vasculature. The inflammatory cell population consists of neutrophils, macrophages, and T lymphocytes, along with eosinophils in some patients. Macrophages are postulated to play an orchestrating role in COPD inflammation by releasing mediators such as TNF-α, IL-8 and LTB4, which are capable of damaging lung structures and/or sustaining neutrophilic inflammation.
[0272] Further, M-CSF/Fms signaling is critical to osteoclast formation and survival of osteoclast precursors. For example, estrogen loss in menopause results in increased M-CSF and thus increased osteoclast number and bone resorption which leads to increased risk of fracture and osteoporosis. Accordingly, blockage of this signal is a target for the inhibition of bone resorption (Teitelbaum, Science. 2000;289:1504; Rohan, Science. 2000;289: 1508.) [0273] Atherosclerosis, an inflammatory disease of the vessel walls, is associated with significant morbidity and mortality. A effect for c-fms inhibition in the treatment and prevention of atherosclerosis depends on several observations (Libby, Nature, 2002:420:868-874.) First, monocytes resident in the arterial intima increase expression of scavenger receptors and internalize modified lipoproteins. The resulting lipid-laden macrophages develop into foam cells characteristic of the atherosclerotic lesion. Macrophages in atheroma secrete cytokines and growth factors involved in lesion progression. Additionally, macrophages replicate within the intima. Through c-fms, M-CSF activates the transition from monocyte to lipid-laden macrophage and augments expression of scavenger receptor A. Indeed, atherosclerotic plaques over-express M-CSF which is critical for atherosclerotic progression. Mice deficient in M-CSF have been found to experience less severe atherosclerosis than mice with normal M-CSF (Rajavashisth, et. al., J. Clin. Invest. 1998;101 :2702-2710; Qiao, et. al., Am. J. Path. 1997; 150:1687-1699). Accordingly, inhibitors of c-fms disrupt M-CSF signaling, compromising monocyte to macrophage foam cell progression, macrophage survival and replication, and cytokine signaling that participates in lesion progression.
[0274] The role of M-CSF and c-fms in emphysema appears to involve the regulation of elastin metabolism through control of matrix metalloproterns. M-CSF has a role in the modulation of the accumulation and function of alveolar macrophages (AMs) in vivo (Shibata et al, Blood 2001 , 98: pp. 2845-2852). Osteopetrotic (Op/Op) mice have no detectable M-CSF and show variable tissue- specific reductions in macrophage numbers. Accordingly, it was hypothesized that AMs would be decreased in number and have altered function in Op/Op mice because of the absence of M-CSF. Shibata et al found that lung macrophages identified in lung sections were decreased in number in 20-day-old Op/Op mice but not Op/Op mice older than 4 months compared with findings in age-matched littermate controls. The numbers of AMs recovered by bronchoalveolar lavage (BAL) were also reduced in young but not adult Op/Op mice compared with controls. Importantly, AMs of Op/Op mice spontaneously release higher levels of matrix metalloproteinases (MMPs) than AMs of controls. Consistent with an increased release of MMP, Op/Op mice have abnormal elastin deposition and spontaneously develop emphysema in the absence of molecular or cellular evidence of lung inflammation. Accordingly, the modulation of metalloelastase activity in macrophages by M-CSF may control the degradation of elastin fibers in lungs or blood vessels.
(0275} Metastatic cancer cells cause bone destruction, with associated fracture, pain, deformation, and hypercalcaemia, due to production of osteoclasticogenic factors including M-CSF by tumor cells (Clohisy et al, Clin. Orthop. 2000, 373: 104-14). Binding of M-CSF to the c-fms product stimulates formation of osteoclasts and osteolytic activity (Kodama et al, J. Exp,. Med. 1991 , 173: 269-72; Feng et al, Endocrinology 2002, 143: 4868-74). Accordingly, inhibition of osteoclast activity at the level of c-fms offers a compelling target for amelioration of bone metastasis
[0276] Macrophage accumulation is a prominent feature in many forms of glomerulonephritis Local proliferation of macrophages within the kidney has been described in human and experimental glomerulonephritis and ma) have an important role in augmenting the inflammatory response Isbel et al (Nephrol Dial transplant 2U01 , 16 1638-1647) examined the relationship betw een local macrophage proliferation and renal expression of M-CSF Glomerular and tubulomterstitial M-CSF expression was found to be up-regulated in human glomerulonephritis, being most prominent m piohferative forms of disease Because this correlates with local macrophage proliferation, it suggests that increased renal M-CSF production plays an important role in regulating local macrophage proliferation m human glomerulonephritis In a model of renal inflammation (UUO- unilateral ureteric obstruction) anti-c-fms antibody treatment reduced maci ophage accumulation (Le Meur ct al , J Leukocyte Biology 2002 72 530-537) Accordingly, inhibition of c-fms offers a target for therapeutic mterv ention in glomerulonephritis
|02771 Insulin resistance and obesity are hallmark of type II diabetes and there is a strong correlation between insulin resistance and abdominal visceral fat accumulation (Bjorntrop, Diabetes Metab Res Rev , 1999, 15 427-441) Current evidence indicates that macrophages accumulating m adipose tissue release TNF-a and other factors that cause adipocyte changes (hypertrophy, lipolysis, reduced insulin sensitivity) and also promote insulin resistance in surrounding tissues Therefore, macrophage accumulation in type 2 diabetes is important for disease progression Accordingly, inhibition of c-fms has potential in preventing the development of insulin resistance and hyperglycemia
[0278] Dewar et al have recently demonstrated that the kinase inhibitor imatimb also specifically targets the macrophage colony stimulating factor receptor, c-fms, at therapeutic concentrations Although this finding has important implications with regard to potential side effects in patients currently receiving imatimb therapy, these results suggest that imatimb may also be useful m the treatment of diseases where c-fms is implicated This includes breast and ovarian cancer and inflammatory conditions such as rheumatoid arthritis Dew ar et al also speculate that imatimb may be used in diseases where bone destruction occurs due to excessive osteoclast activity, such as in the haematologic malignancy, multiple myeloma (Dewar et al , Cell Cycle 2005, 4(7) 851-3)
[0279] To determine the importance or M-CSF in driving macrophage proliferation during acute rejection, Jose et al blocked the M-CSF receptor, c-fms, in a mouse model of acute renal allograft rejection They observed that the severity of tubulomterstitial rejection was reduced m the treatment group as shown by decreased tubulitis and tubular cell proliferation. Macrophage proliferation during acute allograft rejection is dependent on the interaction of M-CSF with its receptor c-fms. They indicate that this pathway plays a significant and specific role in the accumulation of macrophages within a rejecting renal allograft (Jose et al., Am J Transplant 2003, 3(3):294-300).
10280] Further, modulators of both c-fms and c-kit function can be used against diseases such as those indicated above, where in some instances, the dual activity of the modulator for both c-fms and c-kit provides distinct advantages in treating such diseases. The complementary activities provided by a single compound would provide added benefits over compounds targeting one or the other activity, or separate compounds targeting these activities. For example, by attenuating release of macrophage chemo-attractants by mast cells or mast cell chemoattractants by macrophages, these anti-inflammatory effects would synergize with the concomitant inhibition of intrinsic cellular function. Limitations in co-administration are absent in a dual inhibitor. Further, the dual activity may result in much lower effective doses for treatment.
Exemplary diseases associated with TrkA and TrkB
[0281] TrkA: Target kinase TrkA (i.e., neurotrophic tyrosine kinase, receptor, type 1) is a 140 kDa tyrosine kinase encoded by chromosome Iq21-q22 (symbol: NTRKl). TrkA inhibitors may be useful in treating pain (e.g. chronic pain, neuropathic pain), cancer (e.g. prostate cancer, lung cancer, myeloid leukemia, pancreatic cancer), allergic disorders (e.g. asthma), arthritis, diabetic retinopathy, macular degeneration and psoriasis.
[0282] TrkA is a plasma member receptor composed of an extracellular domain (responsible for high affinity binding to nerve growth factor, NGF), a transmembrane segment and an intracellular protein tyrosine kinase domain (responsible to transmit the NGF signal to initiate and coordinate neuronal responses). NGF binding induces TrkA clustering on the membrane and activates the kinase. The kinase initiates a cascade of protein phosphorylation events through multiple pathways including SHC/Ras/MAPK, PI3K and PLCgI . A TrkA kinase inhibitor would not prevent NGF/TrkA binding, but could prevent down-stream signal transduction.
[0283] Nerve Growth Factor (NGF) is produced by a number of tissues and inflammatory cells during tissue injury and host immune response. It initiates and maintains hypersensitivity to incoming stimulus (hyperalgesia) and the perception of non-noxious stimuli (allodynia). Through its high-affinity receptor TrkA, NGF increases the excitation state of sensory neurons leading to the central nervous system (peripheral sensitization), and increases transmitter release from the dorsal spinal cord (central sensitization). In clinical trials, a single NGF subcutaneous injection generated local hyperalgesia persisting up to 7 weeks. At doses above 0.1 mierogram/kg, NGF caused muscle pain thai varied from mild to moderate, primarily in the bulbar and truncal musculature. Intravenous NGF produced earlier and more pronounced systemic effects (Petty et al, 1994, Ann Neurol. 36; 244-6). Conversely, TrkA kinase inhibitors could be used to treat diseases of enhanced states of nociception.
[0284] In Complete Freund's Adjuvant (CFA)-induccd hind-paw inflammation, spinal nerve ligation and streptozoticin-induced neuropathic pain models, a single intraperitoneal injection of anti-NGF reversed established tactile allodynia from day 3 to day 7 following treatment. In the mouse CCI model, anti-NGF reversed tactile allodynia when administered 2 weeks after surgery. Repeated administration of this antibody to CCI mice for 3 weeks produced a sustained reversal of tactile allodynia (Wild et al, 2007, J. Pharmacol. Exp. Ther. 322:282-287).
10285] Prostate tumors that have metastasized to bone frequently induce bone pain which can be difficult to fully conlrol as it seems to be driven simultaneously by inflammatory, neuropathic, and tumorigenic mechanisms. Anti-NGF produced a significant reduction in both early and late stage bone cancer pain related behaviors. This therapy did not influence tumor-induced bone remodeling, osteoblast proliferation, osteoclastogenesis, tumor growth, or markers of sensory or sympathetic innervation in the skin or bone. All nerve fibers that innervate the bone express TrkA and p75, and these are the receptors through which NGF sensitizes and/or activates nociceptors (Halvorson et al, 2005, Cancer Res. 65:9426-35).
[0286] In patients with mild asthma due to exposure to cat allergen, NGF expression was strongly induced in epithelial cells, fibroblasts, blood vessels, and a few infiltrating cells. TrkA mRNA and protein levels in bronchial biopsies were increased significantly after allergen exposure in infiltrating mast cells before the onset of symptoms (Kassel et al, 2001 , Clin Exp Allergy 31:1432-40).
[0287] The late phase reaction in asthma following allergen provocation is dominated by an influx of activated eosinophils into the bronchial lumen, which correlates with the release of eosinophilic products into the airways to increase disease severity. The viability and activation of eosinophils from patients with mild asthma were significantly enhanced after NGF stimulation. Addition of neutralizing anti-NGF antibodies ex vivo abrogated the effects (Nassentein et al, 2003, J Exp Med 198:455-467). TrkA kinase inhibitors could decrease this paracrine loop between the respiratory tract and infiltrating mast cells as well as endobronchial eosinophils, and thus be useful for the treatment of asthma and other allergic disorders. |0288) TrkB: Target kinase TrkB (i e , neurotrophic tyrosine kinase, receptor type 2) is a 145 kDa tyrosine kinase encoded by chromosome 9q22 1 (symbol NTRK2) IrkB inhibitors may be useful in treating \aπous cancers and their metastases (e g prostate cancer, lung cancer, Wilms tumors, neuroblastoma, and pancreatic cancer), and various neuropathies (e g stroke multiple sclerosis, transverse myelitis, and encephalitis)
[0289] In clinical tπals with recombinant BDNF, paresthesia was de\ eloped at the site of subcutaneous injection (Couhe et al, 2000, Gastroenterology 119 41-50) Intrathecal infusion of BDNF in humans also induced paresthesia and warmth as side effects (Ochs et al, 2000, Amyotroph Lateral S cler Other Motor Neuron Disord 1 201-6) Chronic paresthesia is often a symptom of an underlying neurological disease or traumatic nerve damage Paresthesia can be caused by disorders affecting the central nervous system, such as stroke and transient ischemic attacks (mini-strokes), multiple sclerosis, transverse myelitis, and encephalitis Since BDNF binds to TrkB specifically with high affinity these neuropath effects are mediated through TrkB signaling Thus Trkb kinase inhibitors could be used to treat certain patients w ith neuropathy
[0290J BDNF is known to act at the synapses between primary sensory and spmal dorsal horn neurons to affect pam transmission during inflammation The primary afferent is the only source of BDNF in the spinal cord, and it is up-regulated in the dorsal root ganglion (DRG) by peripheral NGF a few days after inflammation, and is transported and released into the superficial dorsal horn in an activity-dependent manner TrkB expression m the dorsal horn also increases foi a few days after inflammation These findings suggest that BDNF may act during the restricted period in the early phase of inflammation Through IrkB, BDNF activates two distinct channels (1) transient receptor potential canonicals (TRPC3), which produces a slow response by opening of a nonselective cation channel, and (2) Na+ channel, which mediates a rapid depolarization in the hippocampus These channels have been strongly associated with inflammatory pam Anti-BDNF significantly increased the withdrawal threshold in CFA-treated rats, a model of inflammatory pam Since the swelling at the site of CFA injection was not affected by antiserum, the residual component might be due to peripheral sensitization (Matayoshi et al, 2005, J Physiol 569 685- 95)
[0291] In patients with neuroblastomas, co-expression of TrkB and BDNF, co-expression of TrkB with N-Myc amplification, and expression of truncated TrkB are found to be associated w ith poorer clinical outcome (Nakagawara et al, 1994 MoI Cell Biol 14 759-767) Co-expression of TrkB with its ligand BDNF could generate a positive feedback loop through autocrine and paracrine loops Also TrkB truncations found in these tumors generate activated forms of the intracellular protein tyrosine kinase The constitutive! y active TrkB signals through multiple pathways to promote cancer initiation, progression and metastasis These truncated TrkB kinases w ere also found in hepatocellular carcinoma (Yang et al, 2005, Cancer Res 65 219-225) lhus 1 rkB inhibitors could be used to treat a sub-population of cancer patients w ith an activated 1 rkB pathway
[0292] In patients with pancreatic cancer, T rkB expression is correlated with perineural invasion positive retroperitoneal margin, and shorter latency to development of liver metastasis (Sclabas et al, 2005, Clin Cancer Res VI l 440-449) Mechanistically, TrkB activates the PBK pathwav to suppress anoikis (apoptosis resulting from loss of cell-matrix interactions) which is one of the physiological barriers to metastasis TrkB kinase inhibition could break down resistance to anoikis of metastasizing tumors (Douma et al 2004, Nature 430 1034-9) Iherefore, TrkB inhibitors could have utility in a broad range of tumor types
Exemplary diseases associated with HGK
[0293] HGK: Target kinase HGK (i e , Hematopoietic progenitor kmasc/Gcrminal center kmase-hke Kinase, aka mitogen-activatcd protein kinase kinase kinase kinase 4) is a 130 kDa serine/threonine kinase encoded by chromosome 2ql 1 2-ql2 (symbol MAP4K4) It is a member of the human STE20/mitogen-activated protein kinase kinase kinase kinase (MAP4K) family of serine/threonine kinases and is the human ortholog of mouse NIK (Nck-mteractmg kinase) 1 he N-terminus of the mature HGK protein has a catalytic kinase domain that shares 47% and 48% ammo acid sequence identity to the catalytic domain of Hematopoietic progenitor kinase 1 (HPKl) and Germinal center kinase (GCK), respectively Yao et al (J Biol Chem 274 21 18-2125, 1999) identified 2 HGK isoforms, one of which has no proline-πch domains, and another, longer variant that contains such domains and appears to be expressed in bram only Northern blot analysis revealed expression of 3 HGK transcripts of approximately 4 6, 6 5, and 8 5 kb m heait, brain, skeletal muscle, pancreas, placenta, liver, lung, and kidney By Western blot analysis with a polyclonal antibody, Yao et al (J Biol Chem 274 21 18-2125 1999) found that the 130 LD protein is expressed in multiple cell lines
[0294] Expression of HGK in transfected cell lines resulted in strong JNK activation and, in turn, c-jun transcriptional activity (Yao et al J Biol Chem 274 21 18-2125, 1999) HGK-induced JNK activation was inhibited by dominant-negative MAP2K4, MAP2K7, and IAKl mutants TNF-alpha also stimulated HGK kinase activity HGK w as identified as a putative effect of Rap2 to activate JNK (Machida et al J Biol Chem 279 1571 1 -15714 2004) T his link establishes HGK as a potential target for a range of metabolic indications, since the JNK pathway clearly antagonizes insulin signaling An HGK inhibitor could re-sensitize fat and muscle cells to insulin [0295] HGK is found to be broadly expressed in human tumor cells and can modulate cellular transformation, invasion, and adhesion (Wright ct al. MoL Cell, Biol. 23: 2068-2082, 2003). Wright ct al showed HGK to be highly expressed in most tumor cell lines relative to normal tissue. An active role for this kinase in transformation was suggested by an inhibition of H-Ras(V12)- induced focus formation by expression of inactive, dominant-negative mutants of HGK in both fibroblast and epithelial cell lines. Expression of an inactive mutant of HGK also inhibited the anchorage-independent growth of cells yet had no effect on proliferation in monolayer culture. Expression of HGK mutants modulated integrin receptor expression and had a striking effect on hepatoeyte growth factor-stimulated epithelial cell invasion. Together, these results suggest an important role for HGK in cell transformation and invasiveness. More recently, a small interfering RNA screen for modulators of tumor cell motility identifies MAP4K4 as a promigratory kinase (Collins et al. Proc. Natl. Acad. Sci. USA, 103: 3775-3780, 2006). Collins et al. showed that the knockdown of the HGK transcript inhibited the migration of multiple carcinoma cell lines, indicating a broad role in cell motility, and potently suppressed the invasion of SKOV-3 cells in vitro. The effect of HGK on cellular migration was found to be mediated through JNK kinase, independent of API activation and downstream transcription. Accordingly, small molecule inhibition of c-Jun N-terminal kinase suppressed SKOV-3 cell migration, underscoring the potential therapeutic utility of mitogen-activated protein kinase pathway inhibition in cancer progression (Collins et al. Proc. Natl. Acad. Sci. USA, 103: 3775-3780, 2006). These studies strongly support HGK as a target in a broad range of oncology indications. In particular, an HGK inhibitor could have utility in blocking the migration, invasion and metastasis in many different tumor types.
[0296] Activation of T-cells by antigens initiates a complex series of signal-transduction events that are critical for immune responses. Mack et al, (Immunol. Lett. 96, 129-145, 2005) developed a genetic screen to survey the functional roles of kinases in antigen mediated T-cell activation and identified 19 protein kinases that were previously implicated in T-cell signaling processes and 12 kinases that were not previously linked to T-cell activation, including HGK. siRNA studies showed a role for HGK in antigen mediated T-cell responses in Jurkat and primary T-cells. In addition, by analyzing multiple promoter elements using reporter assays, Mack et al. have shown that MΛP4K4 is implicated in the activation of the TNF-alpha promoter. Therefore, inhibition of HGK could have broad therapeutic utility for T-cell-mediated autoimmune diseases.
[0297J Insulin-regulated glucose transporter GLUT4 is a key modulator of whole body glucose homeostasis, and its selective loss in adipose tissue or skeletal muscle causes insulin resistance and diabetes. Using an RNA interference-based screen, Tang et al. (Proc Natl Acad Sci U S A. 103:2087-2092, 2006) found 4 negative regulators of insulin-responsive glucose transport in mouse adipocytes: Pctkl , Pftkl , Ikbka (CHUK), and HGK. HGK suppressed expression of adipogenic transcription factors, C/EBPA, C/EBPB, and PPARG, and it suppressed surface expression of GLUT4 (SLC2A4), resulting in attenuated membrane hexose transport activity, RNA interference-mediated depletion of HGK early in differentiation enhanced adipogenesis and triglyceride deposition; in fully differentiated adipocytes, loss of HGK upregulated GLUT4 expression. Conversely, conditions that inhibited adipogenesis, such as TNF-alpha treatment or PPARG depletion, markedly upregulated HGK. Tang et al. (Proc Natl Acad Sci U S A. 103:2087- 2092, 2006) concluded that MAP4K4-dependent signaling inhibited PPARG-responsive gene expression, adipogenesis, and insulin-stimulated glucose transport. Furthermore, TNF-alpha signaling to down-regulate GLUT4 is impaired in the absence of HGK, indicating that HGK expression is required for optimal TNF-alpha action. This study further supports HGK as a target in metabolic disease, and suggests a role for HGK inhibition in ameliorating the pathology in adipocytes.
[02981 In a separate study (Bouzakri and Zierath J. Biol. Chem. 282:7783-7789, 2007), using small interfering RNA (siRNA) to suppress the expression of HGK protein 85% in primary human skeletal muscle cells, TNF-alpha-induced insulin resistance on glucose uptake was completely prevented. HGK silencing inhibited TNF-alpha-induced negative signaling inputs by preventing excessive JNK and ERK-1/2 phosphorylation, as well as IRS-I serine phosphorylation. These results highlight the HGK/JNK/ERK/IRS module in the negative regulation of insulin signaling to glucose transport in response to TNF-alpha. Depletion of HGK also prevented TNF-alpha-induced insulin resistance on AKT and the AKT substrate 160 (AS 160), providing evidence that appropriate insulin signaling inputs for glucose metabolism were rescued. The authors suggested that strategies to inhibit FIGK may be efficacious in the prevention of TNF-alpha-induced inhibitory signals that cause skeletal muscle insulin resistance on glucose metabolism in humans. Moreover, in myotubes from insulin-resistant type II diabetic patients, siRNA against HGK restored insulin action on glucose uptake to levels observed in healthy subjects. This study further supports HGK as a target in metabolic diseases such as type II diabetes, and suggests a role for HGK inhibition in ameliorating the pathology in muscle cells.
[0299] HGK inhibitors may be useful in treating metabolic indications, including re-sensitizing fat and muscle cells to insulin, ameliorating the pathology in adipocytes, ameliorating the pathology in muscle cells, and type II diabetes; a broad range of oncology indications, including blocking the migration, invasion and metastasis in many different tumor types; and T-cell mediated autoimmune diseases. II. Production of c-kit and c-fras related Polypeptides
[0300] TIi e natn e and mutated kinase polypeptides described herein may be chemically synthesized m whole or part using techniques that are well known in the art (see e g , Creighton (1983) Biopolymers 22(1) 49-58)
[0301] Alternat ely, methods which are well known to those skilled in the art can be used to construct expression vectors containing the native or mutated kinase polypeptide coding sequence and appropriate transcπptional/translational control signals These methods include in vitro recombinant DNA techniques, synthetic techniques and in \ι\o recombination genetic recombination See, for example, the techniques described in Mamatis T (1989) Molecular cloning A laboratory Manual Cold Spring Harbor Laboratory, New York Cold Spring Harbor Laboratory Press, and Ausubel, F M et al (1994) Current Protocols in Molecular Biology John Wiley & Sons, Secaucus, N J
[0302] A \anety of host-expression vector systems may be utilized to express the kinase coding sequence These include but are not limited to microorganisms such as bacteria transformed with recombinant bacteriophage DNA, plasmid DNA or cosmid DNA expression vectors containing the kinase domain coding sequence, yeast transformed with recombinant yeast expression vectors containing the kinase domain coding sequence, insect cell systems infected with recombinant virus expression vectors (e g baculovirus) containing the kinase domain coding sequence, plant cell systems infected with recombinant \ irus expression vectors (e g cauliflower mosaic virus, CaMV, tobacco mosaic virus, TMV) or transformed with recombinant plasmid expression vectors (e g Ti plasmid) containing the kinase domain coding sequence, or animal cell s> stems The expression elements of these systems vary in their strength and specificities
[0303] Depending on the host/vector system utilized, any of a number of suitable transcription and translation elements, including constitutive and inducible promoters, may be used in the expression vector For example, when cloning in bacterial systems, inducible promoters such as pL of bacteriophage λ, plac, ptrp, ptac (ptrp-lac hybrid promoter) and the like may be used when cloning in insect cell systems, promoters such as the baculovirus polyhedπn promoter may be used, when cloning in plant cell systems, promoters derived from the genome of plant cells (t g heat shock promoters, the promoter for the small subunit of RUBISCO, the promotei for the chlorophyll a/I) binding protein) or from plant viruses (e g the 35S RNA promoter of CaMV the coat protein promoter of TMV) may be used, when cloning in mammalian cell s> stems, promoters derived from the genome of mammalian cells (e g mctallothionem promoter) or from mammalian viruses (e g the adenovirus late promoter, the vaccinia virus 7 5K promoter) may be used, when generating cell lines, that contain multiple copies of the kinase domain DNA, SV4O-, BPV- and FBV-based vectors may be used with an appropriate selectable marker
[0304] Exemplary methods describing methods of DNA manipulation, vectors, various typeb of cells used, methods of incorporating the vectors into the cells expression techniques protein purification and isolation methods, and protein concentration methods arc disclosed in detail in PCT publication WO 96/18738 This publication is incorporated herein by reference in its entirety, including any drawings Those skilled in the art will appreciate that such descriptions are applicable to the present invention and can be easily adapted to it
III. Binding Assays
[0305] The methods of the present invention can involve assays that arc able to detect the binding of compounds to a target molecule Such binding is at a statistically significant level, preferably with a confidence level of at least 90%, more preferably at least 95, 97, 98, 99% or greater confidence level that the assay signal represents binding to the target molecule, i e , is distinguished from background Preferably controls are used to distinguish target binding from non-specific binding A large variety of assays indicative of binding are known for different target types and can be used for this invention
[0306] Binding compounds can be characterized by their effect on the activity of the target molecule Thus, a "low activity" compound has an inhibitory concentration (IC^o) or effective concentration (EC50) of greater than 1 μM under standard conditions By "very low activity" is meant an IC5O or EC5O of above 100 μM under standard conditions By "extremely low activity" is meant an IC50 or EC50 of above 1 mM under standard conditions By "moderate activity" is meant an IC5O or EC5Q of 200 nM to 1 μM under standard conditions By "moderately high activity" is meant an IC50 or EC50 of 1 nM to 200 nM By "high activity" is meant an IC50 or EC50 of below 1 nM under standard conditions The IC50 or EC50 is defined as the concentration of compound at which 50% of the activity of the target molecule (e g enzyme or other protein) activity being measuied is lost or gained relative to the range of activity observed when no compound is present Activity can be measured using methods known to those of ordinary skill in the art, e g , by measuring any detectable product or signal produced by occurrence of an enzymatic leaction, or other activity by a protein being measured
[0307] By "background signal" in reference to a binding assay is meant the signal that is recorded under standard conditions for the particular assay in the absence of a test compound, molecular scaffold, or ligand that binds to the target molecule Persons of ordinary skill in the art will realize that accepted methods exist and are widely available for determining background signal.
[0308] By "standard deviation" is meant the square root of the variance. The variance is a measure of how spread out a distribution is. It is computed as the average squared deviation of each number from its mean. For example, for the numbers 1, 2, and 3, the mean is 2 and the variance is: σ2 = (T-2)2 + (2-2)2 + (3-2) 2 = 0.667 . 3
Surface Plasmon Resonance
[0309] Binding parameters can be measured using surface plasmon resonance, for example, with a BIAcore* chip (Biacore, Japan) coated with immobilized binding components. Surface plasmon resonance is used to characterize the microscopic association and dissociation constants of reaction between an sFv or other ligand directed against target molecules. Such methods are generally described in the following references which arc incorporated herein by reference. VeIy F. et al., (2000) BIAcore* analysis to test phosphopeptide-SH2 domain interactions, Methods in Molecular Biology. 121 :313-21; Liparoto et al., ( 1999) Biosensor analysis of the interleukin-2 receptor complex, Journal of Molecular Recognition. 12:316-21 ; Lipschultz et al., (2000) Experimental design for analysis of complex kinetics using surface plasmon resonance, Methods. 20(3):310-8; Malmqvist, (1999) BIΛCORE: an affinity biosensor system for characterization of biomolecular interactions, Biochemical Society Transactions 27:335-40; Alfthan, (1998) Surface plasmon resonance biosensors as a tool in antibody engineering, Biosensors & Bioelectronics. 13:653-63; Fivash et al., (1998) BIAcore for macromolecular interaction, Current Opinion in Biotechnology. 9:97-101; Price et al.; (1998) Summary report on the ISOBM TD-4 Workshop: analysis of 56 monoclonal antibodies against the MUCl mucin. Tumour Biology 19 Suppl 1 : 1 -20; Malmqvist et al, (1997) Biomolecular interaction analysis: affinity biosensor technologies for functional analysis of proteins, Current Opinion in Chemical Biology. 1 :378-83; O'Shannessy et al., (1996) Interpretation of deviations from pseudo-fϊrst-order kinetic behavior in the characterization of ligand binding by biosensor technology, Analytical Biochemistry. 236:275-83; Malmborg et al., (1995) BIAcore as a tool in antibody engineering, Journal of Immunological Methods, 183:7-13; Van Regenmortel, (1994) Use of biosensors to characterize recombinant proteins, Developments in Biological Standardization. 83: 143-51 ; and O'Shannessy, (1994) Determination of kinetic rate and equilibrium binding constants for macromolecular interactions: a critique of the surface plasmon resonance literature, Current Opinions in Biotechnology. 5:65-71 ,
[0310] BIAcore*' uses the optical properties of surface plasmon resonance (SPR) to detect alterations in protein concentration bound to a dextran matrix lying on the surface of a gold/glass sensor chip interface, a dextran biosensor matrix In bπef proteins are co\alently bound to the dextran matrix at a known concentration and a ligand for the protein is injected through the dextran matrix Near infrared light, directed onto the opposite side of the sensor chip surface is reflected and also induces an evanescent wave m the gold film which in turn, causes an intensity dip in the reflected light at a particular angle known as the resonance angle Jf the refractn e index of the sensor chip surface is altered (e g by ligand binding to the bound protein) a shift occurs in the resonance angle This angle shift can be measured and is expressed as resonance units (RUs) such that ] 000 RUs is equi\ alent to a change in surface protein concentration of 1 ng/mm These changes are displayed with respect to time along the y-axis of a sensorgram, w hich depicts the association and dissociation of any biological reaction
High Throughput Screening (HTS) Assays
[0311] HTS typically uses automated assays to search through large numbers of compounds for a desired activity Typically HTS assays are used to find new drugs by screening for chemicals that act on a particular enzyme or molecule For example, if a chemical inactivates an enzyme it might prove to be effective m preventing a process in a cell which causes a disease High throughput methods enable researchers to assay thousands of different chemicals against each target molecule very quickly using robotic handling systems and automated analysis of results
(0312] As used herein, ' high throughput screening' or "HTS" refers to the rapid in vitro screening of large numbers of compounds (libraries), generally tens to hundreds of thousands of compounds, using robotic screening assays Ultra high-throughput Screening (uHTS) generally refers to the high-throughput screening accelerated to greater than 100,000 tests per day
[0313] To achieve high-throughput screening, it is advantageous to house samples on a multicontainer earner or platform A multi container earner facilitates measuring reactions of a plurality of candidate compounds simultaneously Multi-well microplates may be used as the carrier Such multi-well microplates, and methods for their use in numerous assays, are both known m the art and commercially available
[0314] Screening assays may include controls for purposes of calibration and confirmation of proper manipulation of the components of the assay Blank wells that contain all of the reactants but no member of the chemical library are usually included As another example, a known inhibitor (or actuator) of an enzyme for which modulators are sought can be incubated with one sample of the assay, and the resulting decrease (or increase) m the enzyme activity used as a comparator or control It will be appreciated that modulators can also be combined with the enzyme activators or inhibitors to find modulators which inhibit the en/yme activation or repression that is otherwise caused by the presence of the known the enzyme modulator
Measuring Enzymatic and Binding Reactions During Screening Assays
[0315] Techniques for measuring the progression of enzymatic and binding reactions, e g . in multicontamer carriers, are known in the art and include, but are not limited to the following
[0316] Spectrophotometric and spectrofluorometπc assays are well known in the art Examples of such assays include the use of colorimetπc assays for the detection of peroxides, as described in Gordon, A J and Ford, R Λ , (1972) The Chemist's Companion A Handbook Of Practical Data, Techniques, And References, John Wiley and Sons N Y , Page 437
|0317] Fluorescence spectrometry ma) be used to monitor the generation of reaction products Fluorescence methodology is gcncrall> more sensitive than the absorption methodology The use of fluorescent probes is well known to those skilled m the art For rev lew s, see Bashf ord et al , ( 1987) Spectrophotometry and Spectrofluorometry A Practiuil Approach, pp 91 -1 14, IRI Piess Ltd , and Bell, (1981 ) Spectroscopy In Biochemistry. VoI I, pp 155-194, CRC Press
[0318] In spcctrofluoromctric methods, enzymes are exposed to substrates that change their intrinsic fluorescence w hen processed bv the target enzyme Typically, the substrate is nonfluorescent and is converted to a fluorophore through one or more reactions As a non-limitmg example, SMase activity can be detected using the Amplex"* Red reagent (Molecular Probes, bugcnc, OR) In order to measure sphingomyelinase activ ity using Amplex4 Red, the following reactions occur First, SMase hydrolyzes sphingomyelin to yield ceramide and phosphorylcliolme Second, alkaline phosphatase hydrolyzes phosphorylcholine to yield choline Third, choline is oxidized by choline oxidase to betame Finally, H2O2, in the presence of horseradish peroxidase, reacts with Amplex*" Red to produce the fluorescent product, Resorufm and the signal therefrom is detected using spectrofluorometry
[0319] Fluorescence polarization (FP) is based on a decrease in the speed of molecular rotation of a fluoiophore that occurs upon binding to a larger molecule, such as a receptor protein, allowing for polarized fluorescent emission by the bound ligand FP is empirically determined by measuring the vertical and horizontal components of fluorophore emission following excitation w ith plane polarized light Polarized emission is increased when the molecular rotation of a fluorophore is reduced A fluorophore produces a larger polarized signal when it is bound to a larger molecule (i e a receptor), slowing molecular rotation of the fluorophore The magnitude of the polarized signal relates quantitativ ely to the extent of fluorescent ligand binding Accoidingly, polarization of the *'bound" signal depends on maintenance of high affinity binding [0320] FP is a homogeneous technology and reactions are very rapid, taking seconds to minutes to reach equilibrium. The reagents are stable, and large batches may be prepared, resulting in high reproducibility. Because of these properties, FP has proven to be highly automatable, often performed with a single incubation with a single, premixed, tracer-receptor reagent. For a review, see Owickiet al., (1997), Application of Fluorescence Polarization Assays in High-Throughput Screening, Genetic Engineering News, 17:27.
[0321] FP is particularly desirable since its readout is independent of the emission intensity (Checovich, W. J., et al., (1995) Nature 375:254-256; Dandliker, W. B., et al., (1981) Methods in Enzymology 74:3-28) and is thus insensitive to the presence of colored compounds that quench fluorescence emission. FP and FRET (see below) are well-suited for identifying compounds that block interactions between sphingolipid receptors and their ligands. See, for example. Parker et al., (2000) Development of high throughput screening assays using fluorescence polarization: nuclear rcccptor-hgand-bindmg and kinase/phosphatase assays, J Biomol Screen 5:77-88.
[0322] Fluorophores derived from sphingolipids that may be used in FP assays are commercially available. For example, Molecular Probes (Eugene, OR) currently sells sphingomyelin and one ceramide flurophores. These are, respectively, N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s- indacene- 3-pentanoyl)sphingosyl phosphocholine (BODIPY® FL C5-sphingomyelin); N-(4,4- difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene- 3-dodecanoyl)sphingosyl phosphocholine (BODIPY® FL C 12-sphingomyelin); and N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s- indacene- 3-pentanoyl)sphingosine (BODIPY® FL C5-ccramide). U.S. Patent No. 4,150,949, (Immunoassay for gentamicin), discloses fluorescein-labelled gentamicins, including fluoresceinthiocarbanyl gentamicin. Additional fluorophores may be prepared using methods well known to the skilled artisan.
[0323] Exemplary normal-and-polarized fluorescence readers include the POLARlON" fluorescence polarization system (Tecan AG, Hombrechtikon, Switzerland). General multiwell plate readers for other assays are available, such as the VERSAMAX* reader and the SPECTRAMAX* multiwell plate spectrophotometer (both from Molecular Devices).
[0324] Fluorescence resonance energy transfer (FRET) is another useful assay for detecting interaction and has been described. See, e.g., Heim et al., (1996) Curr. Biol. 6: 178-182; Mitra et al,, (1996) Gene 173:13-17; and Selvin et al., (1995) Meth. En/ymol. 246:300-345. FRET detects the transfer of energy between two fluorescent substances in close proximity, having known excitation and emission wavelengths. As an example, a protein can be expressed as a fusion protein with green fluorescent protein (GFP). When two fluorescent proteins are in proximity, such as when a protein specifically interacts with a target molecule, the resonance energy can be transferred from one excited molecule to the other As a result, the emission spectrum of the sample shifts, which can be measured by a fluoromctcr, such as a fMAX multrwell fluorotneter (Molecular Devices,
Figure imgf000149_0001
Calif )
[0325] Scintillation proximity assay (SPA) is a particularly useful assay for detecting an interaction with the target molecule SPA is widely used in the pharmaceutical industry and has been described (Hanselman et al , (1997) J Lipid Res 38 2365-2373, Kahl et al , (1996) Anal Biochem 243 282-283, Undenfπend et al , (1987) Anal Biochem 161 494-500) See also U S Patent Nos 4,626,513 and 4,568,649, and European Patent No 0,154,734 One commercially available system uses FLASHPLATE* scintillant-coated plates (NEN Life Science Products, Boston, MA)
[0326] The target molecule can be bound to the scintillator plates by a variety of well known means Suntillant plates are available that are deπvatized to bind to fusion proteins such as GST, His6 or Flag fusion proteins Where the target molecule is a protein complex or a multimer, one protein or subunit can be attached to the plate first, then the other components of the complex added later under binding conditions resulting in a bound complex
[0327] In a typical SPA assay, the gene products in the expression pool will have been radiolabeled and added to the wells, and allowed to interact with the solid phase, which is the immobilized target molecule and scmtillant coating m the wells The assay can be measured immediately or allowed to reach equilibrium Either wa>, when a radiolabel becomes sufficiently close to the scmtillant coating, it produces a signal detectable by a device such as a 1 OPCOUN f NXT* microplate scintillation counter (Packard BioScience Co , Meπden Conn ) If a radiolabeled expression product binds to the target molecule, the radiolabel remains in proximity to the scmtillant long enough to produce a detectable signal
[0328] In contrast, the labeled proteins that do not bind to the target molecule, or bind only bπefTv, will not remain near the scmtillant long enough to produce a signal above background Any time spent near the scmtillant caused b> random Browman motion will also not result in a significant amount of signal Likewise, residual unincorporated radiolabel used during the expression step may be present, but will not generate significant signal because it will be in solution rather than interacting with the target molecule These non-binding interactions will therefore cause a certain level of background signal that can be mathematically remov ed Il too many signals are obtained, salt or other modifiers can be added directly to the assay plates until the desired specificity is obtained (Nichols ct al , (1998) Anal Biochem 257 1 12-1 19)
IV. Kinase Activity Assays [0329] A number of different assays tor kinase activity can be utilized for assaying for acti\e modulators and or determining specificity of a modulator for a particular kinase or group or kinases In addition to the assay mentioned in the Examples below, one of ordinary skill in the art will know of other assays that can be utilized and can modify an assay for a particular application For example, numerous papers concerning kinases described assays that can be used
[0330] Additional alternative assays can employ binding determinations For example this sort of assay can be formatted either m a fluorescence resonance energy transfer (FRET) format, or using an AlphaScreen («mplified /uminescent proximity /lomogeneous assay) format by varving the donor and acceptor reagents that are attached to streptavidm or the phospho-specific antibody
V. Organic Synthetic Techniques
[0331] A wide array of organic synthetic techniques exist in the art to meet the challenge of constructing potential modulators Many of these organic synthetic methods arc described in detail in standard reference sources utilized by those skilled in the art One example of suh a reference is March, 1994, Advanced Organic Chemistry, Reactions, Mechanisms and Structure, New York, McGraw Hill Thus, the techniques useful to synthesize a potential modulator of kinase function are readily available to those skilled in the art ol organic chemical synthesis
[0332] Regarding the synthetic examples described herein, solvents include polar and non-polar solvents known to those of skill m the art, including polar aprotic and polar protic solvents Polar solvents include, without limitation, protic solvents such as methanol, ethanol, isopropyl alcohol, t- butanol, n-butanol, acetic acid, formic acid or water, or aprotic solvents such as tetrahydrofuran (THF), acetonitπle, dioxane, methylene chloπde, dimethylsulfoxide (DMSO), acetone, N,N- dimethylformamide (DMF), N,N-dimethylacetamide (DMA), ethyl acetate, 1 ,2-dimethoxyethane, 1 ,2-dichloroethane, chloroform, 1 ,2-dichloroethane, or pyridine Polar solvents include a mixture of water with any ol the above, or a mixture of any two or more of the above Apolar solvents include, without limitation, toluene, benzene, chlorobenzene, xylenes and hexancs
[0333] Regarding the synthetic examples described herein, reducing agent includes, without limitation, a reducing agent such as catalytic reducing agents using hydrogen and transition metal catalysts such as palladium platinum, rhodium, etc (e g Pt/acetic acid/H?) a mixture of tπfluoroacetic acid and tπethylsilane, borane tetrahydrofuran complex, diborane, borane dimethylsulfide complex, and a combination of sodium borohydπde and boron tπfluoiide, metals such as reduced iron, zinc powder, magnesium etc , metal hydrogen complex compounds such as alkali metal borohydπdes (for example, potassium borohydnde, sodium borohydπde, lithium borohydπde, zmc borohydnde, sodium tnacetoxyborohydπde, etc ), aluminum lithium hydride, etc.; metal hydrides such as sodium hydride, etc.; organic tin compounds (triphenyltin hydride, etc.); and metal salts such as nickel compounds, zinc compounds, tin compounds (for example tin(II) chloride), and samarium lodide/pivalic acid/hexamethylphorphoric triamide.
[0334] Regarding the synthetic examples described herein, oxidizing agent includes, without limitation, an oxidizing agent such as Dess-Martin reagent, TEMPO (2,2,6,6- tetramethylpiperidine-N -oxide), DDQ (2,3-Dichloro-5,6-dicyano- l ,4-bcnzoquinonc), PDC (pyridinium dichromate), PCC (pyridinium chlorochromate), Pyridine. SO3, Chromium trioxide, p- nitroperbenzoic acid, magnesium monoperoxyphthalate, sodium periodate, potassium periodate, hydrogen peroxide, urea peroxide, alkali metal bromates, cumene hydroperoxide, tert-butyl peroxide, peracids such as performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloroperbenzoic acid, o-carboxyperbenzoic acid and the like; sodium metaperiodate, bichromic acid; bichromates such as sodium bichromate, potassium bichromate; permanganic acid; permanganates such as potassium permanganate, sodium permanganate; and lead salts such as lead tetraacetate.
Vl. Alternative Compound Forms or Derivatives
(a) Isomers, Prodrugs, and Active Metabolites
|0335] Compounds contemplated herein are described with reference to both generic formulae and specific compounds. In addition, the invention compounds may exist in a number of different forms or derivatives, all within the scope of the present invention. These include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, prodrugs (e.g. carboxylic acid esters), solvated forms, different crystal forms or polymorphs, and active metabolites.
(b) Tautomers, Stereoisomers, Regioisomers, and Solvated Forms
[0336] It is understood that some compounds may exhibit tautomerism. In such cases, the formulae provided herein expressly depict only one of the possible tautomeric forms. It is therefore to be understood that the formulae provided herein are intended to represent any tautomeric form of the depicted compounds and are not to be limited merely to the specific tautomeric form depicted by the drawings of the formulae.
[0337] Likewise, some of the compounds according to the present invention may exist as stereoisomers, i.e. having the same atomic connectivity of covalently bonded atoms yet differing in the spatial orientation of the atoms. For example, compounds may be optical stereoisomers, which contain one or more chiral centers, and therefore, may exist in two or more stereoisomeric forms (e.g. enantiomers or diastereomers). Thus, such compounds may be present as single stereoisomers (i e , essentially free of other stereoisomers), racemates, and or mixtures of enantiomers and/or diastereomers Λs another example, stereoisomers include geometric isomers, such as as- or trans- orientation of substituents on adjacent carbons of a double bond All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present invention Unless specified to the contrary, all such steroisomeric forms are included within the formulae provided herein
[0338] In some embodiments, a chiral compound of the present invention is in a form that contains at least 80% of a single isomer (60% enantiomeric excess f e e ") or diastereomeric excess ("d e ")), or at least 85% (70% e e or d e ), 90% (80% e e or d e ), 95% (90% e e or d e ), 97 5% (95% c e or d e ), or 99% (98% e e or d e ) As generally understood by those skilled in the art, an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i e , is enantiomerically pure), and an optically pure compound having more than one chiral center is one that is both diastereomeπcally pure and enantiomerically pure In some embodiments, the compound is present m optically pure form
[0339J For compounds in which synthesis involves addition of a single group at a double bond, particularly a carbon-carbon double bond, the addition may occur at either of the double bond- lmked atoms For such compounds, the present invention includes both such regioisomers
|0340] Additionally, the formulae are intended to cover solvated as well as unsolvated forms of the identified structures For example, the indicated structures include both hydrated and non- hydrated forms Other examples of solvates include the structures m combination with a suitable solvent such as isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamme
(c) Prodrugs and Metabolites
[0341] In addition to the present formulae and compounds described herein, the invention also includes prodrugs (generally pharmaceutically acceptable prodrugs), active metabolic derivativ es (active metabolites), and their pharmaceutically acceptable salts
[0342] Prodrugs are compounds or pharmaceutically acceptable salts thereof which, when metabolized under physiological conditions or when conv erted by solvolysis, yield the desired active compound Prodrugs include, without limitation esters, amides, carbamates, carbonates, urcidcs, solvates, or hydrates of the active compound Typically, the prodrug is inactive, or less active than the active compound, but may provide one or more of advantageous handling administration, and/or metabolic properties For example, some prodrugs are esters of the active compound, during metabolysis, the ester group is cleaved to yield the active drug Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
[0343] In this context, a common example of a prodrug is an alkyl ester of a carboxylic acid. Relative to compounds of Formula I, Formula Ia, Formula Ib, Formula Ig, Formula II, Formula Ha, Formula lib, Formula Hc, Formula Hd, Formula He, Formula Hf. Formula Hg, Formula Hh, Formula III, Formula Ilj, Formula Ilk, Formula Hm, Formula Iln, Formula Ho, Formula Up, or Formula III, further examples include, without limitation, an amide or carbamate derivative at the pyrrole nitrogen (i.e. Nl) of the azaindole core.
[0344] As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, CA, 2001), prodrugs can be conceptually divided into two nonexclusive categories, bioprecursor prodrugs and carrier prodrugs. Generally, bioprecursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, that contain one or more protective groups and are converted to an active form by metabolism or solvolysis. Both the active drug form and any released metabolic products should have acceptably low toxicity. Typically, the formation of active drug compound involves a metabolic process or reaction that is one of the follow types:
[0345] Oxidative reactions: Oxidative reactions are exemplified without limitation to reactions such as oxidation of alcohol, carbonyl, and acid functionalities, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon- carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dealkylation, oxidative O- and S-dcalkylation, oxidative deamination, as well as other oxidative reactions.
[0346] Reductive reactions: Reductive reactions are exemplified without limitation to reactions such as reduction of carbonyl functionalities, reduction of alcohol functionalities and carbon- carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions.
[0347] Reactions without change in the oxidation state: Reactions without change in the state of oxidation are exemplified without limitation to reactions such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration at multiple bonds, new atomic linkages resulting from dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecule, and other such reactions. [0348] Carrier prodrugs are drug compounds that contain a transport moiety, e g , that improves uptake and or localized delivery to a site(s) of action Desirably for such a carrier prodrug, the linkage between the drug moiety and the transport moiety is a co\ alent bond, the prodrug is inactive or less active than the drug compound, the prodrug and any release transport moietv are acceptably non-toxic For prodrugs where the transport moiety is intended to enhance uptake, typically the release of the transport moiety should be rapid In other cases, it is desirable to utilize a moiety that provides slow release, e g , certain polymers or other moieties such as cyclodextπns (See, e g , Cheng et al , U S Patent Publ No 2004/0077595, App Ser No 10/656,838 incorporated herein by reference ) Such carrier prodrugs are often advantageous for orally administered drugs Carrier prodrugs can, for example, be used to improve one or more of the following properties increased hpophilicity, increased duration of pharmacological effects, increased site-specificity decreased toxicity and adverse reactions, and/or improvement in drug formulation (e g stability, water solubility, suppression of an undesirable organoleptic or physiochemical property) For example, hpophilicity can be increased by esterifϊcation of hydroxyl groups with lipophilic carboxyhc acids, or of carboxyhc acid groups with alcohols e g , aliphatic alcohols Wermuth, supra
[0349] Prodrugs may proceed from prodrug form to active form in a single step or may have one or more intermediate forms which may themselves have activity or may be inactive
[0350] Metabolites, e g , active metabolites, overlap with prodrugs as described above, e g , bioprecursor prodrugs Thus, such metabolites are pharmacologically active compounds or compounds that further metabolize to pharmacologically active compounds that are derivatives resulting from metabolic process in the body of a subject Of these, active metabolites are such pharmacologically active derivative compounds For prodrugs, the prodrug compound is generally inactive or of lower activity than the metabolic product For active metabolites, the parent compound may be either an active compound or may be an inactive prodrug
[0351] Prodrugs and active metabolites may be identified using routine techniques known in the art See, e g , Bertolmi et al , 1997, J Med Chem , 40 201 1 -2016, Shan et al , 1997, J P harm Sci 86(7) 756-757, Bagshawe, 1995, DrugDev Res , 34 220-230, Wermuth, supra
(d) Pharmaceutically acceptable salts
[0352] Compounds can be formulated as or be in the form of pharmaceutically acceptable baits Contemplated pharmaceutically acceptable salt foπns include, without limitation, mono, bis, tπs, tetrakis, and so on Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered The preparation of such salts can facilitate the pharmacological use by altering the physical characteristics of a compound without preventing it from exerting its physiological effect. Useful alterations in physical properties include lowering the melting point to facilitate transmucosal administration and increasing the solubility to facilitate administering higher concentrations of the drug.
[03531 Pharmaceutically acceptable salts include acid addition salts such as those containing sulfate, chloride, hydrochloride, fumarate, maleate, phosphate, sulfamate, acetate, citrate, lactate, tartrate, methanesulfonate, ethanesulfonate, benzenesulfonate, /?-toluenesulfonate, cyclohexylsulfamate and quinate. Pharmaceutically acceptable salts can be obtained from acids such as hydrochloric acid, maleic acid, sulfuric acid, phosphoric acid, sulfamic acid, acetic acid, citric acid, lactic acid, tartaric acid, malonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclohexylsulfamic acid, fumaric acid, and quinic acid.
|0354] Pharmaceutically acceptable salts also include basic addition salts such as those containing benzathine, chloroprocaine, choline, diethanolamine, ethanolamine, t-butylamine. ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium, ammonium, alkylamine, and zinc, when acidic functional groups, such as carboxylic acid or phenol are present. For example, see Remington's Pharmaceutical Sciences, 19lh ed., Mack Publishing Co., Easton, PA, Vol. 2, p. 1457, 1995. Such salts can be prepared using the appropriate corresponding bases.
[0355] Pharmaceutically acceptable salts can be prepared by standard techniques. For example, the free-base form of a compound can be dissolved in a suitable solvent, such as an aqueous or aqueous-alcohol solution containing the appropriate acid and then isolated by evaporating the solution. In another example, a salt can be prepared by reacting the free base and acid in an organic solvent.
[0356] Thus, for example, if the particular compound is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like. [0357] Similarly, if the particular compound is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include organic salts derived from amino acids, such as L-glycine, L-lysine, and L-arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as hydroxyethylpyrrolidine. piperidine, morpholine or piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
[0358] The pharmaceutically acceptable salt of the different compounds may be present as a complex. Examples of complexes include 8-chlorotheophyllinc complex (analogous to, e.g., dimenhydrinate: diphenhydramine 8-chlorotheophylline (1 : 1) complex; Dramaminc) and various cyclodextrin inclusion complexes.
[0359] Unless specified to the contraiy, specification of a compound herein includes pharmaceutically acceptable salts of such compound.
(e) Polymorphic forms
[0360] In the case of agents that are solids, it is understood by those skilled in the art that the compounds and salts may exist in different crystal or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae.
VII. Administration
[0361] The methods and compounds will typically be used in therapy for human subjects. However, they may also be used to treat similar or identical indications in other animal subjects. In this context, the terms "subject," "animal subject," and the like refer to human and non-human vertebrates, e.g. mammals, such as non-human primates, sports and commercial animals, e.g., equines, bovines, porcines, ovines, rodents, and pets, e.g., canines and felines.
[0362] Suitable dosage forms, in part, depend upon the use or the route of administration, for example, oral, transdermal, transmucosal, inhalant, or by injection (parenteral). Such dosage forms should allow the compound to reach target cells. Other factors are well known in the art, and include considerations such as toxicity and dosage foπns that retard the compound or composition from exerting its effects. Techniques and formulations generally may be found in The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (hereby incorporated by reference herein), [0363] Compounds of the present invention (i e Formula I, Formula Ia, Formula Ib, Formula Ig Formula II Formula Ha, Formula lib, Formula Hc, Formula Hd Formula He, Formula Hf, Formula Hg, Formula Hh, Formula Hi, Formula IIj, Formula Ilk, Formula Hm, Formula Hn, Formula Ho Formula Up, or Formula III, and all sub-embodiments disclosed herein) can be formulated as pharmaceutically acceptable salts
[0364] Carriers or excipients can be used to produce compositions The carriers or excipients can be chosen to facilitate administration of the compound .Examples of carriers include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose, or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycols and physiologically compatible solvents Examples ot physiologically compatible solvents include sterile solutions of water for injection (WFI), salme solution, and dextrose
[0365] The compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, transdermal, or inhalant In some embodiments, oral administration is preferred For oral administration, tor example, the compounds can be formulated into com entional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops
[0366] For inhalants, compounds of the invention may be formulated as dry powder or a suitable solution, suspension, or aerosol Powders and solutions may be formulated with suitable additives known in the art For example, powders may include a suitable powder base such as lactose or starch, and solutions may comprise propylene glycol, sterile water, ethanol, sodium chloride and other additives, such as acid, alkali and buffer salts Such solutions or suspensions may be administered by inhaling via spray, pump atomizer, or nebulizer, and the like I he compounds ot the invention may also be used in combination with other inhaled therapies, for example corticosteroids such as fluticasone propionate, beclomethasone dipropionate, triamcinolone acetomde, budesomde, and mometasone furoate, beta agonists such as albuterol, salmeterol, and formoterol, anticholinergic agents such as ipratropium bromide or tiotropium vasodilators such as treprostinal and lloprost, enzymes such as DNAase, therapeutic proteins, immunoglobulin antibodies, an oligonucleotide, such as single or double stranded DNΛ or RNA, siRNA antibiotics such as tobramycin, muscarinic receptor antagonists, leukotriene antagonists, cytokine antagonists, protease inhibitors, cromolyn sodium, nedocπl sodium, and sodium cromoglycate
[0367] Pharmaceutical preparations for oral use can be obtained, for example, by combining the activ e compounds with solid excipients, optionally grinding a resulting mixture and processing the mixture of granules, after adding suitable auxiliaries, it desired, to obtain tablets or dragee cores
Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, manmtol, or sorbitol; cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymcthylcellulosc (CMC), and/or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrating agents may be added, such as the cross-linked polyvinylpyrrolidone, agar, or alginic acid, or a salt thereof such as sodium alginate.
[0368] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain, for example, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG), and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye-stuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
[0369] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin ("gelcaps"), as well as soft, sealed capsules made of gelatin, and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols (PEGs). In addition, stabilizers may be added.
[0370] Alternatively, injection (parenteral administration) may be used, e.g., intramuscular, intravenous, intraperitoneal, and/or subcutaneous. For injection, the compounds of the invention are formulated in sterile liquid solutions, preferably in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.
[0371] Administration can also be by transmucosal, topical, transdermal, or inhalant means. For transmucosal, topical or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays or suppositories (rectal or vaginal).
[0372] The topical compositions of this invention are formulated preferably as oils, creams, lotions, ointments, and the like by choice of appropriate carriers known in the art. LSuitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohol (greater than C 12). The preferred carriers are those in which the active ingredient is soluble. Emulsifiers, stabilizers, humectants and antioxidants may also be included as well as agents imparting color or fragrance, if desired. Creams for topical application are preferably formulated from a mixture of mineral oil, self- emulsifying beeswax and water in which mixture the active ingredient, dissolved in a small amount solvent (e.g. an oil), is admixed. Additionally, administration by transdermal means may comprise a transdermal patch or dressing such as a bandage impregnated with an active ingredient and optionally one or more carriers or diluents known in the art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
[0373] The amounts of various compounds to be administered can be determined by standard procedures taking into account factors such as the compound 1C so, the biological half-life of the compound, the age, size, and weight of the subject, and the indication being treated. The importance of these and other factors are well known to those of ordinary skill in the art. Generally, a dose will be between about 0.01 and 50 mg/kg, preferably 0.1 and 20 mg/kg of the subject being treated. Multiple doses may be used.
[0374] The compounds of the invention may also be used in combination with other therapies for treating the same disease. Such combination use includes administration of the compounds and one or more other therapeutics at different times, or co-administration of the compound and one or more other therapies. In some embodiments, dosage may be modified for one or more of the compounds of the invention or other therapeutics used in combination, e.g., reduction in the amount dosed relative to a compound or therapy used alone, by methods well known to those of ordinary skill in the art.
[0375] It is understood that use in combination includes use with other therapies, drugs, medical procedures etc., where the other therapy or procedure may be administered at different times (e.g. within a short time, such as within hours (e.g. 1 , 2, 3, 4-24 hours), or within a longer time (e.g. 1 -2 days, 2-4 days, 4-7 days, 1-4 weeks)) than a compound of the present invention, or at the same time as a compound of the invention. Use in combination also includes use with a therapy or medical procedure that is administered once or infrequently, such as surgery, along with a compound of the invention administered within a short time or longer time before or after the other therapy or procedure. In some embodiments, the present invention provides for delivery of compounds of the invention and one or more other drug therapeutics delivered by a different route of administration or by the same route of administration, The use in combination for any route of administration includes delivery of compounds of the invention and one or more other drug therapeutics delivered by the same route of administration together in any formulation including formulations where the two compounds are chemically linked m such a way that they maintain their therapeutic activity when administered In one aspect, the other drug therap\ may be coadministered with one or more compounds of the invention Use in combination by coadministration includes administration of co-formulations or formulations of chemicalK joined compounds, or administration of two or more compounds in separate formulations within a short time ot each other (e g within an hour, 2 hours, 3 hours, up to 24 hours), administered by the same or different routes Co-admimstration of separate formulations includes co-administration
Figure imgf000160_0001
delivery \ ia one device, for example the same inhalant device, the same syringe, etc or administration from separate devices within a short time of each other Co-formulations of compounds of the invention and one or more additional drug therapies delivered by the same route includes preparation of the materials together such that they can be administered by one device, including the separate compounds combined in one formulation, or compounds that are modified such that they arc chemically joined, yet still maintain their biological activity Such chemically joined compounds may have a linkage that is substantially maintained in \ιvo, or the linkage may break down in vivo, separating the two active components
VIII. Manipulation of c-kit and c-fms
[0376] As the full-length coding sequence and ammo acid sequence of c-kit and c-fms from various mammals including human is known, cloning, construction of recombinant c-kit and c-fms, production and purification of recombinant protein, introduction of c-kit or c-fms into other organisms, and other molecular biological manipulations ot c-ktt and c-fms are readil> performed
[0377] Techniques for the manipulation of nucleic acids, such as, e g , subcloning, labeling probes (e g random-primer labeling using Klenow polymerase, nick translation, amplification), sequencing, hybridization and the like are well disclosed in the scientific and patent literature, see, e g , Sambrook, ed , Molecular Cloning a Laboratory Manual (2nd ed ), VoIs 1 -3, Cold Spring Harbor Laboratory, (1989), Current Protocols in Molecular Biology, Ausubel, ed John Wiley & Sons, Inc , New York (1997), Laboratory Techniques in Biochemistry and Molecular Biology Hybridization With Nucleic Acid Probes Part I Theory and Nucleic Acid Preparation Tyssen, ed Elsevier, N Y (1993)
[0378] Nucleic acid sequences can be amplified as necessary for further use using amplification methods, such as PCR, isothermal methods, rolling circle methods, etc , are well known to the skilled artisan See, e g Saiki, "Amplification of Genomic DNA" in PCR Protocols, Inms ct al , Eds , Academic Press, San Diego, CA 1990, pp 13-20, Wharam et al , Nucleic Acids Res 2001 Jun 1 ;29(1 1 ):E54-E54; Hafner et al., Biotechniques 2001 Apr;30(4):852-6, 858, 860 passim; Zhong et al,, Biotechniques 2001 Apr;30(4):852-6, 858, 860 passim,
[0379] Nucleic acids, vectors, capsids, polypeptides, and the like can be analyzed and quantified by any of a number of general means well known to those of skill in the art. These include, e.g., analytical biochemical methods such as NMR, spectrophotometry, radiography, electrophoresis, capillary electrophoresis, high performance liquid chromatography (HPLC), thin layer chromatography (TLC), and hyperdiffusion chromatography, various immunological methods, e.g. fluid or gel precipitin reactions, immunodiffusion, immuno-electrophoresis, radioimmunoassays (RIAs), enzyme-linked immunosorbent assays (ELISAs), immuno-fluorescent assays, Southern analysis, Northern analysis, dot-blot analysis, gel electrophoresis (e.g. SDS-PAGE), nucleic acid or target or signal amplification methods, radiolabehng, scintillation counting, and affinity chromatography.
|0380] Obtaining and manipulating nucleic acids used to practice the methods of the invention can be performed by cloning from genomic samples, and, if desired, screening and re-cloning inserts isolated or amplified from, e.g., genomic clones or cDNA clones. Sources of nucleic acid used in the methods of the invention include genomic or cDNA libraries contained in, e.g., mammalian artificial chromosomes (MACs), see, e.g., U.S. Patent Nos. 5,721 , 1 18; 6,025,155; human artificial chromosomes, see, e.g., Rosenfeld (1997) Nat. Genet. 15:333-335; yeast artificial chromosomes (YAC); bacterial artificial chromosomes (BAC); Pl artificial chromosomes, see, e.g., Woon (1998) Genomics 50:306-316; Pl -derived vectors (PACs), see, e.g., Kern (1997) Biotechniques 23:120-124; cosmids, recombinant viruses, phages or plasmids.
[0381] The nucleic acids used to practice the methods of the invention can be operatively linked to a promoter. A promoter can be one motif or an array of nucleic acid control sequences which direct transcription of a nucleic acid. A promoter can include necessary nucleic acid sequences near the start site of transcription, such as, in the case of a polymerase II type promoter, a TATA element, A promoter also optionally includes distal enhancer or repressor elements which can be located as much as several thousand base pairs from the start site of transcription. A "constitutive" promoter is a promoter which is active under most environmental and developmental conditions. An "inducible" promoter is a promoter which is under environmental or developmental regulation. Λ "tissue specific" promoter is active in certain tissue types of an organism, but not in other tissue types from the same organism. The term "operably linked" refers to a functional linkage between a nucleic acid expression control sequence (such as a promoter, or array of transcription factor binding sites) and a second nucleic acid sequence, wherein the expression control sequence directs transcription of the nucleic acid corresponding to the second sequence. [0382] The nucleic acids used to practice the methods of the invention can also be provided in expression vectors and cloning vehicles, e.g., sequences encoding the polypeptides used to practice the methods of the invention. Expression vectors and cloning vehicles used to practice the methods of the invention can comprise viral particles, baculovirus, phage, plasmids, phagemids. cosmids, fosmids, bacterial artificial chromosomes, viral DNA (e.g. vaccinia, adenovirus, foul pox virus, pscudorabies and derivatives of SV40), Pl -based artificial chromosomes, yeast plasmids, yeast artificial chromosomes, and any other vectors specific for specific hosts of interest (such as bacillus, Aspergillus and yeast). Vectors used to practice the methods of the invention can include chromosomal, non-chromosomal and synthetic DNA sequences. Large numbers of suitable vectors are known to those of skill in the art, and arc commercially available.
[0383] The nucleic acids used to practice the methods of the invention can be cloned, if desired, into any of a variety of vectors using routine molecular biological methods; methods for cloning in vitro amplified nucleic acids are disclosed, e.g., U.S. Pat. No. 5,426,039. To facilitate cloning of amplified sequences, restriction enzyme sites can be "built into" a PCR primer pair. Vectors may be introduced into a genome or into the cytoplasm or a nucleus of a cell and expressed by a variety of conventional techniques, well described in the scientific and patent literature. See, e.g., Roberts (1987) Nature 328:731 ; Schneider (1995) Protein Expr. Purif. 6435: 10; Sambrook, Tijssen or Ausubel. 'lhe vectors can be isolated from natural sources, obtained from such sources as ΛTCC or GenBank libraries, or prepared by synthetic or recombinant methods. For example, the nucleic acids used to practice the methods of the invention can be expressed in expression cassettes, vectors or viruses which arc stably or transiently expressed in cells (e.g. episomal expression systems), Selection markers can be incorporated into expression cassettes and vectors to confer a selectable phenotype on transformed cells and sequences. For example, selection markers can code for episomal maintenance and replication such that integration into the host genome is not required.
[0384] In one aspect, the nucleic acids used to practice the methods of the invention are administered in vivo for in situ expression of the peptides or polypeptides used to practice the methods of the invention. The nucleic acids can be administered as "'naked DNA" (sec, e.g., U.S. Patent No. 5,580,859) or in the form of an expression vector, e.g., a recombinant virus. The nucleic acids can be administered by any route, including peri- or intra-tumorally, as described below. Vectors administered in vivo can be derived from viral genomes, including recombinantly modified enveloped or non-enveloped DNΛ and RNA viruses, preferably selected from baculoviridiae, parvoviridiae, picornoviridiae, herpesveridiae, poxviridae, adenoviridiae, or picomnaviridiae. Chimeric vectors may also be employed which exploit advantageous merits of each of the parent vector properties (See e.g.. Feng (1997) Nature Biotechnology 15:866-870). Such \ iral genomes may be modified by recombinant DNA techniques to include the nucleic acids used to practice the methods of the invention, and may be further engineered to be replication deficient, conditionally replicating or replication competent In altemati\e aspects, \ectors are derrved from the adenoural (e g replication incompetent vectors derived from the human adenovirus genome, see, e g , U S Patent Nos 6,096,718; 6,1 10,458; 6,1 11,911, 5,631 236), adeno-associated \ iral and retroviral genomes Retroviral vectors can include those based upon murine leukemia virus (MuLV), gibbon ape leukemia virus (GaLV), Simian Iminuno deficiency virus (SIV), human immuno deficiency virus (HIV) and combinations thereof, see, e g , U S Patent Nos 6,1 17 681 , 6,107 478, 5,658,775, 5,449,614, Buchscher (1992) J Virol 66 2731 - 2739, Johann (1992) J Virol 66 1635-1640) Adeno-associated virus (AAV)-based \ cctors can be used to transduce cells with target nucleic acids, e g , in the in vitro production of nucleic acids and peptides, and in in vn o and ex vivo gene therapy procedures, see, e g , U S Patent Nos 6,1 10,456 5,474,935, Okada (1996) Gene Ther 3 957-964
[0385] I he present invention also relates to use of fusion proteins, and nucleic acids encoding them A polypeptide used to practice the methods of the invention can be fused to a heterologous peptide or polypeptide, such as N-terminal identification peptides which impart desired characteristics, such as increased stability or simplified purification Peptides and polypeptides used to practice the methods of the invention can also be synthesized and expressed as fusion proteins with one or more additional domains linked thereto for, e g , producing a more immunogenic peptide, to more readily isolate a recombmantly synthesized peptide, to identify and isolate antibodies and antibody-expressing B cells, and the like Detection and purification facilitating domains include, e g , metal chelating peptides such as polyhistidine tracts and histidine-tryptophan modules that allow purification on immobilized metals, protein A domains that allow purification on immobilized immunoglobulin, and the domain utilized in the FLAGS extension/affinity purification system (Immunex Corp, Seattle WA) Ihe inclusion of a cleavable linker sequences such as Factor Xa or enterokinase (In\ itrogen, San Diego CA) between a purification domain and the motif-comprising peptide or polypeptide to facilitate purification For example, an expression vector can include an epitope-encodmg nucleic acid sequence linked to six histidine residues followed by a thioredoxm and an enterokinase cleavage site (see e g , Williams (1995) Biochemistry 34 1787-1797, Dobeli (1998) Protein Expr Puπf 12 404-414) The histidine residues facilitate detection and purification while the enterokinase cleavage site provides a means for purifying the epitope from the remainder of the fusion protein In one aspect, a nucleic acid encoding a polypeptide used to practice the methods of the invention is assembled in appropriate phase with a leader sequence capable of directing secretion of the translated polypeptide or fragment thereof Technology pertaining to vectors encoding fusion proteins and application of fusion proteins are well disclosed in the scientific and patent literature, see e g Ki oil (1993) DNA Cell Biol 12 441 -53
[0386] The nucleic acids and polypeptides used to practice the methods of the invention can be bound to a solid support, e g , for use in screening and diagnostic methods Solid supports can include, e g , membranes (e g nitrocellulose or nylon), a microliter dish (e g PVC, polypropylene or polystyrene), a test tube (glass or plastic), a dip stick (e g glass, PVC, polypropylene, polystyrene, latex and the like), a micro fuge tube, or a glass, silica, plastic, metallic or polymer bead or other substrate such as paper One solid support uses a metal (e g cobalt or mckel)- compπsmg column which binds with specificity to a histidme tag engineered onto a peptide
[0387] Adhesion of molecules to a solid support can be direct (i e , the molecule contacts the solid support) or indirect (a "linker" is bound to the support and the molecule of interest binds to this linker) Molecules can be immobilized either covalently (e g utilizing single reactive thiol groups of cysteine residues (sec, c g , Colliuod (1993) Bioconjugate Chem 4 528-536) or non- covalently but specifically (e g via immobilized antibodies (see, e g , Schuhmann (1991) Adv Mater 3 388-391 , Lu (1995) Anal Chem 67 83-87, the biotm/strepavidm system (see, e g , Iwane (1997) Biophys Biochem Res Comm 230 76-80), metal chelating, e g , Langmuir-Blodgett films (sec, e g , Ng (1995) Langmuir 1 1 4048-55), metal-chelatmg self-assembled monolayers (see, e g , Sigal (1996) Anal Chem 68 490-497) for binding of polyhistidme fusions
[0388] Indirect binding can be achieved using a variety of linkers which are commercially available The reactive ends can be any of a variety of functionalities including, but not limited to ammo reacting ends such as N-hydroxysuccmimide (NHS) active esters, lmidoesters, aldehydes, epoxides, sulfonyl halides, isocyanate, isothiocyanate, and nitroaryl halides, and thiol reacting ends such as pyridyl disulfides, maleimides, thiophthahmides, and active halogens The heterobifunctional crosshnkmg reagents have two different reactive ends, c g , an ammo -re active end and a thiol-reactive end, while homobifunctional reagents have two similar reactive ends, e g , bismaleimidohexane (BMH) which permits the cross-linking of sulfhydryl-containmg compounds The spacer can be of varying length and be aliphatic or aromatic Examples of commercially available homobifunctional cross-linking reagents include, but arc not limited to, the imidoesters such as dimethyl adipimidate dihydrochloride (DMA), dimethyl pimehmidate dihydrochloride (DMP), and dimethyl subeπmidate dihydrochloride (DMS) Heterobifunctional reagents include commercially available active halogen-NHS active esters coupling agents such as N-succmimidyl bromoacctate and N-succmimidyl (4-iodoacetyl)ammobenzoate (SIΛB) and the sulfosuccinimidyl derivatives such as sulfosuccmimidyl(4-iodoacetyl)aminobenzoate (sulfo-SIAB) (Pierce). Another group of coupling agents is the heterobifunctioiial and thiol clcavable agents such as N-succinimidyl 3-(2-pyridyidithio)propionatc (SPDP) (Pierce Chemicals, Rockford, [L).
[0389] Antibodies can also be used for binding polypeptides and peptides used to practice the methods of the invention to a solid support. This can be done directly by binding peptide-specific antibodies to the column or it can be done by creating fusion protein chimeras comprising motif- containing peptides linked to, e.g., a known epitope (e.g. a tag (e.g. FLAG, myc) or an appropriate immunoglobulin constant domain sequence (an "immunoadhesin," see, e.g., Capon (1989) Nature 377:525-531 (1989).
[0390] Nucleic acids or polypeptides used to practice the methods of the invention can be immobilized to or applied to an array. Arrays can be used to screen for or monitor libraries of compositions (e.g. small molecules, antibodies, nucleic acids, etc.) for their ability to bind to or modulate the activity of a nucleic acid or a polypeptide used to practice the methods of the invention. For example, in one aspect of the invention, a monitored parameter is transcript expression of a gene comprising a nucleic acid used to practice the methods of the invention. One or more, or all the transcripts of a cell can be measured by hybridization of a sample comprising transcripts of the cell, or nucleic acids representative of or complementary to transcripts of a cell, by hybridization to immobilized nucleic acids on an array, or "biochip." By using an "array" of nucleic acids on a microchip, some or all of the transcripts of a cell can be simultaneously quantified. Alternatively, arrays comprising genomic nucleic acid can also be used to determine the genotype of a newly engineered strain made by the methods of the invention. Polypeptide arrays" can also be used to simultaneously quantify a plurality of proteins.
[0391] The terms "array" or "microarray" or "biochip" or "chip" as used herein is a plurality of target elements, each target element comprising a defined amount of one or more polypeptides (including antibodies) or nucleic acids immobilized onto a defined area of a substrate surface. In practicing the methods of the invention, any known array and/or method of making and using arrays can be incorporated in whole or in part, or variations thereof, as disclosed, for example, in U.S. Patent Nos. 6,277,628; 6,277,489; 6,261,776; 6,258,606; 6,054,270; 6,048,695; 6,045,996; 6,022,963; 6,013,440; 5,965,452; 5,959,098; 5,856,174; 5,830,645; 5,770,456; 5,632,957; 5,556,752; 5, 143,854; 5,807,522; 5.800,992; 5,744,305; 5,700,637; 5,556,752; 5,434,049: see also, e.g., WO 99/51773; WO 99/09217; WO 97/46313; WO 96/17958; see also, e.g., Johnston (1998) Curr. Biol 8:R171-R174; Schummer (1997) Biotechniques 23 :1087-1092; Kern (1997) Biotechniques 23: 120-124; Solinas-Toldo (1997) Genes, Chromosomes & Cancer 20:399-407; Bowtell (1999) Nature Genetics Supp. 21 :25-32. See also published U.S. patent application Nos. 20010018642; 20010019827; 20010016322; 20010014449; 20010014448; 20010012537; 20010008765.
Host Cells and Transformed Cells
[0392] The invention also provides a transformed cell comprising a nucleic acid sequence used to practice the methods of the invention, e.g. , a sequence encoding a polypeptide used to practice the methods of the invention, or a vector used to practice the methods of the invention. The host cell may be any of the host cells familiar to those skilled in the art, including prokaryotic cells, eukaryotic cells, such as bacterial cells, fungal cells, yeast cells, mammalian cells, insect cells, or plant cells. Exemplary bacterial cells include E. coli, Streptomyces , Bacillus subtilis, Salmonella typhimurium and various species within the genera Pseudomonas, Streptomyces, and Staphylococcus. Exemplary insect cells include Drosophila S2 and Spodoptera Sf9. Exemplary animal cells include CHO, COS or Bowes melanoma or any mouse or human cell line. The selection of an appropriate host is within the abilities of those skilled in the art.
[0393] Vectors may be introduced into the host cells using any of a variety of techniques, including transformation, transfection, transduction, viral infection, gene guns, or Ti-mediated gene transfer. Particular methods include calcium phosphate transfection, DEAE-Dextran mediated transfection, lipofection, or electroporation.
[0394] Engineered host cells can be cultured in conventional nutrient media modified as appropriate for activating promoters, selecting transformants or amplifying the genes used to practice the methods of the invention. Following transformation of a suitable host strain and growth of the host strain to an appropriate cell density, the selected promoter may be induced by appropriate means (e.g. temperature shift or chemical induction) and the cells may be cultured for an additional period to allow them to produce the desired polypeptide or fragment thereof.
[0395] Cells can be harvested by centrifugation, disrupted by physical or chemical means, and the resulting crude extract is retained for further purification. Microbial cells employed for expression of proteins can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents. Such methods are well known to those skilled in the art. The expressed polypeptide or fragment can be recovered and purified from recombinant cell cultures by methods including ammonium sulfate or ethanol precipitation, acid extraction, anion or cation exchange chromatography, phosphocellulose chromatography, hydrophobic interaction chromatography, affinity chromatography, hydroxylapatite chromatography and lectin chromatography. Protein refolding steps can be used, as necessary, in completing configuration of the polypeptide If desired, high performance liquid chromatography (IIPLC) can be emplo>ed for final purification steps
[0396] Various mammalian cell culture systems can also be emplo\ed to express recombinant protein Examples of mammalian expression systems include the COS-7 lines of monkey kidney fibroblasts and other cell lines capable of expressing proteins from a compatible vector, such as the C 127, 3T3, CHO HeLa and BHK cell lines
[0397] The constructs in host cells can be used in a conventional manner to produce the gene product encoded by the recombinant sequence Depending upon the host employed in a recombinant production procedure, the polypeptides produced by host cells containing the vector may be glycosylated or may be non-glycosylated Polypeptides used to practice the methods of the invention may or may not also include an initial methionine amino acid residue
[0398] Cell-free translation systems can also be employed to produce a polypeptide used to practice the methods of the invention Ccll-irec translation systems can use mRNAs transcribed from a DNA construct comprising a promoter operably linked to a nucleic acid encoding the polypeptide or fragment thereof In some aspects, the DNA construct may be linearized prior to conducting an in vitr o transcription reaction The transcribed mRNA is then incubated with an appropriate cell-free translation extract, such as a rabbit reticulocyte extract, to produce the desired polypeptide or fragment thereof
[0399] The expression vectors can contain one or more selectable marker genes to provide a phenotypic trait for selection of transformed host cells such as dihydrofolate reductase or neomycin resistance for eukaryotic cell culture, or such as tetracycline or ampicillin resistance in
[0400] For transient expression in mammalian cells, cDNA encoding a polypeptide of interest may be incorporated into a mammalian expression vector, e g pcDNAl , which is available commercially from Invitrogen Corporation (San Diego, Calif , U S A , catalogue number V490- 20) This is a multifunctional 4 2 kb plasmid vector designed for cDNA expression in eukaryotic systems, and cDNA analysis in prokaryotes, incorporated on the vector are the CMV promoter and enhancei , splice segment and polyadenylation signal, an SV40 and Polyoma \ irus origin of replication, and Ml 3 origin to rescue single strand DNΛ for sequencing and mutagenesis, Sp6 and T7 RNA promoters for the production of sense and anti-sense RNA transcripts and a Col El -like high copy plasmid origin A polylmker is located appropriately downstream of the CMV promoter (and 3' of the T7 promoter) (0401] The cDNA insert may be first released from the above phagemid incorporated at appropriate restriction sites in the pcDNAI polylinker. Sequencing across the junctions may be performed to confirm proper insert orientation in pcDNAI. The resulting plasmid may then be introduced for transient expression into a selected mammalian cell host, for example, the monkey- derived, fibroblast like cells of the COS-I lineage (available from the American Type Culture Collection, Rockville, Md. as ATCC CRL 1650).
[0402] For transient expression of the protein-encoding DNA, for example, COS-I cells may be transfected with approximately 8 μg DNA per 10 COS cells, by DEAE-mediated DNA transfection and treated with chloroquine according to the procedures described by Sambrook et al, Molecular Cloning: A Laboratory Manual, 1989, Cold Spring Harbor Laboratory Press. Cold Spring Harbor N.Y, pp. 16,30-16.37. An exemplary method is as follows. Briefly, COS-I cells are plated at a density of 5 x 106 cells/dish and then grown for 24 hours in FBS-supplcmcnted DMEM/F12 medium. Medium is then removed and cells are washed in PBS and then in medium. A transfection solution containing DEAE dextran (0.4 mg/ml), 100 μM chloroquine, 10% NuSerum, DNA (0.4 mg/ml) in DMEM/F12 medium is then applied on the cells 10 ml volume. After incubation for 3 hours at 37 0C, cells are washed in PBS and medium as just described and then shocked for 1 minute with 10% DMSO in DMEM/F12 medium. Cells are allowed to grow for 2-3 days in 10% FBS-supplemented medium, and at the end of incubation dishes are placed on ice, washed with ice cold PBS and then removed by scraping. Cells are then harvested by centrifugation at 1000 rpm for 10 minutes and the cellular pellet is frozen in liquid nitrogen, for subsequent use in protein expression. Northern blot analysis of a thawed aliquot of frozen cells may be used to confirm expression of receptor-encoding cDNA in cells under storage.
[0403] In a like manner, stably transfected cell lines can also prepared, for example, using two different cell types as host: CHO Kl and CHO Pro5. To construct these cell lines, cDNA coding for the relevant protein may be incorporated into the mammalian expression vector pRC/CMV (Invitrogcn), which enables stable expression. Insertion at this site places the cDNA under the expression control of the cytomegalovirus promoter and upstream of the polyadcnylation site and terminator of the bovine growth hormone gene, and into a vector background comprising the neomycin resistance gene (driven by the SV40 early promoter) as selectable marker.
[0404] An exemplary protocol to introduce plasmids constructed as described above is as follows. The host CHO cells are first seeded at a density of 5x10 in 10% FBS-supplemented MEM medium. After growth for 24 hours, fresh medium is added to the plates and three hours later, the cells are transfected using the calcium phosphate-DNA co-precipitation procedure (Sambrook et al, supra). Briefly, 3 μg of DNA is mixed and incubated with buffered calcium solution for 10 minutes at room temperature. An equal volume of buffered phosphate solution is added and the suspension is incubated for 15 minutes at room temperature. Next, the incubated suspension is applied to the cells for 4 hours, removed and cells were shocked with medium containing 15% glycerol. Three minutes later, cells are washed with medium and incubated for 24 hours at normal growth conditions. Cells resistant to neomycin are selected in 10% FBS- supplemented alpha-MEM medium containing G418 (1 mg/ml). individual colonies of G418- resistant cells are isolated about 2-3 weeks later, clonally selected and then propagated for assay purposes.
EXAMPLES
(0405] A number of examples illustrative of the present invention are described below, in most cases, alternative techniques could also be used. The examples are intended to be illustrative and are not limiting or restrictive to the scope of the invention. Unless specifically noted to the contrary, in cases where a compound number is not preceeded by a "P-" (e.g., "P-OOOl ") in the Examples section, compound naming and/or enumeration is not related to naming and/or enumeration employed in other sections of this application. Similarly, structure and substituent naming and enumeration within the Examples are independent of structure and substituent naming and enumeration in above sections of this application unless clearly indicated otherwise.
(0406] In the following Examples, it is understood that the solvents and reagents used or suggested are not limiting, and can be substituted appropriately with solvents and reagents known to those of skill in the art. Reaction products may be isolated by means known in the art, such as extraction with a suitable solvent, precipitation from a suitable solvent, chromatography using a suitable solvent system, including silica gel column chromatography, HPLC, preparative TLC, and the like. Exemplary methods for synthesis of compounds of the present invention may be found in US Patent Application Publication number US 2007/0032519, the disclosure of which is hereby incorporated by reference. The lH-pyrrolo[2,3-b]pyridinc core of compounds described in the examples may also be referred to as 7-azaindole in the examples.
Example 1: Synthesis of compound of Formula I, where X1, X2, Yi and Y2 are CH and L1 is -CH2-:
|0407J Compounds of Formula I, as described in paragraph (0011], where X), X2, Yi and Y? are CH and L1 is -CH2- or -CO- may be synthesized from 7-azaindole according to one of the following Schemes 1 -3, where R24 is consistent with An, which can be further substituted to provide compounds where R24 is Aη-L^-R1 as described for Formula I.
Scheme - 1
Figure imgf000170_0001
Step - J- Synthesis of compound 2.
|0408] Compound 2 is synthesized from commercially available 7-azaindoIe following the literature procedure (Robinson. J. Am. Chem, Soc, 1955, 77, p. 457),
Step -2- Synthesis of compound of Formula II
[0409] Compound of Formula II, where P is a protecting group, is synthesized by deprotonation using base (e.g. BuLi, NaH) in aprotic solvent like tetrahydrofuran or ether and reacting the anion with a silyl chloride (e.g. TIPS) or an anhydride (e.g. Boc anhydride). The compound is isolated by following standard procedure (quenching with ice-cold brine, work up, and purification by flash silica gel chromatography).
Steps -3 and 4 - Synthesis of compound of Formula 1
[0410] Compounds of Formula I, wherein R24 is Ar1 as defined in Formula I, is synthesized through the reaction of compounds of Formula II with isopropyl chloro formate (or ethyl chloroformate) at room temperature in toluene to give a 3-chloromethyI intermediate. This intermediate is cooled to 78 0C and immediately reacted with an organocopper reagent, which is generated from the reaction between a Grignard reagent (or organolithium reagent) and a solution of copper cyanide and LiCl. The mixture is stirred at -78 0C for one hour and allowed to warm to room temperature. The reaction is quenched with a solution of 4: 1 ammonium chloride: ammonium hydroxide. The reaction is worked up in the usual manner and purified by flash silica gel chromatography to give the nitrogen-protected compound. The final compound can be realized through the deprotection of the protecting group (Boc, TIPS) using standard conditions (TFA or NH4F) at room temperature. Scheme - 2
Figure imgf000170_0002
Step - I — Synthesis of compound 3 [0411] Compound 3 is synthesized by reacting commercially available 7-azaindole. compound 1, with hexamethyltetramine and acetic acid in water with heating to reflux for two hours. After cooling, the desired compound is precipitated and collected by filtration.
Step - 2 - Synthesis of compound of Formula III
[0412] Compound of Formula III, where P is a protecting group, is synthesized by reacting compound 3 with an appropriate reagent to introduce a protecting group (e.g. tert- butyloxycarbonyl di anhydride) and a base (e.g. sodium hydride) in an appropriate solvent (e.g. tetrahydrofuran) typically at room temperature for 12-18 hours. The compound can be isolated by conventional means (e.g. extraction).
Step - 3 ~ Synthesis of compound of Formula IV
[0413] Compound of Formula IV, wherein R24 is Ar1, is synthesized by reacting compound of Formula III in an appropriate solvent (e.g. 1 ,2-dimethoxyethane) with a Grignard reagent of the formula R24MgCl or R24MgBr (e.g. pyridinyl magnesium bromide) or an equivalent nucleophile in an appropriate solvent (e.g. tetrahydrofuran) under inert atmosphere cooled typically to -10 0C. The reaction is typically allowed to warm to room temperature and stirred for 12-18 hours. The desired compound is purified by reverse phase high pressure liquid chromatography.
Steps - 4 and 5 - Synthesis of an intermediate of compound of Formula I [0414] An intermediate of compound of Formula I is synthesized by reacting compound of Formula IV with a reducing agent (e.g. sodium borohydride) in a polar solvent (e.g. ethanol) typically with healing to 80 0C for 1-4 hours. The reaction is quenched with the addition of methanol and concentrated and purified by reverse phase high performance liquid chromatography. Compound of Formula I where R24 is Ar1 is synthesized by reacting this intermediate with an appropriate reagent to remove the protecting group, P, (e.g. hydrochloric acid) in an apolar solvent (e.g. dioxane). The final compound is isolated by standard procedures (e.g. reverse phase preparative high pressure liquid chromatography). Scheme - 3
Figure imgf000171_0001
Step - / Synthesis of compound of Formula F
[0415J Compound of Formula F where R24 is Ar1, is synthesized by reacting compound 1 with an activating agent (e.g. methyl magnesium bromide and zinc dichloride or anhydrous aluminum chloride) and a heteroaryl acid chloride (e.g. nicotinic acid chloride) in a non-reactive solvent (e.g dichloromethane). under inert atmosphere (e.g. argon), at room temperature or with heating up to reflux for 18-24 hours. The compound is isolated by standard procedures (e.g, extraction and silica-gel chromatography).
Example 2: Synthesis of intermediate 3-(6-Chloro-pyridin-3-ylmethyl)-l-triisopropylsi]anj I- lll-pyrrolo[2,3-blpyridine (6) and (3-(6-Bromo-pyridin-3-ylmethyl)-l-triisopropylsilanyl-lH- pyrroloI2,3-b]pyridinc) (6a)
[0416] Compound 6, an intermediate to compounds of Formula I, as described in paragraph 100111, where X1, X2, Y, and Y2 are CH, n is 1, P, Q and T are CH and L1 is -CH2-, may be synthesized in four steps from 7-azaindole according to the following Scheme 4.
Scheme - 4
Figure imgf000172_0001
Step -1- Synthesis ofdimethyl-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-amine (2) [0417] Into a 3-neck round bottom flask was added Isopropyl alcohol (320.0 mL) followed by the addition of 1 H-pyrrolo[2,3-b]pyridine 1 (7.10 g, 60.1 mmol), dimethylamine hydrochloride (5.4 g, 0.066 mol) , and formaldehyde (2.0 g, 0.066 mol). The reaction mixture was stirred at room temperature for 12 hours, and then refluxed for 30 minutes. The suspension solution was evaporated to dryness in vacuo. To the residue was added water (60.0 mL, 3.33 mol) and concentratred hydrochloric acid (6.0 mL, 0.20 mol). The water layer was extracted with ether and the aqueous layer was neutralized with potassium carbonate. The aqueous layer was extracted with dichloromethane, dried over sodium sulfate and concentrated to give the compound, which was then further washed with ether and dried to afford compound 2 (7.1 g, yield = 67.4%), as a white solid.
Step -2- Synthesis ofdimethyl-(l-triisopropyl$ilanyl-lH-pyrrulυ[2,3-b]pyridin-3-ylmethyl)-amine (4)
[0418J Into a round bottom flask 7-Azagramine 2 (5,38 g, 30.7 mmol), N,N-dimethylformamide (25,0 mL), and sodium hydride (1.35 g, 33.8 mol) were combined. Into the reaction was added triisopropylsilyl chloride (6.8 mL, 0.032 mol). The reaction was stirred at 20 0C for 12 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage to give compound 4 (6.0 g, yield = 58.8%) as a colorless oil.
Step - 3- Synthesis of 3-chloromethyl-l-triisopropylsilanyl-lH-pyrwlo[2,3-b] pyridine (5) [0419] Into a round bottom flask was added compound 4 (500.0 mg, 1.51 mmol) and toluene (5.0 mL, 0.047 mol) under an atmosphere of nitrogen. Into the reaction mixture 1 ,0 M isopropyl chloro formate in toluene (1 .6 mL) was added slowly at room temperature. The reaction mixture was stirred for another 2 hours to give desired compound 5 used for next step without purification.
Step -4- Synthesis of3-(6-Chloro-pyridin-3-ylmethyl)-l-triisopropylsilany!-lIl-pyrroIo[2,3- b] pyridine (6)
[0420] Into a round bottom flask was added 5-iodo-2-chloro-pyridine (315.0 mg, 1.32 mmol) and letrahydrofuran (12.0 mL, 0.15 mol) at -40 0C under an atmosphere of nitrogen. Into the reaction 2.0 M of isopropylmagncsium chloride in tetrahydrofuran (0.72 mL, 1.44 mmol) was added. The reaction mixture was stirred for 40 minutes at 40 0C. TLC (hexane/ethyl acetate 2: 1 ) indicated no starting material. Into the reaction mixture 0.6 M of CuCN.2LiCl in tetrahydrofuran (2.4 mL, 1 ,44 mmol) was added. The reaction mixture was allowed to come to room temperature for 5 minutes and trimethyl phosphite (0.29 mL, 2.4 mmol) was added. After 10 minutes, this solution was added into a round bottom flask containing compound 5 (315.0 mg) and toluene (8.0 mL). The reaction was stirred at 20 0C for 40 hours. The reaction mixture was poured into water and the compound extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage (dichloromethane/methanol 1 : 10) to give compound 6 (230 mg, yield = 59.0%) as a white solid. Compound 6a (3-(6-Bromo~pyridin-3- ylmethyl)-l -triisopropylsilany]-lH-pyrrolo[2,3-b]p>τidine) (MS (ESI) [M+H*] ' = 288.1. 290.1) was prepared substituting 5-iodo-2-chloro-pyridine with 5-iodo-2-bromo-pyridine in Step 4, with reaction conditions and work up procedure the same as that for the synthesis of compound 6.
Example 3: Synthesis of intermediate (6-Chloro-pyridin-3-yl)-(lH-pyrrolo[2,3-b]pyridin-3- yl)-methanone (7)
|0421] Compound 7, an intermediate to compounds of Formula I, as described in paragraph 10011], where X1, X2. Y, and Y2 are CH, n is 1 , P, Q and T are CH and L1 is -CO-, may be synthesized in one step from 7-azaindole according to the following Scheme 5. Scheme - 5
Figure imgf000174_0001
[0422] Into a round bottom flask was added aluminum trichloride (16.0 g, 0.12 mol) and dichloromethane (100.0 mL) under an atmosphere of nitrogen. Into the reaction mixture IH- Pyrrolo[2,3-b]pyridine 1 (3.2 g, 0.027 mol) in dichloromethane (20.0 ml.) was added. The reaction was stirred at room temperature for 70.0 minutes and 6-Chloropyπdine-3-carbonyl chloride 8 (5.4 g, 0.031 mol) in dichloromethane (10.0 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. Methanol (10 mL) was added to the reaction mixture and the solvent was evaporated in vacuo. The residue was poured into water and the precipitated compound was removed by filtration. The aqueous layer was extracted with ethyl acetate and the organic layer was dried and concentrated and combined with the solid isolated by filtration to give 7 (6.2 g, yield = 88.6%) as a white solid. MS (ESI) [M+lT]T = 258.
Example 4: Synthesis of benzyl-[5-(lII-pyrroloI2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-OOOl)
[0423] Benzyl-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-OOOl) was prepared in two steps from 3-(6-Chloro-pyridm-3-yhnethyl)-l-triisopropylsilanyl-l H-pyrrolo[2,3- bjpyridine (6) according to Scheme 6.
Scheme - 6
Figure imgf000174_0002
Step -I- Synthesis nf henzyl-[5-(l -triw' opmpylsilunyl- 1 H-pyrrolo[2,3-h] pyridin-3-ybnethyl)- pyridin-2-yl] -amine (10):
[0424] Into a round bottom flask was added 3-(6-Chloro-pyridin-3-ylmethyl)-l - triisopropylsilanyl-lH-pyrrolo[2.3-b]pyridine 6 (160.0 mg, 0.40 mmol. prepared as described in Example 2), benzylamine (32, 0.1 mL. 0.90 mmol), palladium acetate (17.0 mg, 0.076 mmol), toluene (10.0 mL), potassium tert-butoxide (80.0 mg, 0.71 mmol) and 2-(di-t- butylphosphino)biphenyl (31.4 mg, 0.1 1 mmol) under an atmosphere of nitrogen. The reaction was stirred under reflux for 3 hours. TLC and MS indicated no starting material. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage (dichloromethane/methanol 1 :20) to give compound 10 (1 10 mg, yield = 58.5%) as a white solid. MS (ESI) [M+HT = 471.
Step -2- Synthesis ofbenzyl-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P- 0001):
[0425] Into a round bottom flask was added benzyl-[5-(l -triisopropylsilanyl-lH-pyrrolo[2,3- b]pyridin-3-ylmethyl)-p>τidin-2-yl]-amine 10 (400.0 mg, 0.85 mmol), tetrahydrofuran (20.0 ml,) and tetra-n-butyl ammonium fluoride (240 mg, 0.93 mmol). The reaction mixture was stirred at 20 0C for 30 minutes. TLC indicated no starting material. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotage (dichloromethane/methanol 1 : 10) to give compound P-0001 (220 mg, Yield = 82.4%) as a white solid. MS (ESI) [M+HT = 315. |0426] Additional compounds were prepared following the protocol of Scheme 6, substituting benzyl amine with a suitable amine in Step 1 , and using either 3-(6-Chloro-pyridin-3-ylmethyl)-l - triisoproρylsilanyl-l ll-pyrrolo[2,3-b]pyridine 6 or 3-(6-Bromo-pyridin-3-ylmethyl)-l- triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine 6a, in Step 1. The following compounds were made following this procedure:
Dimethyl-[5-(lH-pyiτolo[2,3-b]pyridin-3-ylmethyl)-pyridm-2-yl]-amine (P-0021), (4-methoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-aminc (P-0004), (4-chloro-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0005), (4-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0006), (4-methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0007), and [5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-p>τidin-2-yl]-thiophen-2-ylmethyl-amme (P-0008). The following table indicates the amine used in Step 1 in place of benzyl amine in Column 3, and whether 3-(6-Chloro-pyridin-3-ylmethyl)-l-triisopropylsilanyl-l H-pyrrolo[2,3-b]pyridine or 3-(6- Bromo-pyridin-3-ylmethyl)-l -triisopropylsilanyl-lH-pynOlo[2,3-b]pyridine was used in Step 1 in Column 2 (Cl or Br, respectively), with the compound structure in Column 4, experimental mass spectrometry result in Column 5, and compound number in Column 1.
Figure imgf000176_0001
Example 5: Synthesis of (6-Benzylamino-pyridin-3-yI)-(lH-pyrroIo[2,3-b]pyridin-3-yl)- methanone (P-0002)
[0427] (6-Benzylamino-p^τidin-3-yl)-(l H-pyrrolo[2,3-b]pyτidin-3-yl)-methanone (P-0002) was prepared in one step from (6-Chlαro-pyridin-3-yl)-(l H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (7) according to Scheme 7.
Scheme — 7
Figure imgf000176_0002
[0428] Into a pressure tube was added (6-Chloro-pyridin-3-yl)-(lH-pyrrolo[2,3-b]pyridm-3-} I)- methanone 7 (270,0 mg, 1 ,05 mmol, prepared as described in Example 3). and benzylamine (32,
0.7 rriL. 0.006 mol) and tetrahydrofuran (25.0 niL) under an atmosphere of nitrogen. The reaction mixture was heated to 185 0C for 60 hours. The reaction mixture was concentrated to remove most of the solvent and the residue was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified with biotage
(dichloromethane/methanol 1 :20) to give compound P-0002 (30 mg, yield = 8,7%) as a white solid. MS (ESI) [M+HT = 329.
[0429] Additional compounds were prepared following the protocol of Scheme 7, replacing benzylamine with a suitable amine. The following compounds were made following this procedure:
[6-(4-Fluoro-benzylamino)-pyridin-3-y I]-(I H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-0015),
[6-(3-Fluoro-benzylamino)-pyridin-3-yI]-(lII-pyrroIo[2,3-b]pyπdin-3-yl)-methanone (P-0016),
(lH-Pyrrolo[2,3-b]pyridin-3-y[)-[6-(4-trifluoromethyl-benzyIamino)-pyridin-3-yl]-methanone (P-
0017),
(lH-Pyrrolo[2,3-b]pyridin-3-yl)-{6-[(thiophen-2-ylmethyl)-amino]-pyridin-3-y]}-methanone (P-
0018),
(6-Phenylamino-pyridin-3-yl)-(lH-pyrrolo[2,3-b]p>τidin-3-yl)-methanone (P-0023),
(6-Isopropylamino-pyridin-3-yl)-(lH-pyrτolo[2,3-b]pyridin-3-yl)-methanone (P-0024),
(6-Isobutylamino-pyridin-3-yl)-(l H-pyiτolo[2,3-b]pyτidin-3-yl)-methanone (P-0025),
[6-(3-Bcnzyloxy-phenyIamino)-pyridin-3-yl]-(lH-pyrroIo[2,3-b]pyridin-3-yl)-methanone (P-
0026),
[6-(Cyclopropylmethyl-ammo)-pyridin-3-yl] -( 1 H-pyrrolo [2,3 -b]pyridin-3-yl)-methanone (P-
0030),
[6-(Cyclohexylmethyl-amino)-pyπdin-3-yl]-(lH-pyrrolo[2,3-b]pyridm-3-yl)-methanone (P-0031),
The following table indicates the amine substituted in place of benzylamine in column 2, to provide these compounds, shown by structure in column 3. Column 1 provides the compound number and column 4 gives the experimental mass spectrometry result.
Figure imgf000177_0001
Figure imgf000178_0001
Example 6: Synthesis of Isobutyl-[5-(lH-py rrolo[2,3-b]pyridin-3-ylmethyI)-pyridin-2-yl]- amine P-0028
[0430] Compound P-0028 was synthesized in 1 step from 6-Isobutylamino-pyridin-3-yl)-( lH- pyrrolo[2,3-b]pyridin-3-yl)-methanone P-0025 as shown in Scheme 8.
Figure imgf000179_0001
Step -1 -Synthesis of Isobutyl-[5-(lH-pyrrolo[2, 3-bJpyridin-3-ylmethyl)-pyridin-2-ylJ -amine (P-
0028).
[0431] To (6-Isobutylamino-pyridin-3-yl)-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methanone (P-0025,
60.0 mg, 0.20 mmol, prepared as described in Example 5) in 1 ,2-ethanediol (5.0 ml) was added hydrazine (1.0 inL, 0.032 mol) and potassium hydroxide (200.0 mg, 3.56 mmol). The reaction mixture was heated to 180 0C overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound (P-0028, 10 mg, 16.7%). MS (ESI) [M+H+]~ = 281.
[0432] Cyclopropylmethyl-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0032)
Figure imgf000179_0002
was prepared following the protocol of Scheme 8, substituting (6-Isobutylamino-pyridin-3-yl)-
( lH-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-0025 with [6-(Cyclopropylmethyl-amino)-pyridin-
3-yl]-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-0030 (prepared as described in Example 5).
MS (ESI) [M+H+Γ = 279.
[0433] Cyclohexylmethyl-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0033)
Figure imgf000180_0001
was prepared following the protocol of Scheme 8. substituting (6-Isobutylamino-pyridin-3-yl)- (lH-pyrrolo[2,3-b]pyridm-3-yl)-methanone P-0025 with [6-(Cyclohexylmethyl-amino)-pyridin-3- yl]-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methanone P-0031, (prepared as described in Example 5). MS (ESI) [M+HT = 321.
Example 7: 3-(6-Isopropyl-pyridin-3-ylmethyl)-lH-pyrrolo[2,3-b]pyridine P-0019
10434] 3-(6-lsopropyl-pyridin-3-ylmethyl)-lII-pyrrolo[2,3-b]pyridine P-0019 was synthesized in 2 steps from 3-(6-Chloro-pyridin-3-ylmethyl)-l -triisopropylsilanyl-lH-pyττolo[2,3-b]pyridine 6 as shown in Scheme 9.
Scheme 9
Figure imgf000180_0002
Step - 1 -Synthesis of3-(6-Isopropyl-pyridin-3-ylmethyl)-l-triisopropylsi1anyl-lH-pyrrolo[2,3- b] pyridine (39)
[0435] To 3-(6-Chloro-pyridin-3-ylmethyl)-l -triisopropylsilanyl-1 II-pyrrolo[2.3-b]pyridine (6, 54.0 mg, 0.0001 35 mol, prepared as described in Example 2) in Tetrahydrofuran (4.0 mL) were added [l ,l'-bis(diphenylphosphino)ferrocene]-dichloropalladium(Il) (23.0 mg) and Isopropylmagnesium Chloride (0.15 mL, 2.0 M in Tetrahydrofuran). The reaction was stirred at 20 0C under an atmosphere of Nitrogen for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound 39 (38 mg, 70.4%).
Step-2 -Synthesis of 3-(6-Isopropyl-pyridin-3-ylmethyl)-lII-pyrrolo[2,3-b] pyridine (P-0019) [0436] To 3-(6-Isopropyl-pyridin-3-ylmethyl)-l -triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (39, 35.0 mg, 0.086 mmol) in tetrahydrofuran (3.0 mL) was added tetra-n-butylammonium fluoride (29 mg, 0.1 1 mmol). The reaction was stirred at 20 0C for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound (P-0019, 18,0 mg, 81.9%). MS (ESI) [M+H"]+ - 252.
Example 8: Synthesis of [5-(lH-P}rrolot2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-(4- trifluoromethyl-beiizyl)-amine (P-0003)
[0437] [5-(lH-Pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyridin-2-yl]-(4-triπuoromethyl-benzyl)-amine (P-0003) was prepared in three steps from (6-Chloro-pyridin-3-yl)-(lII-pvrrolo[2.3-b]pyridin-3- yl)-methanone (7) according to Scheme 10.
Scheme 10
Figure imgf000181_0001
Step -J- Synthesis of(JH-Pyrrolo[2,3-bJpyridin-3-yl)-j6-(4-trifluoromethyl-benzyIamino)-pyridin- 3-ylJ '-methanone (P-0017)
[0438] Into a pressure flask was added (6-Chloro-pyridin-3-yl)-(lH-pyrrolo[2,3-b]pyridin-3-yl)- methanone 7 (3.5 g, 0,014 mol, prepared as described in Example 3), 4- (trifluoromethyl)benzylamine (30, 9.0 g, 0.051 mol), tetrahydrofuran (30,0 mL, 0.37 mol), palladium acetate (200.0 mg, 0.890 mmol) and 2-(di-t-butylphosphino)biphenyl (200.0 mg, 0.67 mmol). The reaction mixture was stirred at 180 0C overnight, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. To the residue was added acetic acid ( 15.0 mL) and H2O (5.0 mL). The reaction mixture was stirred at 100 0C for 5 hours and concentrated to remove the acetic acid. The residue was then treated with aqueous Na2HCO3 and extracted with ethyl acetate. The organic layer was washed, dried, concentrated and purified to give compound P-0017 (1.0 g, yield = 18.5%) as a light yellow solid. MS (ESI) [M+HT = 397.
Step -2- Synthesis of(JH~Pyrrolo[2,3-k]pyridin-3-yl)-[6-(4-trifhιoromethyl-bcnzytamino)~pyridin- 3-y IJ -methanol (14) [0439] Into a round bottom flask was added (lH-Pyrrolo[2,3-b]pyridin-3-yi)-[6-(4- triiluoromcfhyl-bcnzylamino)-pyridin-3-yl]-mefhanone P-0017 (210.0 mg, 0.53 mmol) and sodium tetrahydroborate (80.0 mg, 2.1 1 mmol), dissolved in N,N-dimethylformamide (5.0 mL) and ethanol (20.0 mL). The reaction was stirred at room temperature overnight, poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with biotagc (dichloromcthane/methanol 1 :20) to gi\ e compound 14 (63 mg, yield = 30%) as a white solid. MS (ESI) [IVb-HT= 399.
Step -3- Synthesis of [5-(lH-Pyrrolo[2, 3-h]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl- henzylj-amine (P-0003)
[0440] Into a round bottom flask was added (lH-P>τrolo[2,3-b]pyridin-3-yl)-[6-(4- trifluoromethyl-benzylamino)-pyridin-3-yl]-methanol 14 (200.0 mg, 0.50 mmol), trifluoroacetic acid (5.0 mL, 0.065 mol) and triethylsilane (3.0 mL, 0.019 mol). The reaction was stirred at room temperature for 30 min, poured into aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified to give pure compound P-0003 (120.0 mg, yield = 62.8%) as a white solid. MS (ESI) [M+H'] f= 383.
Example 9. Synthesis of compounds of Formula I where n is 1, P, Q and T are CH Xi, X2 and Y2 are CH, Y1 is CR4, L1 is -CH2-, L2 is -NHCH2-, and R1 is 4 substituted phenyl (Formula Ic).
10441] Compounds of Formula Ic, where R4 is as defined for Formula I (paragraph [0011]) and Z is a substituent as defined for optionally substituted aryl, can be synthesized in five Steps from 2- amino-5-bromopyridines as shown in the following general Scheme 1 1.
Scheme 11
Figure imgf000183_0001
Step - 1 - Preparation of compounds of Formula V
[0442] To a solution of an appropriately substituted benzaldehyde (e.g. />trifluoromethyl benzaldehyde) in a non-reactive solvent (e.g. tetrahydrofuran) is added an appropriate 2-amino-5- bromo-pyridine 15, followed by appropriate reagents to effect the reduction (e.g. dibutyltin dichloride and phenylsilaπe). Typically the reaction is heated (e.g. 50 0C) overnight. The solvent is removed at reduced pressure after heating to 50 0C overnight. Isolation by conventional means (e.g. extraction) affords compounds of Formula V. Step -2- Preparation of compounds of Formula VI
|0443] Compound of Formula V is dissolved in a non-reactive solvent (e.g. tetrahydrofuran) and typically cooled at -78 0C under an inert atmosphere. To this mixture is added an organo lithium reagent (e.g. methyl lithium). The reaction mixture is typically stirred at -78 0C for several hours. To this mixture is added an organo lithium reagent (e.g. /erf-butyl lithium), and the mixture is stirred for several hours. The reaction mixture is maintained at -78 0C, and an appropriate formylating reagent (e.g. 1 -piperidine carboxaldehyde) is added. Typically, the reaction is allowed to stir at -78 0C for an additional several hours and slowly warmed to room temperature. Isolation by conventional means (e.g. extraction) affords compounds of Formula VI. Step -3- Preparation of compounds of Formula VII
[0444] Compound of Formula VI is dissolved in a non-reactive solvent (e.g. tetrahydrofuran) and stirred under an inert atmosphere. To this solution is added a base (e.g. triethylamine) and typically a catalyst (e.g. 4-dimethylaminopyridine). Typically, the mixture is stirred for a few minutes and then a reagent appropriate for the introduction of a protecting group (e.g. di-tert- butyldicarbonate) is added. Typically, the reaction is stirred overnight. Isolation by conventional means (e.g. extraction) affords compounds of Formula VII.
Step - 4 - Preparation of compounds of Formula VHI and IX
[0445] 4-Substituted l H-pyrrolo[2,3-b]pyridine XXX is added to a stirring solution of base (e.g. potassium hydroxide) in an appropriate polar protic solvent (e.g. methanol). Compound of Formula VII is added, and the mixture is typically stirred at room temperature for several days. The solvent is evaporated, and 1 M HCl is added to the residue. Isolation by conventional means (e.g. extraction, silica gel chromatography) affords compounds of Formula VIII and IX.
Step - 5 - Preparation of compounds of Formula Ic
[0446] Typically, compounds of Formula VIII and IX is combined and dissolved in an appropriate polar aprotic solvent (e.g. acetonitrile). Reagents appropriate to effect the reduction (e.g. triethylsilane and triffuoroacetic acid) are added. Typically, the reactions are stirred at room temperature for several days. Isolation by conventional means (e.g. extraction, silica gel chromatography) affords compounds of Formula Ic.
Example 10. Synthesis of [5-(4-Methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- (4-trifluoromethyl-benzyl)-amine (P-0011)
Figure imgf000184_0001
[0447] [5-(4-Methoxy-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl- benzyl)-amine P-0011 was synthesized as shown in Scheme 12:
Scheme 12
Figure imgf000185_0001
Step 1: Preparation of(5-Bromo-pyridin-2-yl)-(4-triβuaramethyl-henzyl)-amine (17) |0448] Into a round bottom flask fitted with stirrer and reflux condenser was added 2-amino-5- bromopyridine (15, 1.73 mol, 300 g) and/j-trifluoromethylbenzaldehyde (16, 1.723 mol, 300 g) to a solution of trifluoroaeetie acid (400 mL), triethylsilane (825 mL) and acetonitrile (7500 mL). The reaction was heated to reflux overnight (24 hours). Solvents were removed and the residue was poured into aqueous K2CO^ and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated. The crude compound was crystallized with diethyl ether/hexane to afford compound 17, 420 g (73.6%) as off white solid. MS (ESI) 331.1 and 333.1 (1 : 1 ratio).
Step 2: Preparation of6~(4~Trifluoromethyl-henzylamino)-pyridine-3-carbaldehyde (18) [0449] Into a 5 L round bottom flask was added compound 17 (0.6 mol, 198.6 g,) and tetrahydrofuran (2.5 L) under an atmosphere of argon at -78 0C. Into the reaction mixture was added 1.7 M tcrt-butyllithium in pcntane (SOO mL) over 60 mins. Two hours after the addition of terr-butyllithium, N,N-dimethylformamide ( 100 mL) was added. The reaction mixture was stirred at -78 11C for 2 hours, then allowed to stand at room temperature for another 1 hour. The reaction mixture was poured into saturated ammonium chloride solution and extracted with ethyl acetate. 1 he organic layer was washed with brine, dried over sodium sulfate, concentrated and triturated with hexane/isopropyl ether (1 :1 ) to give aldehyde compound 18.
Step 3: Preparation of(5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carhamιe acid tert- hutγl ester (19)
[0450] Into a 2 L round bottom flask was added di-tcrt-butyldicarbonate (90 g), aldehyde 18 (75 g), diisopropyl ethyl amine (60 g), 4-dimethylaminopyridine (2.0 g,) and dichloromethane (1000.0 mL). The reaction was stirred at room temperature overnight (18 hours) and the solvent was evaporated to give compound 19 (94 g)
Steps 4 and 5: Preparation of [5-(4-Methoxy- 1 H-pyrrolo[2,3-b] pyridin-3-ylmeihyI)-pyridin-2-yl] - (4-triβuoromethyl-benzyl)-amine (P-OOl 1)
[0451 ] Step 4: Into a solution of methanol (20 mL, 0,5 mol) was added sodium hydroxide (0.62 g, 0.016 mol), followed by 4-methoxy-7-azaindole (20, 600 mg, 4 minol, prepared as described in Example 12). Once the mixture was homogeneous, compound 19 (1.7 g, 4.46 mmol) was added and the mixture was stirred at room temperature for 48 hours. The solvent was evaporated and dilute HCl was added to the residue. The residue was extracted with ethyl acetate and washed with 10% sodium bicarbonate, followed by brine. The organic layer was dried over MgSC>4, filtered and evaporated to give a mixture of crude compounds 21 and 22, which was used in the next step. [0452] Step 5: The mixture of 21 and 22 from Step 4 (2.36 g, 4.46 mmol) was dissolved in dichloromethane (60 mL, 0.9 mol) to which triethylsilane (3.6 mL, 0.022 mol) and trifmoroacetic Acid (2.1 mL, 0.027 mol) were added. The resulting mixture was stirred for 48 hours at room temperature. The solvent was evaporated and the mixture was extracted with dichloromethane: methanol (3: 1). The organic layer was washed with saturated bicarbonate followed by brine. The organic layer was dried over MgSO4, filtered and evaporated to give crude compound as a residue. The residue was purified by flash silica gel chromatography to give 1.15 g of solid P-0011 for a 60% yield.
Figure imgf000186_0001
[0453J [5-(4-Methoxy-lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-benzyl)- amine P-0010
Figure imgf000186_0002
was prepared following the protocol of Scheme 12, substituting 4-trifluoro-benzylamine with 4- chloro-benzylamine in Step 1. MS (ESI) [M+H'f= 379.2 and 381.2 (3: 1 ratio), |0454] [5-(4-chloiO-l H-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-benzyl)- amine P-0009
Figure imgf000187_0001
was prepared following the protocol of Scheme 12, substituting 4-trifluoro-benzylamine with 4- chloro-benzylamine in Step 1 and 4-methoxy-7-azaindole with 4-chloro-7-azaindole (24, prepared as described in Example 1 1) in Step 4. MS (ESI) [M-I-H+]*- 381.1 and 383.0.
Example 11: Synthesis of 4-chloro-7-azaiπdole (24)
[0455] 4-chloro-7-azaindole 24 was synthesized in two Steps from 7-azaindole according to the protocol of Scheme 13.
Scheme 13
Figure imgf000187_0002
Step -1 - Synthesis of 1H-Pyrrolo[ 2,3 -b] pyridine 7-oxide (23)
[0456] lH-Pyrrolo[2,3-b]pyridine 7-oxide 23 was synthesized by reacting commercially available 7-azaindole 1 with an oxidizing agent (e.g. rø-CPBA) in a non-reactive solvent (e.g. dimethoxyethane) as described by Schneller, S. W.; Luo, Jiann-Kuan. J. Org. Chem. 1980, 45:4045-4048. The compound was isolated by filtration of the resulting solid that forms upon standing at 5 0C for typically 1-3 h.
Step - 2 Synthesis of 4-chloro-7-azaindole (24)
[0457] 4-chloro-7-azaindole 24 was synthesized by reacting lH-Pyrrolo[2,3-b]pyridinc 7-oxide 23 with a chlorinating agent (e.g. POCl3) neat as described by Schneller, S. W.; Luo, Jiann-Kuan. J. Org. Chem. 1980, 45:4045-4048. Ilie resulting solution after heating for 3-5 h at elevated temperatures (100-150 0C) was neutralized with a base (e.g. NH4OH) until a solid precipitated. The solid was isolated by filtration.
Example 12: Synthesis of 4-methoxy- 7-azaindole (20)
[0458] 4-methoxy-7-azaindole 20 was synthesized in one Step from 4-chloro-7-azaindole according to the protocol of Scheme 14. Scheme 14
Figure imgf000188_0001
24 20
[0459] 4-methoxy-7-a/mndole 20 was prepared by reacting 4-chloio-7-azamdole 24 (prepared as described in Example 9) with sodium hydroxide in methanol as described by Gπgis, N et al , J Heterocyclic. Chem. 1989, 26:317-325.
Example 13: Synthesis of compounds of Formula I where n is 1, P is CR1", Q, T, X1, X2, Yi and Y2 are CH, L1 is -CH2-, L2 is -NHCH2-, and R1 is substituted phenyl (Formula Id).
[0460] Compounds of Formula Id, where R10 is a substituent as defined for optionally substituted heteroarylene (further defined in Scheme 13 below) and RM is a substituent as defined for optionally substituted aryl, can be synthesized m six Steps from appropriately substituted 2- halopyridines as shown in the following general Scheme 15
Scheme 15
Figure imgf000188_0002
Step 1 - Preparation of compounds of Formula XI
[0461] To an appropriately substituted 2-halopyπdme X (e g 2-chloro-6-methoxypyridme), where Y is a halogen, preferably chlorine or bromine, and R10 is a group appropnate to direct the following lithiatinn to the 5-position (e.g. R?o = mcthoxy), in a non-reactive solvent (e.g. tetrahydrofuran) typically cooled in a -78 °C acctonc/dry ice bath is added a solution of organolithium reagent (e.g. tert-butyllithium). The reaction is allowed to stir for a period, typically 1 hour. An appropriate formylating agent (e.g. dimethylformamide) is added and the reaction is allowed to stir cooled for a period and then warmed to room temperature for a period, typically 30 minutes. The reaction can be placed back in the dry-ice bath and quenched with 6 K HCl ( 1.5 mL) followed by water and allowed to warm to room temperature. Isolation by conventional means (e.g. extraction) provides compounds of Formula XI.
Step 2 - Preparation of compounds of Formula XII
[0462] To lH-pyrrolo[2,3-b]pyridine 1 and a compound of Formula XI is added an appropriate polar solvent (e.g. methanol) followed by an appropriate base (e.g. potassium hydroxide). The reaction is typically allowed to stir at room temperature overnight. Isolation by convention means (e.g. extraction, washing and filtering) affords compounds of Formula XIl.
Step 3 - Preparation of compounds of Formula XIII
[0463] To a compound of Formula XII in an appropriate polar solvent (e.g. acetonitrile) is added a reducing agent (e.g. trifluoroacetic acid and triethylsilane). Typically, the reaction is allowed to stir at room temperature overnight. Isolation by conventional means (e.g. extraction and silica gel chromatography) affords compounds of Formula XIII.
Step 4 - Preparation of compounds of Formula XIV
[0464] To a solution of compound of Formula XIII in an appropriate polar solvent (e.g. dimethylformamide) is added a base (e.g. sodium hydride). Typically, the reaction is stirred at room temperature for 30 minutes, and then an appropriate reagent to introduce a protecting group ("P") is added (e.g. triisopropylsilyl chloride). The reaction typically is stirred at room temperature for several hours. Isolation by conventional means (e.g. extraction and silica gel chromatography) affords compounds of Formula XIV.
Step 5- Preparation of compounds of Formula XVI
[0465] To a compound of Formula XIV, an appropriately substituted benzylamine XV (e.g. 4- (trifluoromethyl)benzylamine), a base (e.g. sodium tert-butoxide), a catalyst (e.g. tris(dibenzylideneacetonc)dipalladium(O)), and ligand (e.g. 2,2'-Bis(diphenylphosphino)-l , l'- binaphthyl) are added a non-reactive solvent (e.g. toluene) under an inert atmosphere. Typically, the reaction is heated (e.g. 80 °C) for several hours. Isolation by conventional means (e.g. extraction and silica gel chromatography) affords compounds of Formula XVI. Step 6 — Preparation υf compounds of Formula Id
[0466] To compound of Formula XVI is added an appropriate polar solvent (e.g. tetrahydrofuran) followed by an appropriate reagent to remove the protecting group (e.g. tetra-n- butylammonium fluoride). Typically, the reaction is allowed to stir at room temperature for several hours. Isolation by conventional means (e.g. extraction and silica gel chromatography) affords compounds of Formula Id.
Example 14: Synthesis of compounds of Formula I where n is 1, P is CR", Q, T, X1, X2, Y] and Y2 are CH, L1 is -CH2-, L2 is -NHCH2-, and R1 is substituted phenyl (Formula Ie).
|0467) Compounds of Formula Id, where R32 is a substituent as defined for optionally substituted heteroarylene and R " is a substituent as defined for optionally substituted aryl, can be synthesized in five Steps from appropriately substituted 2-amino-5-bromopyridines as shown in the following general Scheme 16.
Scheme 16
Figure imgf000190_0001
Ie
XXII R = H XXIII R =CH3
Step - 1 - Preparation of compounds of Formula XIX
[0468] To a solution of an appropriately substituted benzaldehyde XVIII (e.g. /7-trifluoromethyl benzaldchyde) in a non-reactive solvent (e.g. tetrahydrofuran) can be added an appropriate 2- amino-5~bromo-pyridine XVII (e.g. 2-amino-5-bromo-6-methylpyridine), followed by appropriate reagents to effect the reduction (e.g. dibutyltin dichloride and phenylsilane). Typically the reaction is heated (e.g. 50 0C) overnight. Isolation by conventional means (e.g. extraction) affords compounds of Formula XIX.
Step -2- Preparation of compounds of Formula XX
[0469) Compound of Formula XIX is dissolved in a non-reactive solvent (e.g. tetrahydrofuran) and typically cooled at -78 0C under an inert atmosphere. To this mixture is added an organolithium reagent (e.g. methyllithium). The reaction mixture is typically stirred at -78 0C for several hours. To this mixture is added an organolithium reagent (e.g. tert-butyllithium) and the mixture is stirred for several hours. The reaction mixture is maintained at -78 0C, and an appropriate formylating reagent (e.g. 1-piperidine carboxaldehyde) is added. Typically, the reaction is allowed to stir at -78 0C for an additional several hours and slowly warmed to room temperature. Isolation by conventional means (e.g. extraction) affords compounds of Formula XX.
Step -3- Preparation of compounds of Formula XXI
[0470] Compound of Formula XX is dissolved in a non-reactive solvent (e.g. tetrahydrofuran) and stirred under an inert atmosphere. To this solution is added a base (e.g. triethylamine) and typically a catalyst (e.g. 4-dimethylaminopyridine). Typically, the mixture is stirred for a few minutes, and then a reagent appropriate for the introduction of a protecting group (e.g. di-tert- butyldicarbonate) is added. Typically, the reaction is stirred overnight. Isolation by conventional means (e.g. extraction) affords compounds of Formula XXI.
Step - 4 - Preparation of compounds of Formula XXII and XXIII
[0471] lH-Pyrrolo[2,3-b]pyridine 1 is added to a stirred solution of base (e.g. potassium hydroxide) in an appropriate polar solvent (e.g. methanol). Compound of Formula XXI is added, and the mixture is typically stirred at room temperature for several days. The solvent is evaporated and 1 M HCl is added to the residue. Isolation by conventional means (e.g. extraction, silica gel chromatography) affords compounds of Formula XXII and XXIII.
Step - 5 Preparation of compounds of Formula Ie
[0472] Typically, compounds of Formula XII and XIII are combined and dissolved in an appropriate polar aprotic solvent (e.g. acetonitrile). Reagents appropriate to effect the reduction (e.g. triethylsilane and trifluoroacetic acid) are added. Typically, the reaction is stirred at room temperature for several days. Isolation by conventional means (e.g. extraction, silica gel chromatography) affords compounds of Formula Ie. Example 15: Synthesis of |6-Methoxy-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]- (4-trifluoromethyl-benzyl)-amine (P-OOl 2)
[0473] [6-Methoxy-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylJ-(4-tritluoromethyl- benzyl)-amine P-0012 was synthesized in five steps from commercially available 2-chloro-6- mcthoxypyridine and 7-azaindole as shown in Scheme 17.
Scheme 17
Figure imgf000192_0001
Step 1 - Preparation of'6-chloro-2-methoxypyridine-3-carbaldehyde (26)
[0474] To 2-Chloro-6-methoxypyridine (25, 0.51 1 g, 3.56 mmol) in tetrahydrofuran (10 mL) cooled in a -78 0C acetone/dry ice bath was added tert-butyl lithium (1.7 M in pentane, 5.0 mL, 7.66 mmol). The reaction was allowed to stir for 1 hour. Dimethylformamide (0.673 mL, 17.4 mmol) was added and the reaction was allowed to continue for an additional 30 minutes at -78 αC, then stirred for 30 minutes outside of the diy-ice bath. The reaction was placed back in the dry-ice bath and quenched with 6 N HCl (1.5 mL) followed by water and allowed to warm to room temperature. The reaction was extracted with diethyl ether and aqueous (I M) sodium bicarbonate. The organic layer was separated, dried with anhydrous magnesium sulfate, filtered and volatiles removed by rotary evaporation, and the resulting yellow solid was dried under vacuum to provide 561 mg of compound 26 (3,27 mmol, 92% yield). MS(ESl) [M+H'j1 = 172.0.
Step 2 - Preparation of(6-chloro-2-methoxypyridin-3-yl)(lH-pγrrolo/2l3-b]pyridin-3-yl)methtmo! (27) [0475] To lH-Pyrrolo[2,3-b]pyridme (1, 0,455 g. 3.85 mmol) and 6-chloro-2-methoxypyridine- 3-carbaldchydc (26, 0.661 g, 3.85 mmol) was added methanol (10 mL) followed by potassium hydroxide (0.310 g, 5.52 mmol). The reaction was allowed to stir at room temperature overnight. The reaction was extracted with diethyl ether/ethyl acetate and water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and volatiles were removed by rotary evaporation to pro\ide a solid that was treated with dichloromethanc and stored in a freezer overnight. The white solid was collected by vacuum filtration and dried in vacuo to give 613 mg of compound 27 (2.12 mmol, 55%). MS(ESI) [M+EfJ = 290.1.
Step 3 - Preparation 3-(6-chloro-2-methoxypyridin-3-ylmethyl)-lH-pyrrolo[2, 3-h] pyridine (28) [0476] To (6-chloro-2-methox>φyridin-3-yl)(lH-pyrrolo[2,3-b]pyridin-3-yl)methanol (27, 0.613 g, 2.12 mmol) in acetonitrile (10 mL) was added trifluoroacetic acid (0.82 mL, 10.0 mmol) followed by triethylsilane (1.69 mL. 10.6 mmol). The reaction was allowed to stir at room temperature for 2 days, then 60 0C for 4 hours. The reaction was extracted with diethyl ether and aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The desired material was isolated from the filtrate by silica gel column chromatography eluting with 1 % methanol in dichloromefhane to give 516 mg of a white solid compound 28 (1.88 mmol. 89%). MS(HSl) [M+H ' J = 274.1.
Step 4 - Preparation 3-(6-chlow-2-methoxypyridin-3-ylmethyl)-l-(triisopropylsilvI)-IH- pyrrolo [2, 3-b] pyridine (29)
[0477] To a clear solution of 3-(6-chloro-2-methoxypyridin-3-ylmefhyl)-l H-pyrrolo[2,3- bjpyridine (28, 0.516 g, 1.88 mmol) in dimethylformamide (10 mL) was added sodium hydride (60% dispersion, 0.1 13 g, 2.82 mmol). After stirring at room temperature for 30 minutes, triisopropylsilyl chloride (600 μL, 2.83 mmol) was added. The reaction was stirred at room temperature for 2 hours, then poured into aqueous (IM) sodium bicarbonate and extracted with ethyl acetate. The organic layer was separarted, dried (magnesium sulfate), filtered and volatiles were removed by rotary evaporation to give a crude solid. The compound was purified by silica gel column chromatography eluting with 2% ethyl acetate in hexanes, This provided 732 mg of the desired compound as a white, crystalline solid (29, 1.70 mmol, 90%). MS(ESI) [M+H ]+ = 430.2.
Step J- Preparation of [6-Methoxy-5-( ' 1 -triisopropylsilanyl- 1 H-pyrrolo[2,3-b] ' pyridin-3-ylmethyl)- pyridin - 2 -yl] -(4- triflu orome thy I- benzyl) -am in e (31 )
10478) 3-(6-chloro-2-methoxypyridin-3-ylmethyl)-l -(triisopropylsilyl)- lH-pyrrolo[2, 3- bjpyridine (29, 0.104 g, 0.242 mmol), 4-(Trifluoromethyl)benzylamine (30, 0.047 g, 0.266 mmol), sodium tert-butoxide (0.0325 g, 0.338 mmol), Tris(dibenzylideneacetone)-dipalladium (0) (0.00062 g, 0.0006 mmol), and 2,21-Bis(diphenylphosphino)-l ,l '-binaphthyl (0,001 1 g, 0.0018 mmol) were added to toluene (2 mL) under nitrogen. The reaction vial was placed in an oil bath at 80 °C for 3 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried (magnesium sulfate), filtered, and volatiles were removed by rotary evaporation The residue was purified by silica gel column chromatography eluting with 2% ethyl acetate in hcxanes. This provided 34 mg of the desired compound 31 (0.060 mmol, 25%).
Figure imgf000194_0001
Step 6 — Preparation of [6-Methoxy-5-(lH-pyrrolo[2, 3-b] pyridin-3-ylmethyl)-pyridin-2-yl] -(4- trifluoromethyl-benzyl)-amine (P-OO 12)
[0479] To [6-Methoxy-5-(l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2- yl]-(4-trifluoromethyl-benzyl)-amine (31, 0.0340 g, 0.0598 mmol) was added tetrahydrofuran (5 mL) followed by tetra-n-butyl ammonium fluoride (IM solution in tetrahydrofuran, 66 μL, 0.0658 mmol). The reaction was allowed to stir at room temperature for 2 hours, then poured into 1 : 1 water: saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over magnesium sulfate, filtered and the volatiles were removed by rotary evaporation. The resulting residue was purified by silica gel column chromatography, eluting with dichloromethane followed by 1 % methanol in dichloromelhane and finally 3% methanol in dichloromethane. This provided 20 mg of the desired compound as a white solid (P-OO 12, 0.048 mmol, 81 %). MS(ESI) [M+HT = 413.2.
Example 16: Synthesis of [6-Methyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- (4-trifluoromethyl-benzyl)-amine (P-0013)
[0480] [6-Methyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-(4-trifluoromcthyl- benzyl)-amine (P-0013) was synthesized in five steps from commercially available 2-amino-5- bromo-6-methylpyridine and 7-azaindole as shown in Scheme 18.
Scheme 18
Figure imgf000195_0001
37 R = H 38 R=CH-,
Step - 1 - Preparation of (5-Bromo-6-methyl-pyridin-2-yl)-(4-trifluoromethyl~benzyl)~amine (34)
[0481] To a solution of/>-trifJuoromethylbenzaldehyde (16, 1 ,00 g, 5.74 mmol) in tetrahydrofuran (9 mL) was added 2-amiπo-5-bromo-6-metliylpyridiπe (33, 1 .08 g, 5.77 mmol), followed by dibutyltin dichloride (40 mg, 0.13 mmol). The mixture was stirred for 5 minutes at 25 0C and phenylsilane (0.69 g, 6.4 mmol) was added. The reaction was heated at 50 0C overnight, then the solvent was removed at reduced pressure. Ethyl acetate was added to the resulting solid which was washed with saturated sodium carbonate, dried over magnesium sulfate and filtered. Concentration under reduced pressure afforded a light yellow solid (34, 1.7 g, 4.93 mmol). MS(ESI) [M + H'] 1 = 345.1.
Step -2- Preparation of2-Methyl-6-(4-trifluommethyl-benzylanύno)-pyrhline-3-curbaldehyde (35)
[0482] (5-Bromo-6-methyl-pjτidin-2-yl)-(4-tπf]uoromethyl-benzyl)-amine (34, 1.7 g, 4.93 mmol) was dissolved in tetrahydrofuran (40 mL) and cooled at -78 0C under a nitrogen atmosphere. To this mixture was added methyllithium (1.6 M in diethyl ether, 5.91 mmol) dropwise over 20 minutes. After the addition of methyllithium was completed, [he reaction mixture was stirred at -78 0C for 2 hours. To this mixture was added teit-butyllithium (1.7 M in pentane, 10.85 mmol) and the mixture was stirred for 4 hours. The reaction mixture was maintained at -78 0C, and 1 -piperidinecarboxaldehyde (0.60 mL, 5.42 mmol) was added dropwise. The reaction was allowed to stir at -78 0C for an additional 2 hours and warming to 25 UC was achieved from the slow evaporation of the dry ice/ acetone cooling bath. The reaction was quenched with ice cold saturated sodium chloride and the resulting mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. Concentration under reduced pressure afforded an orange oil (35, 1.4 g, 4.93 mmol). MS(ESI) [M + H"]τ =
295.1.
Step -3- Preparation of(5-Formyl-6-methyl-pyridin-2-yl)-(4-trifluorornethyl-benzyI)-carbamic acid tert-butyl ester (36)
[0483] 2-Methyl-6~(4-trifluoromethyl-benzylamino)-pyridine-3-carbaldehyde (35, 1.4 g, 4.9 mmol) was dissolved in tetrahydrofuran (22 mL) and was stirred under an atmosphere of nitrogen. To this solution was added 4-dimethylaminopyridine (150 mg, 1.23 mmol) and triethylamine (U.66 mL, 4.9 mmol). The mixture was stirred for 5 minutes before solid di-tert-butyldicarbonate (1 .0 g, 4.9 mmol) was added directly to the reaction mixture. The mixture was stirred overnight at 25 0C and was diluted with ethyl acetate and washed with sodium bicarbonate, followed by washing with saturated sodium chloride. The resulting organic layer was dried over magnesium sulfate, filtered and evaporated to give a beige solid (36, 1.8 g, 4.6 mmol). MS(ESI) [M + Hf] ' = 395.2.
Step - 4 — Preparation of{5-[Hydroxy-(lFI-pyrrolol2,3-bJpyridin-3-yl)-methyl]-6-methyI-pyridin- 2-yl}-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (37) and {5-[Methoxy-(lH- pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6-methyl-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-carbamιc acid tert-butyl ester (38)
[0484] lH-Pyrrolo[2,3-b]pyridine (1, 540 mg, 4.57 mmol) was added to a stirring solution of potassium hydroxide (868 mg, 10.08 mmol) in methanol (33 mL). Once the mixture was homogeneous, (5-formyl-6-methyl-pyridin-2-yl)-(4-trifIuoromethyl-benzyl)-carbamic acid tert- butyl ester (36, 1.8 g, 4.6 mmol) was added and the mixture was stirred at 25 0C for 72 hours. The solvent was evaporated and 1 M HCl was added to the residue. The organic material was extracted with ethyl acetate and washed with 10% sodium bicarbonate, followed by washing with saturated sodium chloride. The organic layer was dried over magnesium sulfate. Concentration under reduced pressure afforded the erode material, which was purified by silica gel column chromatography (0 - 5% methanol in dichloromethane) to yield the desired compounds as a light yellow solid (37 and 38 as a mixture, 294 mg; 13% yield). MS(ESl) [M - H T = 51 1 ,2 for 37 and MS(ESI) [M + H'] 1 = 525.2 for 38.
Step - 5 Preparation of[6-Methyl-5-(lH-pyrrolo[2,3-b]bipyridin-3-y1methyl)-pyridin-2-yl]-(4- triflιιoromethyl-benzyl)-amine (P-0013)
[0485] The combined materials of {5-[Hydroxy-(lH-pyrrolo[2,3-b]pyridin-3-yl)-rnethyl]-6- methyl-pyridin-2-yl} -(4-tπrluoromethyl-benzyl)-carbamic acid tert-butyl ester (37) and {5- [Methoxy-( l H-pyriOlo[2,3-b]pyτidin-3-yl)-methyl]-6-methyl-pyτidin-2-yl} -(4-trifluoromethyl- benzyl)-carbamic acid tcrt-butyl ester (38) (194 mg, 0,378 mmol) were dissolved in acetonitrile (3 mL) and triethylsilane (0.30 mL, 1.9 mmol) and trifluoroacetic acid (0.17 mL, 2.3 mmol) were added. After stirring at 25 0C for overnight, TLC analysis indicated that the reaction was about 50% complete. To the reaction mixture was added triethylsilane (0.30 mL, 1.9 mmol), and trifluoroacetic acid (0.17 mL, 2.3 mmol). The mixture was allowed to stir for another 48 hours at 25 0C and the solvent, excess triethylsilane and trifluoroacetic acid were removed by evaporation. Ethyl acetate was added and washed with saturated sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated at reduced pressure to afford a brown oil. Purification of 80 mg of the crude material was carried out using preparatory chromatography (50% ethyl acetate in hexanes) to afford the compound as an off-white solid (P-0013, 10 mg, 0.025 mmol). MS(ESI) [M + H+]τ = 397.2.
[0486] (4-Chloro-benzyl)-[6-methyl-5-(l H-ρyrrolo[2,3-b]pyridin-3-ylmethyl)-ρyτidin-2-yl]- amine P-0014
Figure imgf000197_0001
was prepared following the protocol of Scheme 18, substituting 4-trifluoromethyl benzaldehyde with 4-chlorobenzaldchyde (40) in Step 1. MS(ESI) [M + H+J+ = 363.1.
Example 17: Synthesis of [5-(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- (4-chloro-benzyl)-amine (P-0038)
[0487] [5-(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro-benzyl)- amme P-0038 was synthesized in 5 steps from commercially available 2-Amino-5-bromopyridine 15 as shown in Scheme 19. Scheme 19
Figure imgf000198_0001
Step 1- Synthesis of(5-Bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine (41)
[0488] To 2-Amino-5-bromopyridine (15, 6.1O g, 0,0352 mol) in toluene (90.0 mL) were added 4-chlorobenzaldehyde (40, 5.00 g, 0.0356 mol), trifluoroacetic acid (8.0 mL, 0.10 mol) and triethylsilane (16.5 mL, 0.103 mol). The reaction was heated to reflux for 48 hours. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated. The crude residue was crystallized with ethyl acetate to give compound (41, 6.8 g, 65.4%).
Step 2 - Synthesis oj 6-(4-Chloro-benzylamino)-pyridine-3-carbaldehyde (42)
[04891 To (5-Bromo-pyridin-2-yl)-(4-chloro-benzyl)-amine (41, 10.00 g, 0.03360 mol) in tetrahydrofuran (400.0 mL) under an atmosphere of nitrogen at -78 0C was added n-butyllithium (17.5 mL, 2.00 M in cyclohexane). After 90 minutes, tert-butyllithium (42.00 mL, 1.70 M in hexane) was added to the reaction. After 80 minutes, N,N-dimethylformamide (6.9 mL, 0.089 mol) was added to the reaction. The reaction mixture was stirred at -78 0C for 2 hours, then allowed to warm to room temperature for 1 hour. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give the crude compound, which was crystallized from ferf-butoxyl methyl ether to provide compound (42, 7.66 g, 92.2%).
Step 3 - Synthesis of(4-Chloro-benzyl)-(5-forinyl-pyridin-2-yl)-carbarnic acid tert-butyl ester (43)
[04901 To 6-(4-Chloro-benzylamino)-pyridine-3-carbaldehyde (42, 2.00 g, 8.1 1 mmol) in dichloromethane (20.0 mL) were added triethylamine (1.70 mL, 12.2 mmol), di-tert- butyldicarbonate (2.00 g, 9.16 mmol) and 4-dimethylaminopyridine (52.3 mg, 0.43 mmol). The reaction was stirred at room temperature for 48 hours. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give compound (43. 2.50 g, 89.3%).
Step 4 - Synthesis of{5-[(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3-yI)-hydroxy-methyl]-pyndιn-2-yl}- (4-chloro-henzyl)-carbamic acid tert-hutyl ester (45)
[0491] To 5-bromo-7-azaindole (44, 198.0 mg, 1.01 mmol) in methanol (30.0 mL. 0.741 mol) were added (4-Chloro-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (43, 355.0 mg, 1.02 mmol) and potassium hydroxide (80.0 mg, 1.42 mmol). The reaction was stirred at room temperature 48 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 8% methanol in dichloromethane to give compound (45, 200.0 mg, 36.8%).
Step 5 ~ Synthesis of [5-(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro- benzylyamine (P-0038)
[0492] To {5-[(5-Bromo-lH-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl}-(4- chloro-ben7yl)-carbamic acid tert-butyl ester (45, 1 80.0 mg, 0.33 mmol) in acetonitrile (30.0 mL) were added trifluoroacetic acid (2.0 mL, 0.026 mol) and tricthylsilanc (4.0 mL, 0.025 mol). The reaction was heated to reflux for 4 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound (P-0038, 120 mg, 85.2%). MS(bSI)[M+Hf] ' = 427.2, 429.2.
[0493] Additional compounds were prepared following the protocol of Scheme 19, optionally replacing 4-chlorobenzaldehyde 40 with an appropriate aldehyde in Step 1 and optionally replacing 5-bromo-7-azaindole 44 with an appropriate azaindole in Step 4. The following compounds were made following this procedure:
[5-(5-Chloro-l H-pynOlo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3- ylmethyl)-amine (P-0181),
[5-(lII-Pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)- amine (P-0182),
3-[6-(4-Chloro-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile (P-0257),
3-[6-(4-Triiluoromcthyl-bcnzylamino)-pyridin-3-ylmcthyl]-l H-pyrrolo[2,3-b]pyridine-5- carbonitrile (P-0269), [5-(5-ChIoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-fluoro-benzyl)-amine
(P-0270),
3-[6-(2-Fluoro-bcnzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbi)nitrile
(P-0271),
(2-Fluoro-benzyl)-[5-(5-mcthyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0272),
3- {6-[(6-Trifluoromethyl-pyridin-3-ylmethyl)-aminoJ-pyridin-3-ylmethyl}- 1 II-pyrrolo[2,3- b]pyridine-5-carbonitrile (P-0273),
3-[6-(2-Trifluoromethy]-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5- carbonitrile (P-0274),
[5-(5-Ch]oro-lH-pyiτolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromcthyl-benzyl)- amine (P-0275),
[5-(5-Mcthyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trinuoromethyl-benzyl)- amine (P-0276),
3-[6-(2,6-Difluoro-bcnzylamino)-pyridin-3-ylmethyl]-l H-p>τrolo[2,3-b]pyridine-5-carbonitrilc
(P-0277),
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2,6-difluoro-benzyl)-amine
(P-0278),
(2-Chloro-benzyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-y]methyl)-pyridin-2-yl]-amine
(P-0279),
(2-Ch]oro-benzyl)-[5-(5-chloro-lH-p>τrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0280),
3-[6-(2-Chloro-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile
(P-0281),
(6-Methoxy-pyridin-3-ylmethyl)-[5-(5-mcthyl-lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyτidin-2- yl]-amine (P-0282),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3- ylmcthy])-amine (P-0283),
3-{6-[(6-Methoxy-pyridin-3-ylmcthyl)-amino]-pyridin-3-ylmethyl}-lH-pyrrolo[2,3-b]pyridine-5- carbonitrile (P-0284),
(2-Methoxy-pyridin-3-ylmethyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-}'lmethyl)-pyridin-2- ylj-amine (P-0285),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-methoxy-pyridin-3- ylmethyl)-amine (P-0286),
3- {6-[(2-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-l H-p>τrolo[2,3-b]pyridine-5- carbonitrile (P-0287), (2-Ethoxy-bcnzyl)-[5-(lH-pyττolo[2,3-b]pyridin-3-ylmethyl)-pyπdin-2-yl]-amine (P-0288),
(2,5-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amiπe (P-0296),
(2,5-Difluoro-benzyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]p\τidin-3-ylmcthyl)-pyridiπ-2-yl]-amine
(P-0297),
[5-(5-C'hloro-lH-pyrrolo[2,3-bJpyridin-3-ylmcthyl)-p>τidin-2-yl]-(2,5-difluoro-benzyl)-amine
(P-0298),
3-[6-(2,5-Difluoro-benzylamino)-pyridin-3-ylmethyl]- lH-pyrτolo[2,3-b]pyridme-5-carbonitrile
(P-0299),
3-[6-(2-Trifluoromethoxy-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridinc-5- carbonitrile (P-0321),
[5-(lH-Pyrrolϋ[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethoxy-benzyl)-amine
(P-0322),
3-[6-(2-Ethoxy-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile
(P-0323),
[5-(5-Fluoro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluorϋmethyl-bt;nzyl)- amine (P-0325),
[5-(5-Methoxy-lH-ρyrrolo[2,3-b]pyridiπ-3-ylmethy])-pyridin-2-yl]-(2-trifluoromethyl-beπzyl)- amine (P-0326),
(2-Chloro-benzyl)-[5-(5-fIuoro-l H-pyrrolo[2,3-b]pyridin-3-ylniethyl)-pyridin-2-yl]-amine
(P-0327),
(2-Chloro-benzyl)-[5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0328),
(2,5-Difluoro-benzyl)-[5-(5-fluoro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0329),
(2,5-Difluoro-benzyl)-[5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0330),
[5-(5-Fluoro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)- amine (P-0331),
(6-Methoxy-p>τidin-3-ylmethyl)-[5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethy])-pyridin-2- yl]-amine (P-0332),
(2,6-Difluoro-benzyl)-[5-(5-fluoro-lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0333),
(2,6-Difluoro-benzyl)-[5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0334),
(2-Mcthoxy-bcnzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethy])-pyridin-2-yl]-amine (P-0336).
3 - [6-(2-Methoxy-benzylamino)-pyridin-3-ylmethyl] - 1 H-pyrrolo [2,3 -b]pyridine-5 -carbonitπle (P-0337),
(2.6-Difluoro-benzyl)-[5-(l H-pyrrolo[2,3-b]ρyridin-3-ylmethyl)-pyridm-2-yl]-amine (P-0340), and
(2,6-Difluoro-benzyl)-[5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0341 ).
The following tabic indicates the aldehyde used in Step 1 in Column 3 and the azaindole used in
Step 4 in Column 2 to provide the compound of Column 4. Column 1 provides the compound number and Column 5 the measured mass spectrometry result.
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
203
Figure imgf000205_0001
[0494] Additional compounds were prepared following the protocol of Scheme 19, Steps 4 and 5, replacing (4-Ohloro-benzyl)-(5-formyl-p\τidin-2-yl)-carbamic acid tert-butyl ester 43 with an appropriate protected aldehyde and 5-bromo-7-azaindole 44 with an appropriate azaindole in Step 4. Aldehydes were prepared as described in Example 60. The following compounds were made following this procedure:
3- {2-Chloro-6-[(6-trifluoromethyl-pyτidin-3-ylmethyl)-amino]-pyridm-3-ylmethyl}-lH- pyrrolo[2,3-b]pyridine-5-carbomtπle (P-0232),
[6-Chloro-5-(5-rnethyl-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl- pyτidin-3-ylmethyl)-amine (P-0233),
[6-Chloro-5-(5-methyl-l II-pyrrolo[2,3-b]pyridiπ-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl- pyridin-3-ylmethyl)-amine (P-0234),
(3-Chloro-pyridin-4-ylmethyl)-[5-(5-chloro-lH-pyrrolof2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0235),
3-{6-[(3-Chloro-pyπdin-4-ylmethyl)-amino]-pyridin-3-ylmethyl} -l H-pyrrolo[2,3-b]pyridine-5- carbonitrile (P-0256),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-difluoromethoxy-benzyl)- amine (P-0338).
3-[6-(2-Difluoromcthoxy-bcnzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyi idine-5- carbonitrile (P-0339),
The following table indicates the aldehyde used in Column 2 and the azaindole used in Column 3 to provide the compound of Column 4. Column 1 provides the compound number and Column 5 the measured mass spectrometry result.
Figure imgf000206_0001
Figure imgf000207_0001
Example 18: Synthesis of l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde 47.
[0495] Compound 47 was synthesized in 2 steps from 7-azaindole 1 as described in Scheme 20.
Scheme 20
Figure imgf000207_0002
Step 1 - Preparation of lH-pyrroh[2,3-h]pyridine-3-carhaldehyde (46): [0496] To lH-Pyrrolo[2,3-b]pyridme (1, 16.0 g, 135 mmol) in water (1 10 mL), were added hexamethylenetetramine (26.0 g, 185 mmol), and acetic acid (55.0 mL, 967 mmol). The reaction was refluxed for 12 hours. Water (329 mL) was added and the reaction was cooled to room temperature. The reaction was filtrated and washed with water to give compound (46, 15.0 g, 76%). MS(ESI)[M+HT = 147.
Step 2 - Preparation of l-triisopropy!silanyl-lH-pyrrolo[2,3-b]pyridine-3-carhaldehyde (47): |0497] To lH-Pyrrolo[2,3-b]pyridine-3-carbaldehyde (46. 4.05 g, 27.71 mmol) in tetrahydrofuran (30.0 mL) were added sodium hydride (60% in mineral oil, 1.5 g, 38 mmol) and triisopropylsilyl chloride (8.0 mL, 38 mmol) under an atmosphere of nitrogen. The reaction was stirred for 2 hours at room temperature. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography cluting with 10 % ethyl acetate in hexane to give compound (47, 3.0 g, 36%). MS(ESI)[M+H*]' = 303, [0498] Htert-Butyl-dimethyl-silanyl)-3-iodo4Hφym>lo[2,3-b]p>τidinc 66
Figure imgf000208_0001
was prepared following the protocol of Scheme 20 Step 2, substituting lH-Pyrrolo[2,3-b]pyridine- 3-carbaldehyde 46 with 3-iodo-lH-pyrrolo[2,3-b]pyridine and triisopropylsilyl chloride with tert- Butyl-dimcthyl-silyl chloride.
[0499] l-Benzenesulfonyl-lH-pyrroloβ.S-bJpyridine-S-carbaldchydc 55
Figure imgf000208_0002
was prepared following the protocol of Scheme 20, substituting triisopropylsilyl chloride with bcnzcncsulfonyl chloride in Step 2.
Example 19: Synthesis of N-[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-4- trifluoromethyl-benzenesulfonamide (P-0071)
[0500] N-[5-(lH-Pyτrolo[2,3-b]pyridin-3-ylmethyl)-p\τidin-2-yl]-4-trifluoromethyl- bcnzcncsulfonamide P-0071 was synthesized in 3 steps from 2-Amino-5-bromopyridine 15 as shown in Scheme 21 ,
Scheme 21
Figure imgf000208_0003
Step 1 - Synthesis ofN-(5-Bromo-pyridin-2-yl)-4-lriβuυrυmethyl-benzenasιdfυnamide (49):
[0501] To 2-Λmino-5-bromopyridinc (15, 1.50 g, 8,67 mmol) in acctonitrilc (20,0 niL) were added pyridine (6.0 mL, 0.074 mol), 4-dimethylaminopyridine (0.10 g, 0.82 mmol) and 4- trifluoromethyl-benzenesulfonyl chloride (48, 2.14 g, 8.75 mmol). The reaction mixture was stirred at room temperature overnight. The reaction was concentrated, poured into water, acidified with 1 N HCl to pli = 2, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was washed with ethyl acetate to give a white solid as desired compound (49, 2.80 g, 84 8%). MS (ESI) [M+H*]' - 381.0. 383.0.
Step 2 - Synthesis ofN-5-[Hydroxy-(l-triisopropyIsiIanyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]- pyridin-2-yl-4-triβuoromethyl-benzenesιdfonamide (50):
[0502] To N-(5-Bromo-pyridin-2-yl)-4-trifluoromethyl-benzenesulfonamide (49, 0.96 g, 2.5 mmol) in tetrahydrofuran (50.0 mL) under an atmosphere of nitrogen at -78 0C, tert-butyllithium (4.62 mL, 1.70 M in hexane) was added slowly. After 15 minutes, 1 -triisopropylsilanyl-l H- pyrrolo[2,3-b]pyridine-3-carbaldehyde (47, 0.30 g, 0.99 mmol, prepared as described in Example 18) in tetrahydrofuran (15.0 mL) was added to the reaction. After 30 minutes, the reaction was allowed to come to room temperature for 10 minutes. The reaction was poured into water, acidified with IN HCl to pH around 2, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid compound (50, 0.55 g, 90.1%). MS (ESI) [M+HT = 605.3.
Step 3 - Synthesis of N-[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-4-trifluoromethyl- benzenesulfonamide (P-0071):
[0503] To N-5-[Hydro xy-(l -triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridin- 2-yl-4-trifluoromcthyl-bcnzcncsulfonamide (50, 0.27 g, 0.45 mmol) in acetonitrile (15.0 mL) were added trifluoroacetic acid (1 .0 mL, 0.013 mol) and triethylsilane (2.0 mL, 0,012 mol). The reaction was heated to 85 0C for 1 hour. The reaction was concentrated, poured into water and extracted with ethyl acetate. The organic layer was purified with silica gel column chromatography eluting with 50% ethyl acetate in hexane to give a white solid compound (P-0071, 28.5 mg, 14.7%). MS (ESI) [M+H+]+ = 433.2. [0504] 4-Chloro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-benzamide P-0074
Figure imgf000210_0001
was prepared following the protocol of Scheme 21 , substituting 4-trifluoromethyl-benzenesulfonyl chloride 48 with 4-chloro-benzoyl chloride in step 1 , MS (ESI) [M+IT] ' = 363.2.
Example 20: Synthesis of N-[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]-4- trifluoromethyl-benzamide (P-0072)
[0505] N-[5-(lH-Pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyridin-2-yl]-4-trifluoromcthyl-bcnzamidc P-0072 was synthesized in one step from (3-(6-Bromo-pyridin-3-ylmethyl)-l -triisopropylsilanyl- l H-pyrrolo[2,3-b]pyridine 6a as shown in Scheme 22.
Scheme 22
Figure imgf000210_0002
Step 1 — Synthesis ofN-[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-4-1riβuυrυmethyl- benzamide (P-0072):
[0506] To 3-(6-Bromo-pyridin-3-ylmethyl)-lH-pyrrolo[2,3-b]pyτidine (6a, 50.0 mg, 0.000174 mol, prepared as described in Example 2) in 1 ,4-dioxane (4.0 mL) were added 4-tπfluoromcthyl- benzamide (51, 70.0 mg, 0.37 minol), Xanthphos (15.0 mg, 0.026 mmol), cesium carbonate (130.0 mg, 0.40 mmol) and Tris(dibenzylideneacGtonc)-dipalladium(0) (25,0 mg, 0.024 mmol) under an atmosphere of nitrogen. The reaction was heated to 120 0C for 10 minutes in a CEM Discover microwave instrument. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 50% ethyl acetate in hexane to give a white solid (P-0072, 4.7 mg, 6.8%). MS (ESI) [M+ H+]^ = 397.2, [0507] 4-Fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide P-0073
Figure imgf000211_0001
was prepared following the protocol of Scheme 22. substituting 4-trifluoromethyl-benzamide with 4-fluoromethyl-benzamide, MS (HSI) [M+H '] ' = 347.2.
Example 21 : Synthesis of (4-Chloro-phenyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-ylmethyl]-amine (P-0078)
[0508] (4-Chloro-phenyl)-[5-(lH-pyrrolo[2,3-b]pjτidin-3-ylmethyl)-pyridin-2-ylmethyl]-amine P-0078 was synthesized in 3 steps from 5-Bromo-pyridine-2-carbaldehyde 52 as shown in Scheme 23.
Scheme 23
Figure imgf000211_0002
Step I - Synthesis of(5-Bromo-pyndin-2-ylmcthyl)-(4-chloro-phenyl)-amine (54):
[0509] To 5-Bromo-pyridine-2-carbaldehyde (52, 1.00 g, 5.38 mmol) in acetonitrile (50.0 mL) were added p-chloroaniline (53, 0.686 g, 5.38 mmol), triethλlsilane (6.00 mL, 0.0376 mol) and trifluoroacetic acid (3.00 mL, 0.0389 mol). The reaction was heated to reflux for 3 hours. The reaction was concentrated, poured into water and then extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (54, 0.75 g, 47.0%). Step 2- Synthesis of (1 -Benzenesulfonyl- 1 H-pyrrolo[2,3-b] pyridin-3-yl)-6- [{4-chloro- phenvl amino) -methyl] -pyridin-3-γl-methanol (56):
[05101 To (5-Bromo-pyridin-2-ylmethyl)-(4-chloro-phenyl)-arnine (54, 0.380 g, 1 ,28 mmol) in tetrahydrofuran (15,0 mL) under an atmosphere of nitrogen at -78 0C was added n-butyllithium (0.850 mL. 1.60 M in hexane). After 10 minutes, l ,2-bis-(chloro-dimethyl-silanyl)-ethanc (0.135 g, 0.627 mmol) in tetrahydrofuran (5.0 mL) was added to the reaction. The reaction was allowed to warm to room temperature for 40 minutes. The reaction was cooled to -78 °C, followed by addition of 1.70 M tert-butyllithium in hexane (1.58 mL). After 30 minutes, 1-benzenesulfonyl- l H-pyτrolo[2,3-b]pyridine-3-carbaldehyde (55, 0.380 g, 1.33 mmol, prepared as described in Example 18) in tetrahydrofuran (10.0 mL) was added to the reaction. After 20 minutes, the reaction was allowed to warm to room temperature. The reaction was poured into waler and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 50% ethyl acetate in hexane to give compound (56, 0.30 g, 46.0%). MS (ESI) [M+Hf]' = 505.3.
Step 3- (4-Chloro-phenyl)-5-[methoxy-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methylJ-pyridin-2- ylmethyl-amine (57):
[0511 ) To ( 1 -Benzcncsulfonyl- 1 II-pyrrolo[2,3-b]pyridiπ-3-yl)-6-[(4-chloro-phenylamino)- methyl]-pyridin-3-yl-methanol (56, 120.0 mg, 0.24 mmol) in methanol (20.0 mL) were added potassium hydroxide (0.400 g, 7.13 mmol) and water (5.0 mL, 0.28 mol). The reaction was heated to 50 0C for 10 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give compound (57, 30 mg, 33.0%). MS (ESI) [M+H*]"1 = 379.4.
Step 4- Synthesis of(4-Chhrυ-phenyl)-[5-(lH-pyrrolo[2, 3-b]pyridin-3-vlmethyl)-pyridin-2- ylmethyl] -amine (P-0078):
[0512[ To (4-Chloro-phenyl)-5-[methoxy-(lH-pyrroIoL2,3-b]pyridin-3-yl)-methyl]-pyridin-2- ylmethyl-amine (57, 20.8 mg, 0.055 mmol) in acetonitrile (10.0 mL) were added trifluoroacetic acid (0.50 mL, 6.5 mmol) and triethylsilane (1.00 mL, 6.26 mmol). The reaction was heated to reflux for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% methanol in dichloromethane to give compound (P-0078, 6.1 mg, 32.0%). MS (ESI) [M+H+]+ = 349.4. Example 22: Synthesis of (4-Chloro-bcnzyl)-[6-fluoro-5-(IH-pyrrolo[2,3-bIpyridin-3- ylmethyl)-pyridin-2-yl]-amine (P-0082)
[0513J (4-Chloro-benzyl)-[6-fluoro-5-( l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine P-0082 was synthesized in 8 steps from 2,6-Difluoropyridine 58 as shown in Scheme 24
Scheme 24
Figure imgf000213_0001
Step 1 - Synthesis of 2,6-Difluoro-nicotinic acid (59):
[0514] To 2,6-difluoropyridine (58, 7.10 g, 0.0617 mol) in tetrahydrofuran (150,0 mL) under an atmosphere of nitrogen at -78 3C, n-butyllithium (26.0 mL, 2.50 M in hexane) was addded slowly. After 30 minutes, dry ice (3.0 g) was added to the reaction. After 1 hour, the reaction was allowed to warm to room temperature, then poured into water and extracted with ethyl acetate. The aqueous layer was acidified with 1 N HCl to pH - 4-5 and extracted with ethyl acetate. The organic layer was dried over anyhydrous sodium sulfate, filtered and concentrated to give the crude compound as a light yellow solid (59, 5.6 g, 57.0%).
Step 2 - Synthesis of 2, 6-Diβuoro-nicotinic acid methyl ester (60): [OSl 5] To 2,6-difluoro-nicolinic acid (59. 5.60 g, 0,0352 mol) in methanol (60.0 mL) was added concentrated sulfuric acid (1.0 mL, 0.019 mol). The reaction was heated to reflux overnight, then poured into water, basified with IM potassium carbonate to pH around 9, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a yellow oil (60, 3.5 g, 57.0%).
Step 3 Synthesis of6-(4-Chloro-benzylamino)-2-fluorn-nicotinic acid methyl ester (62):
[0516] To 2,6-difluorύ-nicotinic acid methyl ester (60, 2.00 g, 0.01 16 mol) in N1N- dimethylformamide (20.0 mL). under an atmosphere of nitrogen at -40 0C, was added p- chlorobenzylamine (61, 2.60 mL, 0.0214 mol). The reaction was stirred at -40 0C to -20 °C for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluling with 25% ethyl acetate in hexane to give compound (62, 2.0 g, 58.7%).
Step 4 - Synthesis of [6~(4-Chloro-henzylamino)-2-βuoro-pyridin-3-yl] -methanol (63):
[0517] To 6-(4-Chloro-benzylamino)-2-fluoro-nicotinic acid methyl ester (62, 2.00 g, 6.79 mmol) in tetrahydrofuran (100.0 mL) was added lithium tetrahydroalummate (13.6 mL, 1.00 M in Tetrahydrofuran) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. To the reaction was added an excessive amount of NaSCVl 01 LO, and then stirred for 1 hour. Filtration, concentration and purification with silica gel column chromatography elutmg with 30% ethyl acetate in hexane provided compound 63 (1.0 g, 55.0%).
Step 5 Synthesis of6-(4-Chloro-ben∑ylamino)-2-βuoro-pyridine-3-carbaldehyde (64):
[0518] To [6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-yI]-mcthanol (63, 1.0 g, 3.7 mmol) in tetrahydrofuran (50,0 mL) was added Dess-Martin periodinane (1 .75 g, 4.12 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (64, 0.67 g, 68.0%).
Step 6 Synthesis of(4-Chloro-benzyl)-(6-fluoro-5-formyl-pyridm-2-yl)-carbamic acid tert-butyl ester (65):
[0519] To 6-(4-Chloro-benzylamino)-2-fluoro-pyridine-3-carbaldehyde (64, 670.0 mg. 2.53 mmol) in dichloromcthane (16.2 mL) were added di-tert-butyldicarbonate (1.23 g, 5.65 mmol) and 4-dimcthylaminopyridine (16 2 mg, 0 133 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a white solid (65, 0.63 g, 68 0%).
Step 7 --- Synthesis of '(5-[ 1 '-(tert-Butyl-dimethyl-silanyl)- lH-pyrroh[2 ',3-bj 'pyridin-3-ylj ' -hydroxy - methyl- 6-jluoro-pyridiyι-2-yl )-(4-chlυro-benzyl)-carbamic acid teri-butyl ester (67):
10520) To l -(tert-butyl-dimethyl-silanyl)-3-iodo-lH-pyπOlo[2,3-b]pyridine (66, 0.53 g, 0.0015 mol) and tetrahydrofuran (15.0 mL), under an atmosphere of nitrogen at -20 0C, was added isopropylmagnesium chloride (0.78 mL, 2.0 M in tetrahydrofuran). The reaction was allowed to warm to 0 0C (around 80 minutes), then cooled to -20 0C, followed by addition of (4-Chloro- benzyl)-(6-fluoro-5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (65, 0.200 g, 0.55 mmol) in tetrahydrofuran (6.0 mL). The reaction was allowed to warm to room temperature in 1 hour, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hcxanc to give a yellow solid (67, 0.20 g. 61.1%). MS (ESI) [M+H~] ' = 597.4.
Step 8 - Synthesis of(4-Chlυrυ-benzyl)-[6-flιιoro-5-(lH-pyrrolo[2,3-b]pyridιn-3-ylmethvl)- pyridin-2-yl) '-amine (P-0082):
|0521] To (5-[l-(tert-Butyl-dimethyl-silanyl)-lH-pyrrolo[2,3-b]pyridin-3-yl]-hydroxy-methyl-6- fIuoro-pyridin-2-yl )-(4-chloro-benzyl)-carbamic acid tert-butyl ester (67, 0.10 g. 0.17 mmol) in acctonitrile (10.0 mL) were added triethylsilane (1.00 mL, 6.26 mmol) and trifluoroacetic acid (0.50 mL, 6.5mmol). The reaction was heated to reflux for 2 hours, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a white solid (P-0082, 43.2 mg, 70.0%). MS (ESI) [M+IT]+ = 367.4.
Example 23: Synthesis of (4-Chloro-benzyl)-[6-methoxy-5-(lH-pyrrolo[2,3-b]pyridin-3- ylm eth yl) -pyridin-2 -yl] -amine (P-0081 ) .
[0522] (4-Chloro-benzyl)-[6-methoxy-5-(lH-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyridin-2-y[]- amine P-0081 was synthesized in 2 steps from (4-Chloro-benzyl)-(6-fluoro-5-formyl-pyridin-2- yl)-carbamic acid tert-butyl ester 65 as shown in Scheme 25.
Figure imgf000216_0001
Step 1 - Synthesis of(4-Chloro-benzyl)-5-[hydroxy-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6- methoxy-pyridin-2-yl-carbamic acid tert-butyl ester (68):
[0523] To lH-Pyrrolo[2,3-b]pyridine (1, 90.0 mg, 0.76 mmol) in methanol (30.0 mL) were added (4-chlorn-benzyl)-(6-fluoro-5-formyl-pyτidm-2-yl)-carbamic acid tert-butyl ester (65, 300.0 mg, 0.82 mmol) and potassium hydroxide (720.0 mg, 12.83 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound (68, 60 mg, 15.9%). MS (ESI) [M+H']f = 495.3.
Step 2 - Synthesis of(4-Chloro-benzyl)-[6-methoxy-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl] -amine (P-0081).
[0524] To (4-Chloro-benzyl)-5-[hydroxy-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-6-methoxy- pyridin-2-yl-carbamic acid tert-butyl ester (68, 40.0 mg, 0.081 mmol) in acetonitπle (10.0 mL) were added trifluoroacetic acid (0.30 mL, 0.0039 mol) and triethylsilane (0.60 mL, 0.0038 mol). The reaction was heated to reflux for 3 hours. The reaction was concentrated to remove the solvents, then purified with silica gel column chromatography eluting with 40% ethyl acetate in hexane to give compound (P-0081, 10 mg, 32.7%). MS (ESI) [M+HT = 379.4.
Example 24: Synthesis of 5-(lH-Pyrrolo|2,3-b]pyridin-3-ylmethyl)-pyridine-2-carboxylic acid (4-chloro-phenyl)-amide (P-0076)
[0525] 5-(lH-Pyiτolo[2,3-b]pwidm-3-ylmethyl)-ρyridine-2-carboxylic acid (4-chloro-phenyl)- amide P-0076 was synthesized in 3 Steps from 5-Bromo-pyridine-2-carbonyl chloride 69 as shown in Scheme 26. Scheme 26
Figure imgf000217_0001
Step 1 Synthesis of5-Bromo-pyridine-2-carboxy!ic acid (4-chloro-pheny!)-amide (70):
[0526] To 5-Bromo-pyridine-2-carbonyl chloride (69, 0.76 g, 3.4 mmol) in acetonitrile (29.0 mL) were added p-chloroaniline (53, 0.702 g, 5.50 mmol), 4-dimethylamino-pyridine (0.12 g, 0.96 mmol) and pyridine (2.9 mL, 0.036 mol). The reaction was stirred at 68 0C overnight, then poured into water, acidified with 1 N HCl to pH around 1 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered, The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane to give a white solid (70, 0.75 g, 70.0%).
Step 2 - Synthesis of5-[Hydroxy-(l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyndιn-3-yl)-methγl]- pyridine-2-carboxylic acid (4-chloro-phenyl)-amide (71):
[0527] To 5-Bromo-pyridine-2-carboxylic acid (4-chloro-phenyl)-amide (70, 0.50 g, 1.60 mmol) in tetrahydrofuran (20.0 mL). under an atmosphere of nitrogen at -78 0C, tert-butyllithium (3.02 mL, 1.70 M in Hexane) was added. After 20 minutes, l-triisopropylsilanyl-l H-pyrrolo[2,3- b]pyridine-3-carbaldehyde (47, 0.39 g, 1.3 mmol, prepared as described in Example 18) in tetrahydrofuran ( 10.0 mL) was added to the reaction. The reaction was stirred at -78 0C for 1 hour, then allowed to warm to room temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as colorless oil (71, 100 mg. 14%). MS (ESI) [M+HT - 535.3.
Step 3 ~- Synthesis of5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyndine-2-carboxylic acid (4- chlυro-phenylj-amide (P-0076): [0528] To 5-[Hydroxy-(l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridine-2- carboxylic acid (4-chloro-phenyl)-amide (71, 100.0 mg, 0, 19 mmol) in acetonitrile (10.0 mL) were added trifluoroacetic acid (0.20 mL, 2.6 mmol) and triethylsilane (0.40 ml,, 2.5 mmol). The reaction was stirred at 80 0C for 2 hours. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a yellow solid compound (P-0076, 5.5 mg, 8.1 %). MS (HSi) [M-H J- = 361.1.
Example 25: Synthesis of I6-(3-Hydroxy-phenylamino)-pyridin-3-yl]-(lH-pyrroIo[2,3- b]pyridin-3-yl)-πiethanone (P-0027)
[0529] [6-(3-IIydroxy-phenylamino)-pyridin-3-yl]-(l H-pyrrolof2,3-b]pyridin-3-yl)-mcthanone P-0027 was synthesized in 1 Step from [6-(3-Benzyloxy-phenylamino)-pyridin-3-yl]-(lH- pyrrolo[2,3-bJpyridin-3-yl)-methanone P-0026 as shown in Scheme 27.
Figure imgf000218_0001
[0530] To [6-(3-Benz>loxy-phenylaminυ)-pyridin-3-yl]-(lH-pyrrolo[2,3-b]pyridin-3-yl)- methanone (P-0026, 12.0 mg, 0.0285 mmol) in methanol (5.0 mL) was added 20% palladium hydroxide on carbon (10.0 mg) under an atmosphere of hydrogen. The reaction was stirred at room temperature for 5 hours. Filtration and concentration gave compound (P-0027, 3.5 mg, 37%). MS (ESI) [M-t-HT- 331.
Example 26: Synthesis of 3-[6-(3-Trifluoromethyl-benzyloxy)-pyridin-3-ylπiethyl]-lH- pyrrolo[2,3-b]pyridine P-0057
[0531] 3-[6-(3-Trifluoromethyl-benzyloxy)-pyridin-3-ylmethylJ-lH-pyrrolo[2,3-b]pyridine P- 0057 was synthesized in 4 steps from commercially available 7-azaindole as shown in Scheme 28. Scheme 28
Figure imgf000219_0001
Step 1 - Preparation of(6-Chloro-pyridin-3-yl)-(lH-pyrrolo[2,3-b]pyridin-3-yI)-methanone (7):
[0532| To 7-azaindole 1 in dichloromethane was added 6-chloronicotinoyl chloride 8, followed by aluminum chloride, under an atmosphere of nitrogen at -10 0C, The reaction was stirred and allowed to warm to room temperature overnight. The reaction was quenched with 3 N hydrochloric acid and concentrated hydrochloric acid was added until all solids dissolved. The mixture was extracted with dichloromethane and the combined organic portions were dried with magnesium sulfate, filtered, and the filtrate was concentrated. The resulting solid material was recrystallized from chloroform/hexane to provide (6-Chloro-pyridin-3-yl)-(lH-pyrrolof2.3- b]pyridin-3-yl)-methanone 7 and used in the next step without further purification.
Step 2 - Preparation of(lH-pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-triflιιoromethyl-ben∑yloxy)-pyridin- 3-ylJ-methanone (73):
[0533] To (6-Chloro-pyridm-3-yl)-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methanone 7 in DMSO was added (3-trifluoromethyl-phenyl)-methanol 72. Sodium hydride was added and the reaction was heated to 60 0C for two hours. The reaction was quenched with water and extracted with ethyl acetate. The organic portion was dried with magnesium sulfate and concentrated to provide ( IH- pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanone 73, which was used in the next step without additional purification.
Step 3 - Preparation (lH-Pyrrolύ[2,3-b]pyridin-3-yl)-[6-(3-triβuoromethyl-benzyloxy)-pyridin-3- y!J-methano/ (74):
[0534] To (lH-pyrrolo[2,3-b]pyridin-3-yl)-[6-(3-trifluoromethyl-benzyloxy)-pyridin-3-yl]- methanone 73 in ethanol was added sodium borohydride. After one hour, the reaction was quenched with water and extracted with ethyl acetate. The organic portion was dried with magnesium sulfate and concentrated to provide (lH-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(3- trifluoromethyl-benzyloxy)-pyridin-3-yl]-methanol 74, which was used in the next step without additional purification.
Step 4 - Preparation of 3-[6-(3-Trιfluoromethyl-benzyloxy)-pyridin-3-ylmethyl] - 1 H-pyrrolo[2,3- b] pyridine, P-0057
|0535] (lII-Pyrrolo[2>3-b]pyridm-3-yl)-[6-(3-trifluoromcthyl-bcnzyloxy)-pyridin-3-ylJ-methaπol 74 was dissolved in 9: 1 tnfluoroacetic acid: triethylsilane. The reaction was stirred at room temperature for 15 hours. The reaction was diluted with water and extracted with ethyl acetate and concentrated. The cnide material was purified by reverse phase HPLC to provide 3-[6-(3- Trifluoromethyl-bcnzyloxy)-pyridin-3-ylmethylJ-lH-pyrrolo[2,3-b]pyridine P-0057. MS (ESI) [M+H+]+=384.3.
[0536] Additional compounds may be prepared using steps 2-4 of Scheme 28, replacing (3- trifluoromethyl-phenyl)-methanol with an appropriate benzyl alcohol. The following compounds were made following this procedure:
3-[6-(4-Chloro-benzyloxy)-pyridin-3-ylmefhyl]-lH-pyrrolo[2,3-b]pyridine (P-0056) 3-[6-(3-Chloro-benzyloxy)-pyridin-3-ylmethyl]-l H-pyrrolo[2,3-b]pyridine (P-0055) The benzyl alcohols used in step 2 of this procedure are indicated in column 2 of the following table, with the compound structure indicated in column 3. Column 1 provides the compound number and Column 4 the measured mass spectrometry result.
Figure imgf000220_0001
Example 27: Synthesis of [2-Chloro-6-(4-chloro-benzyIamino)- pyridin-3-yl|-(lH-pyrrolo[2,3- b]pyridin-3-yl)-methanαπe P-0048
[0537] [2-Chloro-6-(4-chloro-benzylamino)- pyridin-3-yl]-(lH-p>τrolo[2,3-b]pyridin-3-yl)- methanone P-0048 was synthesized in 3 steps from commercially available 2,6-dichloropyridinc- 3-carboxylic acid 75 as shown in Scheme 29.
Scheme 29
Figure imgf000221_0001
Step 1— Preparation of2,6-dichloropyridine-3-carbonyl chloride (76):
[0538] To 2,6-dichloropyridine-3-carboxylic acid (75, 1.00 g, 0.00521 mol) in dichloromethane (75 mL) was added 2 M Oxalyl chloride (2.61 mL, 0.727 g, 0.00573 mol). The solution began to show vigorous gas evolution, which slowed but continued for about 2 hours. The reaction was allowed to continue at room temperature for an additional 3 hours. The reaction was concentrated to give the compound as a brown oil that crystallized on standing (76, 1.09 g, 99%).
Step 2- Preparation of (2l 6-dichloropyridin-3-yl}(lH-pyrrolo[2,3-b]pyridin-3-yl)methanone (77):
[0539] To Aluminum trichloride (4.18 g, 0.0314 mol) and dichloromethane (97.5 mL, 1.52 mol) under an atmosphere of nitrogen was added lH-Pyrrolo[2,3-b]pyridine (1, 828.5 mg, 0.0070 mol) in dichloromethane (5,0 mL). The reaction was stirred at room temperature for 60 minutes, then added 2,6-dichloropyridine-3-carbonyl chloride (76, 1.09 g, 0.00523 mol) in dichloromethane (6.0 mL). The reaction was stirred at room temperature for 2 hours. A precipitate formed, and nitromethane was added in ~1 mL portions until almost all solid dissolved (8 mL). After an additional 60 minutes at room temperature, the reaction was slowly poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give 1.54 g of solid, which turned dark purple on sitting overnight, The solid was treated with dichloromethane, and the insoluble material was collected by vacuum filtration to give compound (77, 863 mg, 57%). MS (ESI) [M+H*]* = 292.2.
Step J- Preparation of[2-Chloro-6-(4-chloro-benzylanτinoj- pyridin-3-yl]-(lH-pyrrυ1o[2, 3-bJpy idin-3-yl)-methanone (P-0048) :
[0540] To (2,6-dichloropyridin-3-yl)(l H-pyrrolo[2,3-b]pyridin-3-yl)methanone (77, 0,0570 g, 0.195 tnmol) was added 2-propanol (1.5 mL) followed by p-chlorobenzylamine (61, 49.8 μL, 0.410 mmol). The reaction was microwaved at 300 watts, 100 0C for 10 minutes, at 120 °C for 10 minutes, and finally at 150 0C for 10 minutes. Additional p-chlorobenzylamine (50 μL. 0.410 mmol) was added and the reaction continued at 150 °C for 20 minutes The reaction was extracted with ethyl acetate and 1 M sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane followed by 1 % methanol to give compound (P- 0048, 47 mg, 61 %). MS (ESI) [M+hT] ' = 397.3.
[0541] Additional compounds may be prepared according to Scheme 29, replacing 2,6- dichloropyridine-3-earboxylic acid with an appropriate carboxylic acid. (6-(4- chlorobenzylamino)-2-(trifluoromethyl)pyridin-3-yl)(l H-pyrrolo[2,3-b]pyridin-3-yl)methanone P- 0070
Figure imgf000222_0001
was made following this protocol, using 6-Chloro-2-trifluoromefhyl-nicotinic acid as the carboxylic acid (prepared in two steps from commercially available 2-chloro-6- (trifluoromcthyl)pyridine according to Cottet, F. and Schlosscr. M. Eur. J. Org. Chem. 2004, 3793- 3798). MS (ESI) [M+H+]+ = 431.2.
Example 28: Synthesis of 3-((lH-pyrrolo|2,3-b]pyridin-3-yl)methyl)-6-(4- chlorobenzylamino)pyridin-2-ol P-0051
[0542] 3-((l H-pyrrolo[2,3-b]pyτidin-3-yl)methyl)-6-(4-chlorobenzylamino)p>τidm-2-ol P-0051 was synthesized in 2 steps from [2-Chloro-6-(4-chloro-benzylammo)- pyridin-3-ylJ-(lH- pyrrolo[2,3-b]pyidin-3-y])-mefhanone P-0048 as shown in Scheme 30.
Figure imgf000223_0001
Step 1— Preparation of (6-(4-chlυrυbenzylamino)-2-chloropyridin-3-yl)(lIl-pyrrolo[2, 3-bJ 'pyridin- 3-yl)methanol (P-0050):
[0543] To [2-Chloro-6-(4-chloro-benzylamino)-pyridin-3-yl]-(lH-pyrrolo[2,3-b]p>τidin-3-yl)- methanone (P-0048, 0.045 g, 0.00011 mol, prepared as described in Example 27) was added methanol (10 mL) and sodium borohydride (0.00428 g. 0.0001 13 mol). The reaction was allowed to stir at 50 0C overnight. The volatiles were removed from the reaction, and the resulting material was extracted with ethyl acetate and IM aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane followed by 1 % methanol in dichloromethane to give the compound (P-0050, 31 mg, 68%). MS (ESl) [M+H*] ' = 399.2.
Step 2- Preparation of3-((lH-pyrrolo[2,3-b]pyridin-3-yl)methyl)-6~(4~ chlorobenzylamino)pyridin-2-ol (P-0051):
[0544] To (6-(4-chlorobenzylamino)-2-chloropyridin-3-yl)(lH-pyrrolo[2,3-b]pyridm-3- yl)methanol (P-0050, 0,028 g, 0.000070 mol) dissolved in acetonitrile (1 mL) was added triethylsilane (42.6 uL, 0.000266 mol) and trifluoroacetic acid (28.4 uL, O.OOO368 mol). The reaction was heated at 85 0C overnight. The reaction was extracted with ethyl acetate and saturated sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromethane, 3%, 5% and finally 10% methanol in dichloromethane to give the compound as a white solid (P-0051, 20 mg, 78%). MS (ESl) [M^H+J+ = 365.3.
Example 29: Synthesis of 5 substituted 7-azaindole intermediates
(0545] 5-(2-Moφholm-4-yl-ethoxyHH-pyrrolo[2,3-b]pyridine 79 was synthesized in 1 Step from commercially available 5-bromo-azaindole as shown in Scheme 31. Scheme 31
Figure imgf000224_0001
-Step 7 - 5-(2-Morpholιn-4-yl-ethoxy)-lH p\rrolo[2 3-bJpyndme (79)
[0546] To 4-morpholmeethanol (30 mL, 0 2 mol) in N, N-dimethylformamide (30 πiL) w as slowly added sodium hydnde (7 g, 60% dispersion in mineral oil, 0 2 mol) Alter the solution turned clear, a solution of 5-bromo-7-azamdole (44, 1 0 g 0 0051 mol) in N,N dimethylformamide (5 mL) and copper(I) bromide (1 4 g, 0 0098 mol) were added The reaction mixture was stirred at 120 0C under nitrogen for 2 hours The reaction mixture was concentrated and the iesidue was dissolved in ethyl acetate and water The organic layer was collected, washed with a solution of ammonium chloride and ammonium hydroxide (4 1), brine, and dried over magnesium sulfate After removal of solvent, the residue was purified by silica gel column chromatography elutmg with ethyl acetate in hexane to provide the compound as an off-white solid (79, 0 62 g, 50%) MS (FSI) [M+H+]+ = 248 25
[0547] Additional 5-substituted 7-azamdoles were prepared following the protocol of Scheme 31 , replacing 4-morphohneethanol with either 2-diethylammo-ethanol, 3-diethylammo-propan-l- ol, 2-pipeπdm-l-yl-ethanol, or 2-pyrrohdm-l-yl-ethanol to piovide diethyl-[2-(l H-pyrrolo[2,3- b]pyπdin-5-yloxy)-ethyi]-amine, Dicthyl-[3-(lH-pyrrolo[2,3-b]pyridin-5-yloxy)-propyl]-amine, 5- (2-piperidin-l-yl-ethoxy)-l H-pyrrolo[2,3-b]pyridine, and 5-(2-pyrrolidin-l -yl-ethoxy)-lH- pyrrolo[2,3-b]pyridine, respectively
Example 30: Synthesis of {5-[5-(2-Morpholin-4-yl-ethoxy)-lH-pyrrolo[2,3-Z>]p\ridin-3- ylmethyl]-pyridin-2-yl}-(4-trifluoromethyl-benzyl)-amine P-0065
[0548] {5-[5-(2-Moφholin-4-yl-ethoxy)-l H-pyrrolo[2,3-ό]pyridin-3-ylmethyl]-pyridm-2-yl}-(4- tπfluoromethyl-benzyl)-amme P-0065 was synthesized in 4 Steps from (5-bromo-pyπdin-2-yl)-(4- tπfluoromethylbenzyl)-amine 17 as shown in Scheme 32 Scheme 32
Step I -- Preparation of6-(4-Trifluoromethyl-benzylamino)-pyridine-3-carbaldehyde (18):
[0549] To a solution of (5-bromo-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-amine (17, 3,55 g, 0.0107 mol, commercially available, or prepared as described in Example 10) in tetrahydrofuran (150 mL) was added teτ/-butyllithium (13.2 mL. 1.70 M in pentane, 0.0224 mol) slowly under an atmosphere of nitrogen at -78 0C over 10 minutes. The reaction mixture was stirred at -78 0C for 90 minutes. N, N-Dimethylformamide (2.2 mL, 0.028 mol) was added slowly into the reaction mixture. The reaction mixture was stirred at -78 0C for 2 hours, then allowed to warm to room temperature. After stirring at room temperature for 2 hours, the reaction mixture was poured into ice water and extracted with ethyl acetate. I he organic phase was washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a light yellow solid (18, 1.67 g, 56%).
Step 2 - Preparation of(5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbarmc acid tert- butyl ester (19):
[0550] To a solution of 6-(4-tifluoromethyl-benzylamino)-pyridine-3-earbaldehyde (18. 3.7 g, 0.013 mol) and di-ter?-butyldicarbonate (3.4 g, 0.016 mol) in dichloromethane (100 mL) was added N,N-diisopropylcthylaminc (4.6 mL, 0.026 mol) and 4-diethylammopyridine (0.2 g, 0.002 mol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and then dissolved in ethyl acetate. The solution was washed with hydrochloric acid (10%), saturated sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (19, 4,38 g, 87%).
Step 4 Preparation of(5-{Hydroxy-[5-(2-morpholin-4-yl-ethoxy)-lH-pyrrolo[2, 3-b]pyridin-3- yl]-methyl}-pyridin-2-yl)-(4 -trifliioromethyl-benzylj-carhamic acid tert-butyl ester (80):
[0551] A mixture of (5-Fonnyl-pyridin-2-yl)~(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (19, 315 mg, 0.828 mmol), 5-(2-morpholin-4-yl-cthoxy)-lH-pyrrolo[2,3-bJpyridine (79, 205 mg, 0.829 mmol, prepared as described in Example 29), and potassium hydroxide (70 mg, 1 mmol) in methanol (25 mL) was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the compound as a yellow solid (80, 0.2 g, 40%). MS (ESI) [M+HT = 628.42.
Step 5 - Preparation of {5-[5-(2-MorphoUn-4-yl-ethoxy)-l H-pyrrolo[2,3-h] pyridin-3-ylmethyl] - pyridin-2-yl}-(4-trifluorom ethyl-hen∑yl)-amine (P-0065):
[0552] A mixture of (5-{Hydroxy-[5-(2-morpholin-4-yl-ethoxy)-lH-pyrrolo[2,3-/?]pyridin-3-yl]- methyl}-pyridin-2-yl)-(4 -trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (80, 0.2 g, 0.3 mmol), tricthylsilane (4 mL, 0.02 mol), and trifluoroacctic acid (2 mL, 0.02 mol) in acctonitrilc (30 mL) was refluxed for 2 hours. After removal of solvent, the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the compound as a light yellow solid (P-0065, 17 mg, 10%). MS (ESI) [M+HT = 512.42.
[0553] Additional compounds may be prepared using steps 3 and 4 of Scheme 32, using (5- FoπτiyI-pyi"idin-2-yl)-(4-trifluoromethyl-benzyi)-carbamic acid fcrf-butyl ester 19 or replacing it with (5-Formyl-pyridin-2-yl)-(4-chloro-bcnzyl)-carbamic acid fe/Y-butyl ester (43, prepared as described in Example 17) and replacing 5-(2-Morpholin-4-yl-ethoxy)-lH-pyrrolo[2,3-/jlpyridine 79 with an appropriate azaindole, prepared as in Example 29 or 5-methoxy-7-azaindole (prepared as described in Example 31) or with commercially available 5-chloro-7-azaindole. The following compounds were made following this procedure;
[5-(5-Methoxy-lH-pyrrolo[2,3-ij]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)- amine (P-0053),
[5-(5-Chloro-l H-pyrrolo[2,3-έ]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-trifluoromethyl-benzyl)- amine (P-0054), (4-Chloro-benzyl)-[5-(5-methoxy-lH-pyπ"olo[2,3-/)]p\ridin-3-ylmethyl)-p>τidin-2-yl]-amine (P-
0058).
C4-Chloro-bcnzyl)-[5-(5-chloro-l H-pyrrolo[2.3-έ]pyridin-3-ylmethyl)-p>τidm-2-yl]-amine (P-
0059),
{5-[5-(2-Diethylamino-ethoxy)-lH-pyrro!o[2.3-/j]pyπdm-3-ylmethyl]-pyridin-2-yl}-(4- tπfluorometh} l-benzyl)-ammc (P-0060),
(4-Chloro-benzyl)- {5-[5-(2-morpholin-4-yl-ethoxy)-l H-pyrrolo[2,3-b]pyτidin-3-ylmethyl]- pyτidin-2-yl} -amine (P-0063),
{5-[5-(2-P>τrolidm-l-yl-ethoxy)-l H-pyrrolo[2,3-/;]pyridin-3-ylmethyl]-pyridin-2-yl}-(4- tπfluoromethyl-bcnzyl)-amme (P-0064),
{5-[5-(3-Diethylamino-propoxy)-l H-pyrrolo[2,3-&]pyridin-3-ylmethyl]-pyridin-2-yl}-(4- trifluoromethyl-benzyl)-amme (P-0066).
(4-Chloro-benzyl)- {5-[5-(3-diethylamino-propoxy)-lII-pyrrolo[2,3-έ']pyτidin-3-ylmethyl]-pyridin-
2-yl}-amine (P-0069),
The aldehyde and azaindole used in step 4 of this procedure are indicated in columns 2 and 3 of the following table, respectively, with the compound structure indicated in column 4 Column 1 provides the compound reference number and Column 5 the experimental mass spectrometry result.
Figure imgf000227_0001
Figure imgf000228_0001
Example 31 : Synthesis of 3-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-yImethyI]-l H- pyrrolo[2,3-b]pyridin-5-ol P-0061:
[0554] 3-[6-(4-Trifluoromethyl-ben2ylamino)-pyridin-3-ylmethyl]-l H-pyrrolo[2,3-b]pyridin-5- ol P-0061 was synthesized in 6 Steps from 5-bromo-7-azaindole 44 as described in Scheme 33. Scheme 33
Figure imgf000229_0001
Step 1 - Preparation of5-Methoxy-lH-pyrrolo[2,3-b]pyridine (81):
[0555] To a mixture of 5-bromo-7-azaindole (1 g, 0.005 mol) in N, N-Dimethylformamide (20 mL) and methanol (20 πiL) were added sodium methoxide (13 g, 0,24 mol) and Copper (I) bromide (0.7 g, 0.0048 mol) at room temperature. The reaction mixture was stirred at 120 0C under nitrogen for 3 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. The organic layer was collected, washed with a solution of ammonium chloride and ammonium hydroxide (4: 1 ), brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (81, 0.4 g, 50%). MS (ESI) [M+H*]" = 149.09.
Step 2 - Preparation of lH-Pyrrυlυ[2,3-b]pyridin-5-ol (82):
[0556] To a solution of 5-mcthoxy-lH-pyrrolo[2,3-&Jpyridine (81, 0.5 g, 3 mmol) in tetrahydrofuran (20 mL) was added boron tribromide (1.5 g, 6.0 mmol) at 0 0C. The reaction mixture was allowed to warm to room temperature, then stirred at room temperature for 3 hours. The reaction mixture was quenched by methanol. After repeated addition of methanol and removal of solvent, the concentrated reaction mixture was dissolved in ethyl acetate and water. The organic layer was collected, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (82, 0.18 g, 40%). Step 3 - Preparation υf 5-Triisoprυpylsitanyloxy-l H-pyrrolo[2,3-b] pyridine (83);
[0557] To a solution of lII-Pyrrolo[2,3-6]pyridm-5-ol (0.5 g, 0.004 mol) and 1 H-imida/ole (0.98 g, 0.014 mol) in N,N-dimethylformamide (5 mL) was added triisopropylsilyl chloride (1 niL. 0.005 mol). The reaction mixture was stirred at room temperature overnight. Dichloromethane (10 mL) was added and the solution was washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a viscous liquid (83, 0.4 g, 40%),
Step 4 - Preparation of{5-[Hydroxy-(5-triisopropylsilanyloxy-lH-pyrrolo[2,3-b]pyridin-3-yl)- methyl]-pyridin-2-yl}-(4-trifluoromethyl-hen:yl)-carbamic acid tert-bυtyl ester (84):
|0558) A mixture of (5-Formyl-pyridin-2-yl)-(4-trifluoromcthyl-benzyl)-carbamic acid fert-butyl ester (19, 41 mg, 0.1 1 mmol, prepared as described in Example 30), 5-tπisopropylsilanyloxy-l H- pyrrolo[2,3-b]pyridine (83, 34 mg, 0.12 mmol) and potassium hydroxide (9.8 mg, 0.17 mmol) in methanol (10 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate, washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a viscous liquid (84, 0.05 g, 70%). MS (ESI) [M+HT = 671.38.
Step 5 - Preparation of(4-Trifluoromethγl-benzyl)-[5-(5-triisopropylsιlanyloxy-lH-pyrrolol2,3- b] pyridin-3-ylmethyl)-pyridin-2-yl] -amine (85):
[0559] A mixture of {5-[hydroxy-(5-triisopropylsilanyloxy-lH-pyrrolo[2,3-/>]pyridin-3-yl)- methyl]-pyridin-2-yl} -(4-trifluoromcfhyl-bcnzyl)-carbamic acid tert-butyl ester (84, 0.05 g, 0.07 mmol), trifluoroacetic acid (0.5 mL, 0.006 mol), and triethylsilane ( 1 mL, 0.006 mol) in acetonitrile (10 mL) was refluxed for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a viscous liquid (85, 0.04 g, 97%). MS (ESI) [M+H+]1 = 555.38.
Step 6 - Preparation of3-[6-(4-Triβuoromethyl-benzylamino)-pyrιdin-3-ylmethyl]-lH- pyrrolol2,3-bJpyridin-5-ol (P-0061):
[0560] To (4-Trifluoromethyl-ben2yl)-[5-(5-triisopropylsilanyloxy-l H-pyrrolo[2,3-έ]p>τidin-3- ylmethyl)-pyr idin-2-yl]-amine (85, 0.13 g, 0.23 mmol) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (3 mL, 1.0 M in tetrahydrofuran, 3 mmol). The reaction mixture was stirred at room temperature overnight, and then was stirred at 65 0C for 48 hours. The reaction mixture was concentrated and purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a viscous liquid (P-0061, 0.062 g, 66%). MS (ESI) [M+HT = 399.19,
[0561] 3-[6-(4-Chloro-beπzylamino)-pyridin-3-ylmethyl]-l H-p>nτolo[2,3-/?]pyi-idin-5-ol P-0062
Figure imgf000231_0001
was prepared following the protocol of Scheme 33, replacing (5-Formyl-pyridin-2-yl)-(4- trifluoromethy]-benzyl)-carbamic acid tert-bιύy\ ester 19 with (5-Formyl-pyridin-2-yl)-(4-chloro- benzyl)-carbamic acid rerf-butyl ester (43, prepared as described in Example 17). MS (ESI) [M+H+]+ = 365.2.
Example 32: Synthesis of N-[5-(lH-Pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-4- trifluoromethyl-benzamide P-0067
[0562] N-[5-(lII-Pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridii>2-yl]-4-trifluoromcthyl-bcnzamidc P-0067 was synthesized in 2 Steps from 7-azaindole 1 as described in Scheme 34,
Scheme 34
Figure imgf000231_0002
Step J - Preparation of (6-Bromo-pyrιdin-3-yl)-(lH-pyrrolo[2,3-b]pyridιn-3-vl)-methanone (87);
[0563] To a solution of lH-Pyrrolo[2,3-b]pyridine (1, 1.2 g, 0.010 mol) in dichloromethane (50 mL) was added 6-bromo-nicotinoyl chloride (86, 2.6 g. 0.012 mol) at -10 0C. After the solution turned clear, aluminum trichloride (10.2 g, 0.0765 mol) was added in one portion with vigorous stirring. The reaction mixture was stirred at -10 0C for 30 minutes, then was allowed to warm to room temperature and stirred at room temperature overnight. The reaction was quenched with ice water and neutralized with sodium bicarbonate. The solution was extracted with dichloromethane, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the compound as a white solid (87, 0.35 g, 1 1 %).
Step 2 -- Preparation ofN-[5-(lH-Pyrrolo[2,3-b]pyrιdme-3-carbonyl)-pyrιdin-2-yl]-4- trifluoromethyl-benzamide (P-0067):
10564] A mixture of (6-bromo-pyridin-3-yl)-(lH-p\τrolo[2,3-/?]pyridin-3-yl)-methanone (87, 160 mg, 0.53 mmol), 4-trifluoromethyl benzamide (51, 130 mg, 0.69 mmol), xanthphos (9 mg, 0.02 mmol), cesium carbonate (245 mg, 0.752 mmol), and tris(dibenzylideneacetone)dipalladium (0) (5 mg, 0.005 mmol) in toluene (2 mL) in a sealed tube was stirred at 1 10 0C for 1 hour. The reaction was quenched with water and extracted with dichloromethane. The organic layer was collected, washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified with silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (P-0067, 0.42 mg, 19%). MS (ESI) [M+Hτ]τ - 41 1.17.
[0565] N-[5-( lH-P>τrolo[2,3-έ]pyridine-3-carbonyl)-pyridin-2-yl]-4-trifluoromethyl- benzenesulfonamide P-0068
Figure imgf000232_0001
was prepared following the protocol of Scheme 34, replacing 4-trifluoroinethyl benzamide 51 with 4-trifluoromethyl-benzenesulfonamide in Step 2. MS (ESI) [M+H"]+ = 445.1.
Example 33: Synthesis of [(S)-l-(4-Chloro-phenyl)-ethyll-[5- (lH-pyrrolo[2,3-bjpyridiπ-3- ylmethy l)-pyridin-2-yl]-amine P-0075
[0566] [(S)-l-(4-Chloro-phenyl)-ethyl]-[5- (lH-pyrrolo[2,3-b]pyridin-3-ylmethy l)-pyridin-2- yl]-amine P-0075 was synthesized in 3 Steps from 7-azaindole 1 as described in Scheme 35. Scheme 35
Figure imgf000233_0001
Step 1 - Preparation of(6-Bromo-pyridin-3-ylj-(lH-pyrrolo[ 2,3-bJpyridin-3-ylj-methanol (89):
[05671 A mixture of lH-Pyrrolo[2,3-ό]pyridine (1, 1 ,2 g, 0.010 mol), 6-bromo-pyridine-3- carbaldehyde (88, 1.8 g, 0.0097 mol), and potassium hydroxide (1.8 g, 0.032 mol) in methanol (25 ml) was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the compound as a white solid (89, 1.4 g, 45%), or may be used as mixture of 89 and 90 in Step 2.
Step 2 - Preparation of3-(6-Bromo-pyridin-3-ylmethyl)-lH-pyrrolo[2,3-b]pyridine (91):
[0568] A mixture of (6-bromo-pyridin-3-yl)-(lH-pyrrolo[ 2,3-£]pyridin-3-yl)-methanol (89, 1 g, 0.003 mol) and 3-[(6-bromo-pyridin-3-yl)-methoxy-methyl]-lH-pyrrolo[2,3-£>]pyridine (90, 2 g, 0.006 mol), triethylsilane (1 niL, 0.006 mol), and trifluoro acetic acid (0.5 mL, 0.006 mol) in acetonitrile (25 mL) was refluxed for 2 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. The organic layer was collected, washed with saturated sodium bicarbonate, brine, and dried over sodium sulfate. After removal of the solvent, the residue was purified with silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (91, 0.75 g, 60%). MS (ESl) [M+H'T = 288.06, 290,00. Step 3 - Preparation υf [(S)- 1 ' -(4-Chloro-phenyl)-ethyl) '- [5- (lH-pyrrolo[2,3-b]pyridin-3-ylmethy l)-pyridin-2-ylJ -amine P-0075;
|0569] A mixture of 3-(6-bromo-pyridin-3-ylmethyl)4H-pyrrolo[2,3-£>]pyπdme (91, 100 mg, 0,0003 mol) and (S)-l-(4-chloro-phenyl)-ethylamine (92, 0,5 g, 0.003 mol) in N-methylpyrrolidine (3 mL) was stirred at 150 0C in microwave for 100 minutes. The reaction mixture was concentrated under vacuum and the residue was purified with silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (P-0075, 0.03 g, 20%). MS (ESI) [M+HT = 363.1 8.
Example 34: Synthesis of (4-ChIoro-ben/:yI)-[4-chIoro-5-(lH-pyrroIo/2,5-ύypyridiπ-3- yImethyI)-thiazoI-2-yI]-aminc P-0ϋ83
10570] (4-Chloro-benzyl)-[4-chloro-5-(lH-pyrrolo/ r2,i-έ7pyridin-3-ylmethyl)-thiazol-2-yl]- amine P-0083 was synthesized in 4 steps from 2,4-Dichloro-thiazole-5-carbaldehyde 93 as described in Scheme 36.
Scheme 36
Figure imgf000234_0001
Step 1 - Preparation of4-Chloro-2-(4-chloro-benzylarninaj-thiazoIe-5-carbaldehyde (94):
[0571] To a solution of p-chlorobenzylamine (61, 283 mg, 2,00 mmol) and N1N- Diisopropylethylamine (0.697 mL) in tetrahydrofuran (2OmL) was slowly added 2,4-Dichloro- thiazole-5-carbaldehyde (93, 364 mg, 2.00 mmol) in tetrahydrofuran ( 1 OmL) at room temperature The reaction was stirred at room temperature overnight. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a yellow solid (94, 0.3 g, 50%), MS (ESI) [M- 11+] = 286.97,
Step 2 Preparation of(4-Chloro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid ten- butyl ester (95):
|0572] To a solution of 4-Chloro-2-(4-chloro-benzylamino)-thiazolc-5-carbaldehyde (94, 0.32 g, 0.001 1 mol) in dichloromethane (20 mL) was slowly added N,N-diisopropylethylamine (0.4 mL, 0.002 mol), 4-dimethylaminopyridine (27 mg, 0.22 mmol), and a solution of di-tert- butyldicarbonate (290 mg, 0.0013 mol) in dichloromethane (5 mL) at room temperature. The reaction mixture was stirred at room temperature overnight, then poured into iced water, extracted with dichloromethane, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a light brown solid (95, 0.32 g, 74%). MS (ESI) [M+H+] = 387.26.
Step 3 - Preparation of(4-Chloro-ben∑yl)-{4-chloro-5-[hydroxy-(l-triisopropylsilanyl-lH- pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazυl-2-yl}-carhamic acid tert-butyl ester (97):
[0573] To a solution of 3-Iodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (96, 99 mg, 0.25 mmol) in tetrahydrofuran (5 ml) at -20 °C under nitrogen was added 2.0 M solution isopropylmagnesium chloride in tetrahydrofuran (0.2 ml, 0.31 mmol). The reaction mixture was stirred for 1.5 hours, then allowed to warm to 5 0C. After the reaction mixture was cooled down to -20 0C, a solution of (4-Chloro-bcnzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (95. 80 mg, 0.2 mmol) in tetrahydrofuran (5 mL) was slowly added. The reaction mixture was stirred for 2.5 hrs, then allowed to warm to 5 0C. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as an off-white solid (97, 76 mg, 50%). MS (ESI) [M+H+] = 661.32, 663.32.
Step 4 - Preparation υf(4-Ch1oro-henzyl)-[4-chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)- thiazol-2-ylj '-amine (P-0083):
[0574] A mixture of (4-Chloro-benzyl)-{4-chloro-5-[hydroxy-(l-triisopropylsilanyl-lH- pyrrolo[2,3-b]pyridin-3-yl)-methyl]-thiazol-2-yl}-carbamic acid tert-butyl ester (97, 76 mg, 0.1 1 mmol), triethylsilane (0.5 mL, 3 mmol), and trifluoroacetic acid (0.25 mL, 3.2 mmol) in acctonitrile (5 mL) was refluxed for 3 hours. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with sodium bicarbonate, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a yellow solid (P-0083, 5.6 mg, 14%). MS (ESI) [M+H+] = 389.35, 390.36.
Example 35: Synthesis of [2-(4-Chloro-benzylamino)-thiazol-5-yl]-(lH-pyrroloI2,3- b]pyridiii-3-yl)-methanone P-0077:
[0575] [2-(4-Chloro-benzyIamino)-thiazol-5-yl]-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methanone P- 0077 was synthesized in 2 steps from 2-Bromo-thiazole-5-carboxylic acid 98 and l ll-pyrrolo/^.i- έ>/pyridine 1 as shown in Scheme 37.
Scheme 37
Figure imgf000236_0001
Step 1 - Preparation of (2-Bromo-thiazol-5-yl)-( 1 H-pyrrolo[2 ,3-b] pyridin-3-yl)-methanone (99):
[0576] A suspension of 2-Bromo-thiazole-5-carboxylic acid (98, 0.5 g, 0.002 mol) in oxalyl chloride (3 mL) was stirred at room temperature until it turned into a clear solution. Solvent was removed and the residue was dried over vacuum. A light yellow solid was obtained and was dissolved in dichloromethane (10 mL) and slowly added to a solution of Ill-Pyrrolo[2.3- bjpyridine (1, 0.34 g, 0.0029 mol) in dichloromethane (30 mL) at -10 0C. To the mixture was then added aluminum trichloride (2.6 g, 0.019 mol) in one portion with vigorous stirring. The reaction was held at -10 0C for 30 minutes, then allowed to warm to room temperature. The reaction mixture was stirred at ambient temperature overnight. The reaction was quenched with icc-watcr and acidified with hydrochloric acid (10%) to pH 4. The solution was then extracted with dichloromethane. The organic layer was collected, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a white solid (99, 12 mg, 2%). MS (ESI) [M-H+] = 369,09.
Step 2 - Preparation uf[2-(4-Chloro-benzylamino)-thiazoi-5-yl]-(lH-pyrrolo[2,3-b]pyridin-3-yl)- methanone (P-0077): |0577] A mixture of (2-Bromo-thiazol-5-yl)-(l H-pyrrolo[ 2,3-bJpyridin-3-yl)-methanone (99, 5 tng, 0.02 mrnol), p-chlorobenzylamine (61, 10 mg, 0,08 mmol), and N.N-Diisopropylethylamine (10 μL, 0.08 ramol) in tetrahydrfuran (10 niL), in a sealed reaction vessel, was stirred room temperature overnight. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography elutmg with ethyl acetate in hexane to provide the compound as a light yellow solid (P-0077, 2 mg, 30%). MS (ESI) [M+H+] = 305.90. 307.88.
Example 36: Synthesis of 3-((5-chloro-3-methyl-l-phenyl-lH-pyra7ol-4-yl)methyl)-lH- pyrrolo!2,3-bj pyridine P-0080
[0578] 3-((5-chloro-3-methyl-l -phenyl-lH-pyrazol-4-yl)methyl)-lH-pyrrolo[2,3-b]pyridine P- 0080 was synthesized in 2 steps from 5-chloro-3-methyl-l -phenyl-lH-pyrazole-4-carbaldehyde 100 and 7-azaindole 1 as shown in Scheme 38.
Scheme 38
Figure imgf000237_0001
Step 1 - Preparation of 3-((5-chloro-3-methyI-l -phenyl-1 H-pyrazol-4-yl)(tnethoxy)methyl)-l H- pyrrolo[2,3-b] pyridine (P-0079) :
[05791 To lH-Pyrrolo[2,3-b]pyridine (1, 0.100 g, 0.846 mmol) and 5-chloro-3-mcthyl-l-phenyl- lH-pyrazole-4-carbaldehyde (100, 0.205 g, 0.931 mmol) was added 2 mL of methanol to give a solution. Potassium hydroxide (0 0475 g, 0.846 mmol) was added and the reaction was allowed to stir at room temperature for 48 hours. The reaction was extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with a gradient of 0-5% methanol in dichloromethane to give the compound (P-0079, 32 mg, 1 1 %). MS (ESI) [M-t-H'f = 353.2.
Step 2 - Preparation of3-((5-chloro-3-methvl-!-phenyl-lH-pyrazol-4-yl)methy0-lH-pyrrolol2,3- b] pyridine (P-0080): [058Oj To 3-((5-chloro-3-methyl-l -phenyl-lH-pyrazol-4-yl)(methoxy)mcthyl)-lH-pyrrolo[2,3- b]pyridine (P-0079, 0.030 g, 0.085 mmol) was added acetonitrile ( 10 mL, 0.2 mol). Trifluoroacetic acid (500 uL, 0.006 mol) and triethylsilane (500 uL, 0.003 mol) were added and the reaction allowed to stir at room temperature for 16 hours. The reaction was extracted with ethyl acetate and water. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with dichloromcthane followed 5% methanol in dichloromethane to give the compound as a yellowish foam (P-0080, 29 mg, 98%). MS (ESI) [M+HT = 323.2.
Example 37: cKit Kinase Domain and Construction of c-Kit sequences
[0581] c-Kit cDNA sequence is available from NCBI, e.g., as GenBank accession number NM_000222. Using this sequence, c-kit DNA sequences can be cloned from commercially available libraries (e.g. cDNA libraries) or can be synthesized by conventional cloning methods.
|0582] Using conventional cloning methods, constructs encoding three c-kit polypeptides were prepared, and used to express c-kit kinase domain polypeptides. One such active c-kit kinase domain sequence included residues P551-S948, with the deletion of residues Q694-T753.
Example 38: Expression and Purification of c-Kit kinase domain
[0583] Purified c-kit kinase domain can be obtained using conventional expression and purification methods. Exemplary methods are described, for example, in Lipson ct al., U.S. 20040002534 (U.S. application 10/600, 868, filed June 23, 2003), which is incorporated herein by reference in its entirety.
Example 39: Binding Assays
[0584] Binding assays can be performed in a variety of ways, including a variety of ways known in the art. For example, as indicated above, binding assays can be performed using fluorescence resonance energy transfer (FRET) format, or using an AlphaScreen.
[0585] Alternatively, any method which can measure binding of a ligand to the ATP-binding site can be used. For example, a fluorescent ligand can be used. When bound to c-kit. the emitted fluorescence is polarized. Once displaced by inhibitor binding, the polarization decreases.
[0586] Determination of IC50 for compounds by competitive binding assays. (Note that Kj is the dissociation constant for inhibitor binding; KD is the dissociation constant for substrate binding.) For this system, the IC50, inhibitor binding constant and substrate binding constant can be interrelated according to the following Formula:
[0587] When using radiolabeled substrate
K1= IC50
1+ [L*]/KD
[0588] the ICs0 ~ K1 when there is a small amount of labeled substrate.
Example 40: Cell-based assays of c-fms kinase activity or c-kit kinase activity.
[0589] M-CSF dependent RAW264.7 cells were seeded on a 12 well plate, 2.5x105 cells/well and the cells were allowed to attach overnight at 37 0C, 5% CO2 The cells were then starved in serum-free medium overnight at 37 0C, 5% CO2. The cells were treated with compound for 1 hour in serum-free media (1 % DMSO final concentration); and then stimulated with 20 ng/ml M-CSF for 5 minutes. After stimulation, the cells were lysed on ice, and the lysates were centrifuged at 13,000 rpm for 1 minute. The amount of protein in the sample was quantitated, sample buffer was added, and the samples were boiled at 95 0C for 10 minutes. The samples were then centrifuged at 13,000 rpm for 1 minute. The samples (15-20 μg/lane) were loaded and run on 4-12% tris-glycine gel at 75V, and then transferred onto a PVDF membrane. The membrane was blocked for 1 hour with 5% BSA in PBS/1 % Tween-20 (PBST); or 5% milk, depending on the primary antibody used. Then the blots were incubated with primary antibody overnight at 4 degrees with gentle shaking. After incubation with the capture antibody, the membranes were washed 3 x 10 minutes with PBST; then incubated with detection antibody Goat Anti-Rabbit-HRP for 1 hour, with gentle shaking. The membranes were washed again 3 x 10 minutes with PBST. ECL Plus substrate was then added to the blots, the image captured with chemiluminescence camera, and the bands quantitated for pFMS and FMS levels.
|0590] The Fms inhibitors may also be assessed using M-NFS-60 mouse myelogenous leukemia cell line (ΛTCC catalog #CRL-1838). This cell line proliferation is stimulated by M-CSF. which binds and activates the fms tyrosine kinase receptor. Inhibitors of fms kinase activity reduce or eliminate the M-CSF stimulated kinase activity, resulting in reduced cell proliferation. This inhibition is measured as a function of compound concentration to assess TC50 values. M-NFS-60 cells were seeded at 5 x 104 cells per well of a 96 well cell culture plate in 50 μl of cell culture medium of RPMI 1640 (CellGro Mediatech catalog #10-040-CV) supplemented with 10 % FBS (HyClone catalog #SH30071.03). Compounds were dissolved in DMSO at a concentration of 1 mM and were serially diluted 1 :3 for a total of eight points and added to the cells to final concentrations of 10, 3.3, 1.1 , 0.37, 0.12, 0.041 , 0.014 and 0.0046 μM in 100 μl cell culture medium (final concentration 0.2% DMSO). Cells were also treated with staurosporine as a positive control. The cells were stimulated by adding 20 μl of 372 ng/ml M-CSF to a final concentration of 62 ng'ml (R&D Systems catalog #216-MC). The cells were incubated at 37 0C, 5% CO2 for three days. CellTiter-G1o Buffer (Promega Cell Viability Assay catalog #G7573) and substrate were equilibrated to room temperature, and enzyme/substrate Recombinant Firefly Luciferase/Beetle Luciferin was reconstituted. The cell plates were equilibrated to room temperature for 30 minutes, then lysed by addition of an equivalent volume of the Celltiter-Glo Reagent. The plate was mixed for 2 minutes on a plate shaker to lyse the cells, then incubated for 10 minutes at room temperature. The plates were read on a Victor Wallac II using Luminescence protocol modified to read 0.1 s per well. The luminescence reading assesses the ΛTP content, which correlates directly with cell number such that the reading as a function of compound concentration was used to determine the IC50 value.
(0591] The c-Kit inhibitors were assessed using M-07e cell line (DSMZ catalog #ACC 104). The M-07e proliferation is stimulated by SCF (Stem Cell Factor), which binds and activates c-Kit tyrosine kinase receptor. Inhibitors of c-Kit kinase reduce or eliminate the SCF mediated kinase activation, resulting in reduced cell proliferation of SCF stimulated cells. This inhibition is measured by the effect of compound concentration on cell growth to assess IC50 values. M-07e cells were seeded at 5 x 104 cells per well of a 96 well cell culture plate in 50 μl of cell culture medium of Iscove's Medium IX (MOD, CellGro Mediatech catalog #15-016-CV) supplemented with 10% FBS (HyClone catalog #SH30071.03). Compounds were dissolved in DMSO at a concentration of 0.1 mM and were serially diluted 1 :3 for a total of eight points and added to the cells to final concentrations of 1 , 0.33, 0.1 1 , 0.037, 0.012, 0.0041. 0.0014 and 0.00046 μM in 100 μl cell culture medium (final concentration 0.2% DMSO). Cells were also treated with staurosporine as a positive control. Cells were stimulated by adding 20 μl of 600 ng/ml SCF to a final concentration of 100 ng/ml (Biosource International SCF kit ligand catalog #PHC21 15) in cell culture medium. The cells were incubated at 37 0C, 5% CO2 for three days. CellTiter-Glo Buffer (Promega Cell Viability Assay catalog #G7573) and substrate were equilibrated to room temperature, and enzyme/substrate Recombinant Firefly Luciferase/Beetle Luciferin was reconstituted. The cell plates were equilibrated to room temperature for 30 minutes, then lysed by addition of an equivalent volume of the Celltiter-Glo Reagent. The plate was mixed for 2 minutes on a plate shaker to lyse the cells, then incubated for 10 minutes at room temperature. The plates were read on a Victor Wallac II using Luminescence protocol modified to read 0.1 s per well. The luminescence reading assesses the ATP content, which correlates directly with cell number such that the reading as a function of compound concentration is used to determine the IC50 value.
[0592] This cell based assay was also used to assess phosphorylation. Samples were prepared with compounds as described for the growth inhibition assay only M-07e cells were seeded at 2 x 10" cells per well in a 96 well filter plate. Cells were incubated for 1 hour at 37 0C with the compounds as described above, and then stimulated by adding SCF to a final concentration of 50 ng/ml and incubated for 10 minutes at 37 0C. The culture medium was removed by centrifugation and the cells were lysed by addition of 30 μl lysis buffer (25 mM Tπs HCl pH 7.5, 150 niM NaCT, 5 mM EDTΛ, 1% Triton XlOO, 5 mM NaF, 1 mM NaVanadate, 10 mM Beta-glycerophosphate. no EDTA (Boehringer-Roche catatalog #1873580) and placed on ice for 30 minutes. A 15 μl aliquot of the lysate was taken and assayed according to Biosource Immunoassay Kit: Human c- Kit [pY823] (Catalog ft KHO0401) by diluting the aliquot with 85 μl dilution buffer in the assay plate, incubating for 2 hours at room temperature and washing the plate 4 times with wash buffer. Detection antibody (100 μl) was added to the plate and samples incubated for 1 hour at room temperature, then washed 4 times with wash buffer. HRP anti-rabbit antibody (100 μl) was added and samples incubated for 30 minutes at room temperature, then washed 4 times with wash buffer. Stabilized chromogen (100 μl) was added and samples incubated for 15-25 minutes at room temperature, then washed 4 times with wash buffer. Stop solution (100 μl) was added and the samples read on a Wallac Victor reader at 450 nm. The absorbance was plotted against the compound concentration and the IC50 concentration was determined.
[0593] Additional cell based assays can be correlated to the Fms activity of compounds of the invention. For example, the ability of osteoclast precursor cells (commercially available from Lonza) to differentiate into mature osteoclasts, due to stimulation by M-CSF and RANKL, in the presence of compounds, can be measured using a method analogous to that previously reported (Hudson et al., Journal of Urology, 1947, 58:89-92), where the amount of acid phosphatase in the supernatant (i.e. TRAP5b excreted by mature osteoclasts) is proportional to the number of mature osteoclasts present. In another example, the ability of M-CSF-dependent murine macrophage cells (BACl .2F5) to proliferate in the presence of compounds can be measured by culturing cells as previously described (Morgan et al., Journal of Cellular Physiology, 1987, 130:420-427) and determining cell viability by analysis of ATP levels in the cell culture (Crouch et al., Journal of Immunological Methods, 1993, 160:81-8).
Example 41: c-Kit, c-Fms, TrkA, and HGK Activity Assays
[0594] The effect of potential modulators of kinase activity of c-kit and other kinases can be measured in a variety of different assays known in the art, e.g., biochemical assays, cell-based assays, and in vivo testing (e.g. model system testing). Such in vitro and/'or in vivo assays and tests can be used in the present invention. As an exemplary kinase assay, the kinase activity of c-kit or Fins is measured in AlphaScreening (Packard BioScience).
Exemplary c-kit biochemical assay
[0595] The c-kit (or kinase domain thereof) is an active kinase in AlphaScreen. IC^ values are determined with respect to inhibition of c-Kit kinase activity, where inhibition of phosphorylation of a peptide substrate is measured as a function of compound concentration. Compounds to be tested were dissolved in DMSO to a concentration of 20 niM. These were diluted 30 μl into 120 μl of DMSO (4 mM) and 1 μl was added to an assay plate. These were then serially diluted 1 :3 (50 μl to 100 μl DMSO) for a total of 8 points. Plates were prepared such that each kinase reaction is 20 μl in Ix kinase buffer (50 mM HEPES, pH 7.2, 5 mM MgCl2, 5 mM MnCl2, 0.01% NP-40, 0.2% DSA), 5% DMSO and 10 μM ATP. Substrate was 100 nM biotin-(E4Y)3 (Open Source Biotech, Inc.). C-kit kinase was at 0.1 ng per sample. After incubation of the kinase reaction for 1 hour at room temperature, 5 μl of donor beads (Streptavidin coated beads (Perkin Elmer Life Science) final concentration 1 μg/ml) in stop buffer (5OmM EDTA in Ix kinase buffer) was added, the sample was mixed and incubated for 20 minutes at room temperature before adding 5 μl of acceptor beads (PY20 coated beads (Perkin Elmer Life Science) final concentration 1 μg/ml) in stop buffer. The samples were incubated for 60 minutes at room temperature and the signal per well was read on AlphaQuest reader. Phosphorylated substrate results in binding of the PY20 antibody and association of the donor and acceptor beads such that signal correlates with kinase activity. The signal vs. compound concentration was used to determine the IC50.
[0596] Compounds were also tested using a similar assay with a 10-fold higher ATP concentration. For these samples, compounds to be tested were dissolved in DMSO to a concentration of 20 mM. These were diluted 30 μl into 120 μl of DMSO (4 mM) and 1 μl was added to an assay plate. These were then serially diluted 1 :3 (50 μl to 100 μl DMSO) for a total of 8 points. Plates were prepared such that each kinase reaction is 20 μl in I x kinase buffer (25 mM HEPES, pH 7.5, 2 mM MgCl2, 2 mM MnCl2, 0.01 % Tween-20, 1 mM DTT, and 0.001% BSA), 5% DMSO and 100 μM ATP. Substrate was 30 nM biotin-(E4Y)10 (Upstate Biotech, Cat# 12- 440). C-kit kinase was at 1 ng per sample. After incubation of the kinase reaction for 1 hour at room temperature, 5 μl of donor beads (Streptavidin coated beads (Perkin Elmer Life Science) final concentration 10 μg/ml) in stop buffer (25 mM HEPES pH 7.5, 100 mM EDTA, 0.3% BSA) was added, the sample was mixed and incubated for 20 minutes at room temperature before adding 5 μl of acceptor beads (PY20 coated beads (Perkin Elmer Life Science) final concentration 10 μg/ml) in stop buffer. The samples were incubated for 60 minutes at room temperature and the signal per well was read on AlphaQuest or Envision reader (Perkin Elmer Life Science). Phosphorylated substrate results in binding of the PY20 antibody and association of the donor and acceptor beads such that signal correlates with kinase activity. The signal vs. compound concentration was used to determine the IC50.
[0597] The c-kit enzyme used in the above assay was either optained from Cell Signaling Technology (Cat. #7754) or was prepared as follows: A plasmid encoding kit (DNA and encoded protein sequences shown below) was engineered using common polymerase chain reaction (PCR) methods. Complementary DNA cloned from various human tissues were purchased from Invitrogen, and these were used as substrates in the PCR reactions. Specific custom synthetic oligonucleotide primers were designed to initiate the PCR product, and also to provide the appropriate restriction enzyme cleavage sites for ligation with the plasmids. The entire sequence encoding the enzyme was made through a gene synthesis procedure, using custom synthetic oligonucleotides covering the entire coding sequence (Invitrogen, see below).
[0598J The plasmid used for ligation with the kinase-encoding inserts was derivative of pET (Novagen) for expression using E. coli. The Kit kinase was engineered to include a Histidine tag for purification using metal affinity chromatography. The kinase-encoding plasmid was engineered as bicistronic mRNA to co-express a second protein that modifies the kinase protein during its expression in the host cell. Protein tyrosine phosphatase I B (PTP), was co-expressed for dephosphorylation of the phospho-Tyrosines,
[0599] For protein expression, the plasmid containing the Kit gene was transformed into E. coli strains BL21 (DE3)RIL and transformants selected for growth on LB agar plates containing appropriate antibiotics. Single colonies were grown overnight at 37°C in 200ml TB (Terrific broth) media. 16xlL of fresh TB media in 2.8L flasks were inoculated with 10ml of overnight culture and grown with constant shaking at 37°C. Once cultures reached an absorbance of 1 .0 at 600nm, IPTG was added and cultures were allowed to grow for a further 12 to 18hrs at temperatures ranging from 12-30°C. Cells were harvested by centrifugation and pellets frozen at -800C until ready for lysis.
[0600] For protein Purification; frozen E. coli cell pellets were resuspended in lysis buffer and lysed using standard mechanical methods. Protein was purified via poly-Histidine tags using immobilized metal affinity purification IMAC. The Kit kinase was purified using a 3 step purification process utilizing; IMAC, size exclusion chromatography and ion exchange chromatography. The poly-Histidine tag was removed using Thrombin (Calbiochem). [0601] Compounds were assayed using a similar assay to that described above, using in a final reaction volume of 25 μl: c-Kit (h) (5-10 mU) in 8mM MOPS pH 7.0. 0.2 mM EDTΛ, 10 niM MnCl2, 0.1 mg'ml poly (GIu, Tyr) 4:1, 10 mM MgAcetate and γ- 33P-ATP (approximately 500 cpm/pmol), with appropriate concentrations of compound. Incubated for 40 minutes at room temperature and stopped by addition of 5 μl of 3% phosphoric acid. Spotted 10 ul of each sample onto Filtermat A and washed 3x with 75 mM phosphoric acid, once with methanol, dried and measured on scintillation counter (performed at Upstate USA, Charlottesville, VA).
[0602] Compounds P-0001, P-0002, P-0003, P-0004, P-0005, P-0006, P-0007, P-0008, P-0009, P-0010, P-001 1 , P-OO 12, P-OO 13, P-OO 14, P-0015, P-OO 16, P-0017, P-0018, P-0020, P-0022, P-0024, P-0025, P-0026, P-0027, P-0028, P-0030, P-0031, P-0032, P-0033, P-0038, P-0053, P-0054, P-0055, P-0056, P-0057, P-0058, P-0059, P-0060, P-0061, P-0062, P-0063, P-0064, P-0065, P-0066, P-0069, P-0071 , P-0072, P-0073, P-0074, P-0075, P-0078, P-0082, P-0092, P-0093, P-0094, P-0095, P-0096, P-0097, P-0098, P-0099, P-0100, P-0101 , P-0102, P-0103, P-0104, P-0105, P-0107, P-0108, P-0109, P-Ol 1 1 , P-Ol 12, P-Ol 13, P-Ol 14, P-Ol 15, P-Ol 16, P-Ol 18, P-0120, P-0121 , P-0122, P-0123, P-0125, P-0126, P-0127, P-0128, P-0129, P-0131 , P-Ol 32, P-0138, P-0143, P-0144, P-Ol 45, P-0148, P-0154, P-0156, P-0157, P-0159, P-0161 , P-0163, P-0170, P-0171 , P-0173, P-0174, P-0176, P-0177, P-0179, P-0180. P-0181 , P-Ol 82, P-0186, P-Ol 87, P-0188, P-0190, P-0192, P-0193, P-0194, P-0195, P-Ol 97, P-Ol 99, P-0201 , P-0203, P-0205, P-0206, P-0208, P-021 1 , P-0212, P-0213, P-0214, P-0215, P-0216, P-0217, P-0218, P-0219, P-0221 , P-0222, P-0224, P-0225, P-0226, P-0228. P-0234, P-0237, P-0239, P-0240, P-0242, P-0243, P-0244, P-0245, P-0246, P-0252, P-0253, P-0255. P-0257, P-0258, P-0259, P-0260, P-0262, P-0263, P-0264, P-0265, P-0266, P-0267. P-0268, P-0269, P-0270, P-0271, P-0272, P-0273, P-0274, P-0275, P-0276, P-0277, P-0278. P-0279, P-0280, P-0281 , P-0282, P-0283, P-0284, P-0285, P-0286, P-0287, P-0288, P-0289, P-0290. P-0291 , P-0294, P-0297, P-0298, P-0301 , P-0302, P-0303, P-0305, P-0306, P-0307, P-0308, P-0309, P-031 1. P-0312, P-0313, P-0314, P-0316, P-0319, P-0320, P-0321, P-0322, P-0323, P-0324. P-0325, P-0326, P-0327, P-0328, P-0329, P-0330, P-0331 , P-0332, P-0334, P-0336, P-0337, P-0338, P-0339, P-0340, P-0341 , P-0342, P-0343, P-0344, P-0345, P-0346, P-0347, P-0348, P-0350. P-0351 , P-0352, P-0354, P-0355, P-0356, P-0357. P-0358, P-0359, P-0361 , P-0362, P-0363. P-0365, P-0366, P-0367, P-0368, P-0369, P-0370, P-0371 , P-0372, P-0373, P-0375, P-0376, P-0377, P-0378, P-0379, P-0382, P-0383, P-0385, P-0387, P-0390, P-0392, P-0393, P-0394, P-0395, P-0396, P-0402, P-0404, P-0406, P-0407, P-0408, P-0409, and P-0412 had IC0 of less than 1 μM in at least one of the c-kit assays described above in Examples 40 and 41.
Kit
PCR primers
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
Figure imgf000248_0001
P1332.N6 BI PTP KIT M552-K948-X COD
(Nucleic Acid SEQ ID NO:_ ) (Protein SEQ ID NO:_ ) taatacgactcactataggggaattgtgagcggataacaattcccctctagaaataattt tgtttaactttaagaaggagatataccatgggtcaccaccatcaccatcatatgtacgaa
M G H H H H H H M Y E gttcagtggaaagttgttgaagaaatcaacggtaacaactacgtttacatcgacccgacc
V Q W K V V E E I N G N N Y V Y I D P T cagctgccgtacgaccacaaatgggagttcccgcgtaaccgtctgtctttcggtaaaacc
Q L P Y D H K W E F P R N R L S F G K T ctgggtgcgggtgcgttcggtaaagttgttgaagcgaccgcgtacggtctgatcaaatct
L G A G A F G K V V E A T A Y G L I K S gacgcggcgatgaccgttgcggttaaaatgctgaaaccgtctgcgcacctgaccgaacgt
D A A M T V A V K M L K P S A H L T E R gaagcgctgatgtctgaactgaaagttctgtcttacctgggtaaccacatgaacatcgtt
E A L M S E L K V L S Y L G N H M N I V aacctgctgggtgcgtgcaccatcggtggtccgaccctggttatcaccgaatactgctgc
N L L G A C T I G G P T L V I T E Y C C tacggtgacctgctgaacttcctgcgtcgtaaacgtgactctttcatctgctctaaacag
Y G D L L N F L R R K R D S F I C S K Q gaagaccacgcggaagcggcgctgtacaaaaacctgctgcactctaaagaatcttcttgc
E D H A E A A L Y K N L L H S K E S S C tctgactctaccaacgaatacatggacatgaaaccgggtgtttcttacgttgttccgacc
S D S T N E Y M D M K P G V S Y V V P T aaagcggacaaacgtcgttctgttcgtatcggttcttacatcgaacgtgacgttaccccg
K A D K R R S V R I G S Y I E R D V T P gcgatcatggaagacgacgaactggcgctggacctggaagacctgctgtctttctcttac
A I M E D D E L A L D L E D L L S F S Y caggttgcgaaaggtatggcgttcctggcgtctaaaaactgcatccaccgtgacctggcg
Q V A K G M A F L A S K N C I H R D L A gcgcgtaacatcctgctgacccacggtcgtatcaccaaaatctgcgacttcggtctggcg
A R N I L L T H G R I T K I C D F G L A cgtgacatcaaaaacgactctaactacgttgttaaaggtaacgcgcgtctgccggttaaa
R D I K N D S N Y V V K G N A R L P V K tggatggcgccggaatctatcttcaactgcgtttacaccttcgaatctgacgtttggtct
W M A P E S I F N C V Y T F E S D V W S tacggtatcttcctgtgggaactgttctctctgggttcttctccgtacccgggtatgccg
Y G I F L W E L F S L G S S P Y P G M P gttgactctaaattctacaaaatgatcaaagaaggtttccgtatgctgtctccggaacac
V D S K F Y K M I K E G F R M L S P E H gcgccggcggaaatgtacgacatcatgaaaacctgctgggacgcggacccgctgaaacgt
A P A E M Y D I M K T C W D A D P L K R ccgaccttcaaacagatcgttcagctgatcgaaaaacagatctctgaatctaccaaccac
P T F K Q I V Q L I E K Q I S E S T N H atctactctaacctggcgaactgctctccgaaccgtcagaaatagtcgactgaaaaagga
I Y S N L A N C S P N R Q K - agagt
Additional biochemical and cell-based assays
[0603] In general, any protein kinase assay can be adapted for use with c-kit. For example, assays (e.g. biochemical and cell-based assays) as described in Lipson et al., U.S. Patent Publ, 20040002534 (incorporated herein by reference in its entirety) can be used in the present invention, In vivo model system testing
[0604] For in vivo testing, a suitable animal model system can be selected for use. For example, for multiple seerosis, the rodent experimental allergic encephalomyelitis (EAE) is commently used. This system is well-known, and is described, for example, in Steinman, 1996, Cell 85:299- 302 and Secor et al.. 2000, J Exp. Med 5 :813-821 , which are incorporated herein by reference in their entireties,
[0605] Similarly, other model systems can be selected and used in the present invention.
Exemplary Fms biochemical assay
[0606] IC50 values were determined with respect to inhibition of Fms kinase activity, where inhibition of phosphorylation of a peptide substrate is measured as a function of compound concentration. Compounds to be tested, dissolved in DMSO (1 μL), were added to a white 384- well plate (Costar #3705). Working stocks of Fms kinase (Upstate Biotech, #14-551 ), biotin- (E4Y)io substrate (Upstate Biotech, Cat# 12-440), and ATP (Sigma, Cat#Λ-3377) were prepared in 8 mM MOPS pH 7.4, 2 mM MgCl2, 8 mM MnCl,, 2 mM DTT, and 0.01 % Twcen-20. All components were added to the 384-well plate for a final concentration of 0.5 ngΛvell Fms, 30 nM biotin-(E4Y)io (Upstate Biotechnology) and 10 μM ATP in a volume of 20 μL. Each sample was at 5% DMSO. The plate was then incubated for 60 minutes at room temperature. Just before use, working stocks of donor and acceptor beads from the AlphaScreen PY20 Detection Kit (PerkinElmer, Cat#676601 M) were prepared in 8 mM MOPS, pH 7.4, 100 mM EDTA, 0.3% BSA. To stop the reaction, the plate was uncovered in the dark and 5 μl of Donor Beads solution (Streptavidin beads) was added to each well. The plate was incubated at room temperature for 20 minutes. Five microliters of Acceptor Beads solution (PY20 coated beads) were then added to each well. The final concentration of each bead was 20 μg/mL. The plates were incubated at room temperature for 60 minutes. Fluorescence signal was recorded on the Fusion Alpha reader or AlphaQucst reader. Phosphorylated substrate results in binding of the PY20 antibody and association of the donor and acceptor beads such that signal correlates with kinase activity. The signal vs. compound concentration was used to determine the IC50.
[0607] Compounds were also tested using a similar assay with a 10-fold higher ATP concentration. Compounds to be tested, dissolved in DMSO ( 1 μL), were added to a white 384- well plate (Costar #3705). Working stocks of Fms kinase (Upstate Biotech, #14-551 ), biotin- (E4Y),o substrate (Upstate Biotech, Cat# 12-440), and ATP (Sigma, Cat#A-3377) were prepared in 25 mM HEPES pH 7.5, 0.5 mM MgCl2, 2 mM MnCl2 2 mM DTT, 0.01 % RSA, and 0.01 % Tween- 20. All components were added to the 384-well plate for a final concentration of 0.5 ng/wcll Fms,
30 nM biotin-(E4Y)]0 (Upstate Biotechnology) and 100 μM ATP in a volume of 20 μL. Each sample was at 5% DMSO, The plate was then incubated for 30 minutes at room temperature. Just before use, working stocks of donor and acceptor beads from the AlphaScrecn PY20 Detection Kit (PerkinElmer, Cat#676601M) were prepared in 25 mM HEPES pH 7.5, 100 rriM EDTA, 0.01 % BSA. To stop the reaction, the plate was uncovered in the dark and 5 μl of Donor Beads solution (Strcptavidin beads) was added to each well. The plate was incubated at room temperature for 20 minutes. Five microliters of Acceptor Beads solution (PY20 coated beads) were then added to each well. The final concentration of each bead was 10 μg/mL. The plates were incubated at room temperature for 60 minutes. Fluorescence signal was recorded on the AlphaQuest or Envision reader. Phosphorylated substrate results in binding of the PY20 antibody and association of the donor and acceptor beads such that signal correlates with kinase activity. The signal vs. compound concentration was used to determine the IC50.
[0608] Compounds were assayed using a similar assay to that described above, using in a final reaction volume of 25 μl: Fms (h) (5-10 mil) in 8mM MOPS pH 7.0, 0.2 mM EDTA, 250 mM
KKKSPGEYVNIEFG (SEQ ID NO: ), 10 mM MgAcetate and γ- 33P-ATP (approximately 500 cpm/pmol), with appropriate concentrations of compound. Samples were incubated for 40 minutes at room temperature and stopped by addition of 5 μl of 3% phosphoric acid. 10 μl of each sample is spotted onto a P30 filtermat and washed 3x with 75 mM phosphoric acid, once with methanol, dried and measured on scintillation counter (Upstate USA, Charlottesville, VA).
[0609] Compounds P-OOOl , P-0002, P-0003, P-0004, P-0005, P-0006, P-0007, P-0008, P-0009, P-0010, P-001 1 , P-0013, P-0014, P-0015, P-OOl 6, P-0028, P-0032, P-0033, P-0038, P-0053, P-0054, P-0055, P-0056, P-0057, P-0058, P-0059, P-0060, P-0061, P-0062, P-0063, P-0064, P-0065, P-0066, P-0069, P-0072, P-0073, P-0074, P-0075, P-0076, P-0078, P-0081 , P-0082, P-0092, P-0093, P-0094, P-0095, P-0096, P-0097, P-0098, P-0099, P-0100, P-0101 , P-0102, P-0103, P-0104, P-0105, P-0106, P-0107, P-0108, P-0109, P-OU O, P-01 1 1 , P-01 12, P-01 13, P-O l 14, P-Ol 15, P-O l 16, P-Ol H, P-O l 18, P-Ol 19, P-0120, P-0121, P-0122, P-0123, P-0125, P-0126, P-0127, P-0128, P-0129, P-0130, P-0131, P-0132, P-0134, P-0135, P-0136, P-0137, P-0140, P-0141, P-0142, P-0143, P-0144, P-0145, P-0146, P-0147, P-0148, P-0149, P-0150, P-015 K P-0152, P-0153, P-0154. P-0156, P-0157, P-0158, P-0159, P-0160, P-0161 , P-0163, P-0164, P-0165, P-0167, P-0168, P-0169, P-0170, P-0171, P-0172, P-0173, P-0174, P-0175, P-0176, P-0179, P-0180, P-Ol Sl , P-0182, P-0183, P-0185, P-0186, P-01 87, P-0188, P-0189. P-0190, P-0191 , P-01 92, P-0193, P-Ol 94, P-Ol 95, P-0196, P-0197, P-01 98, P-0199, P-0200, P-0201, P-0202, P-0203, P-0204, P-0205, P-0206, P-0207, P-0208, P-0209, P-0210. P-021 1 , P-0212, P-0213, P-0214, P-0215, P-0216, P-0217, P-0218. P-0219, P-0220, P-0221 , P-0222, P-0223, P-0224, P-0225, P-0226, P-0227, P-0228, P-0229, P-0230, P-0231 , P-0232, P-0233, P-0234, P-0235. P-0236, P-0237, P-0238, P-0239, P-0240, P-0241 , P-0242, P-0243, P-0244, P-0245, P-0246, P-0247. P-0248, P-0249, P-0250, P-0251, P-0252, P-0253, P-0254, P-0255, P-0256, P-0257, P-0258, P-0259. P-0260, P-0261 , P-0262, P-0263, P-0264, P-0265, P-0266. P-0267, P-0268, P-0269, P-0270, P-0271 , P-0272, P-0273, P-0274, P-0275, P-0276, P-0277, P-0278. P-0279, P-0280, P-0281 , P-0282, P-0283, P-0284, P-0285, P-0286. P-0287, P -0288, P-0289, P-0290, P-0291 , P-0292, P-0293, P-0294, P-0295, P-0296, P-0297, P-0298, P-0299, P-0300, P-0301, P-0302, P-0303, P-0304, P-0305, P-0306, P-0307, P-0308, P-0309, P-0310, P-031 1 , P-0312, P-0313. P-0314, P-0315, P-0316, P-0317, P-0318, P-0319, P-0320, P-0321 , P-0322, P-0323, P-0324, P-0325, P-0326, P-0327, P-0328, P-0329, P-0330, P-0331, P-0332, P-0333, P-0334, P-0335, P-0336, P-0337, P-0338. P-0339, P-0340, P-0341 , P-0342, P-0343, P-0344, P-0345, P-0346, P-0347, P-0348, P-0349, P-0350, P-0351 , P-0352, P-0353, P-0354, P-0355, P-0356, P-0357, P-0358, P-0359, P-0360, P-0361, P-0362, P-0363, P-0364, P-0365. P-0366, P-0367, P-0368, P-0369, P-0370, P-0371 , P-0372, P-0373, P-0374, P-0375, P-0376, P-0377, P-0378, P-0379, P-0380, P-0381 , P-0382, P-0383, P-0384, P-0385, P-0386, P-0387, P-0390, P-0391 , P-0392, P-0393, P-0394, P-0395, P-0396, P-0402, P-0403, P-0404, P-0405, P-0406, P-0407, P-0408, P-0409, and P-0412 had IC50 of less than 1 μM in at least one of the Fms assays described above in Examples 40 or 41.
Exemplary TrkA biochemical assay
[0610] Compounds were similarly assayed to determine ICW values with respect to inhibition of TrkA kinase activity, where inhibition of phosphorylation of a peptide substrate was measured as a function of compound concentration. Compounds tested were dissolved in DMSO (1 μL) and added to a white 384-wcll plate (Costar #3705). Working stocks of TrkA kinase (Upstate Biotech, #14-571), biotin-(E4Y)10 substrate (Upstate Biotech, Cat# 12-440), and ATP (Sigma, Cat#Λ-3377) were prepared in 25 niM Hepes pH 7.5, 10 mM MnCl2. 1 mM DTT, and 0.01 % Tween-20. All components were added to the 384-well plate for a final concentration of 1 ng/well TrkA, 30 nM biotin-(E4Y)io (Upstate Biotechnology) and 100 μM ATP in a volume of 20 μL. Each sample was at 5% DMSO. The plate was then incubated for 40 minutes at room temperature. Just before use. working stocks of donor and acceptor beads from the AlphaScreen PY20 Detection Kit (PerkinElmer, Cat#676601M) were prepared in 25 mM Hepes pH 7.5, 100 mM EDTA, 0,3% BSA. To stop the reaction, the plate was uncovered in the dark and 5 μl of Donor Beads solution (Streptavidin beads) was added to each well. The plate was incubated at room temperature for 20 minutes. Five microliters of Acceptor Beads solution (PY20 coated beads) were then added to each well. The final concentration of each bead was 10 μg/mL. The plates were incubated at room temperature for 60 minutes. Fluorescence signal was recorded on the AlphaQuest or Envision reader. Phosphorylated substrate results in binding of the PY20 antibody and association of the donor and acceptor beads such that signal correlates with kinase activity. The signal vs. compound concentration was used to determine the IC ^Q Compounds P-0157. P-0171 , P-0179, P-0180. P-0303, and P-0412 had IC50 of less than 1 μM m this TrkA assay
Exemplary HGK biochemical assay
[0611] The MAP4K4 (or kinase domain thereof) is an active kinase in AlphaScreen ICs^ values are determined with respect to inhibition of MΛP4K4 kinase activity, where inhibition of phosphorylation of a peptide substrate is measured as a function of compound concentration Compounds to be tested were dissolved in DMSO to a concentration of 20 mJVl 1 hese were diluted 30 μl into 120 μl of DMSO (4 mM) and 1 μl was added to an assay plate These were then serially diluted 1 3 (50 μl to 100 μl DMSO) for a total of 8 points Plates were prepared such that each kinase reaction is 20 μl in I x kinase buffer (20 mM Ins, pH 7 4, 10 mM MgCl2, ImM DTT 0 01 % Tween-20), 5% DMSO and 10 μM ATP Substrate was 10 nM biotin-ERM (T567/T564/T558, Cell Signaling, Inc , cat#1344) MAP4K4 kinase was at 0 5 ng per sample After incubation of the kinase reaction for 40mm at room temperature, 5 μl of donor beads and protein A acceptor beads (Perkin Elmer Life Science, cat# 67606017) at final concentration 1 μg/ml m stop buffer (20 mM Tπs, pH 7 4,20OmM Nacl, 10OmM EDTA ,0 03% BSA) was added, along with Phospho-FRM Antibody (T567/T564/T558, Cell Signaling, Inc , cat#3141 ) at 1 1000 dilution The samples were incubated for 2 hours at room temperature and the signal per well was read on AlphaQuest reader Phosphorylated substrate results m binding of the antibody which binds to protein A acceptor bead and association of the donor and acceptor beads is such that the signal correlates with kinase activity The signal vs compound concentration was used to determine the IC0 Compounds P-0156. P-0177, P-0179, P-0195, P-0201 , P-0203, P-0206, P-0207, P-0231, P-0240. P-0241, P-0255, P-0324, P-0341 , and P-0403 had IC,0 of less than 1 μM in this HGK assay
Evample 42: Site-directed Mutagenesis of c-Kit, c-Fms and other Kinases
[0612] Mutagenesis of c-kit and other kinases (as well as other sequences of mteiest) can be carried out according to the following procedure as described m Molecular Biology Current Innovations and Future Trends Eds A M Griffin and H G Griffin (1995) ISBN 1 -898486-01 -8 Horizon Scientific Press, PO Box 1 , Wymondham, Norfolk, U K among others
(0613] In vitro site-directed mutagenesis is an invaluable technique for studying protein structure-function relationships, gene expression and vector modification Several methods hav e appeared in the literature but many of these methods require smgle-stranded DNA as the template I he reason for this, historically, has been the need for separating the complementary strands to prevent reanneahng Use of PCR in site-directed mutagenesis accomplishes strand separation by using a denaturing step to separate the complementing strands and allowing efficient polymerization of the PCR primers. PCR sitc-dircctcd methods thus allow site-specific mutations to be incorporated in virtually any double-stranded plasmid; eliminating the need for M13-bascd vectors or single-stranded rescue.
[0614] It is often desirable to reduce the number of cycles during PCR when performing PCR- based site-directed mutagenesis to prevent clonal expansion of any (undesired) second-site mutations. Limited cycling which would result in reduced product yield, is offset by increasing the starling template concentration. A selection is used to reduce the number of parental molecules coming through the reaction. Also, in order to use a single PCR primer set, it is desirable to optimize the long PCR method. Further, because of the extendase activity of some thermostable polymerases it is often necessary to incorporate an end-polishing step into the procedure prior to end-to-end ligation of the PCR-generated product containing the incorporated mutations in one or both PCR primers.
[0615] The following protocol provides a facile method for site-directed mutagenesis and accomplishes the above desired features by the incorporation of the following steps: (i) increasing template concentration approximately 1000-fold over conventional PCR conditions; (ii) reducing the number of cycles from 25-30 to 5-10; (iii) adding the restriction endonuclease DpnJ (recognition target sequence: 5-Gm6ATC-3, where the A residue is methylated) to select against parental DNA (note: DNA isolated from almost all common strains ol' E. coli is Dam-methylated at the sequence 5-GATC-3); (iv) using Taq Extender in the PCR mix for increased reliability for PCR to 10 kb; (v) using Pfu DNA polymerase to polish the ends of the PCR product, and (vi) efficient intramolecular ligation in the presence of T4 DNA ligase.
[0616] Plasmid template DNA (approximately 0.5 pmole) is added to a PCR cocktail containing, in 25 ul of Ix mutagenesis buffer: (20 mM Tris HCl, pll 7.5; 8 mM MgC12; 40 ug/ml BSA); 12-20 pmolc of each primer (one of which must contain a 5-prime phosphate), 250 uM each dNTP, 2.5 U Taq DNA polymerase, 2.5 U of Taq Extender (Stratagene).
|0617] The PCR cycling parameters are 1 cycle of: 4 min at 94 C, 2 min at 50 C and 2 miπ at 72°C; followed by 5-10 cycles of 1 min at 940C, 2 min at 54 C and 1 min at 72°C (step 1).
[0618] The parental template DNA and the linear, mutagenesis-primer incorporating newly synthesized DNA are treated with Dpnl (10 U) and Pfu DNA polymerase (2.5U). This results in the Dpnl digestion of the in vivo methylated parental template and hybrid DNA and the removal, by Pfu DNA polymerase, of the Taq DNA polymerase-extended base(s) on the linear PCR product. [06191 The reaction is incubated at 37°C for 30 mm and then transferred to 72°C for an additional 30 min (step 2).
[0620] Mutagenesis buffer (I x, 1 15 ul. containing 0.5 niM ATP) is added to the DpnI-digested, Pfu DNA polymerasc-polished PCR products,
[0621] The solution is mixed and 10 ul is removed to a new microfuge tube and T4 DNA ligase (2-4 U) added,
[0622] The ligation is incubated for greater than 60 min at 37°C (step 3).
[0623] The treated solution is transformed into competent E. coli (step 4).
[0624] In addition to the PCR-based site-directed mutagenesis described above, other methods are available. Examples include those described in Kunkel (1985) Proc. Natl. Acad. Sci. 82:488- 492; Eckstein et al. (1985) Nucl. Acids Res. 13:8764-8785; and using the GeneEditor™ Site- Directed Mutagenesis System from Promega.
Example 43 Synthesis of 3,5-DimethyI-4-(lII-pyrrolo[2,3-blpyridin-3-ylmethyl)-pyrazole- 1-carboxylic acid bcnzylamide P-0084
[0625] 3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>τazole-l -carboxylic acid benzylamide P-0084 was synthesized in 6 steps from dimethyl-(lH-pyrrolo[2,3-b]pyridin-3- ylmethyl)-aminc 2 as shown in Scheme 158.
Scheme - 158
Figure imgf000255_0001
Step 1: Preparation of 3-Dimethylaminomethyl-pyrrolo [2, 3-b] pyridine- 1 -carboxγhc acid ten- butvl ester (511) [0626] To dimethyl-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-ainiiie (2, 2.50 g, 14.3 mmol, prepared as described in Example 2, Scheme 4, Step 1) in tetrahydrofuran (200.0 mL) was added sodium hydride (0.685 g, 60% in mineral oil, 17.1 mmol). After 10 minutes, άi-tert- butyldicarbonate (3.74 g, 17.1 mmol) was added to the reaction. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give as a white solid (511, 3.80 g. 96.7%).
Step 2: Preparation of 3-Chloromethyl-pyrrolo[2,3-b]pyridine- 1 -carboxylic acid tert-butyl ester (512)
[0627] To 3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-l -carboxylic acid tert-butyl ester (511, 2.60 g, 9.44 mmol) in toluene (50.00 mL) was added isopropyl chloroformate (1 1 3 mL, 1.0 M in toluene) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (512, 2.0 g, 79.4%).
Step 3 - Preparation of ' 3-(2-Acetyl-3-oxo-butyl)-pyrrolo [2, 3-b] pyridine- 1 -carboxylic acid tert- butyl ester (513):
[0628] To acetylacetone (0.563 g, 5.62 mmol) in dimethyl sulfoxide (29.0 mL) was added sodium hydride (0.225 g, 60% in mineral oil, 5.62 mmol). After 20 minutes, 3-chloromethyl- pyrrolo[2,3-b]pyridine-l -carboxylic acid tert-butyl ester (512, 1.00 g, 3.75 mmol) was added to the reaction. The reaction was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give a colorless oil (513. 0.59 g, 48.0%). MS (ESI) [M+H+]+ = 331.4.
Step 4 — Preparation of 3-(3,5-Dimethyl-IJI-pyrazol-4-ylmethyl)-pyrrolo[2,3-h]pyridine-l- carboxylic acid tert-butyl ester (514)
[0629] To 3-(2-acetyl-3-oxo-butyl)-pyrrolo[2,3-b]pyridine-l -carboxylic acid tert-butyl ester (513, 1.20 g, 3.63 mmol) in methanol (15.0 mL), cooled to -20 0C under an atmosphere of nitrogen, was added hydrazine (0.128 g, 4.00 mmol) in dichloromethane (6.0 mL). The reaction was stirred for 2 hours. The reaction was concentrated to remove the solvents, and the residue was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 60% ethyl acetate in hcxanc to give a white solid (514, 1 ,0 g, 84,4%). MS (ESI) [M+H']"= 327.4.
Step 5 - Preparation of3-(!-Benzylcarbamoyl-3,5-dimethyl-lH-pyrazol-4-ylmethyl)-pyrrolo[2,3- h] pyridine- 1 -carhoxylic acid tert-hutyl ester (515)
[0630] To 3-(3,5-dimethyl-lH-pyrazol-4-ylmethyl)-p>τrolo[2,3-b]pyτidine-l-carboxylic acid tert-butyl ester (514, 60.0 mg, 0.18 mmol) in dichloromethane (6.0 mL) were added 1 ,8- diazabicyclo[5.4,0]undec-7-ene (0.033 mL, 0.220 mmol) and benzyl isocyanate (29.4 mg, 0.220 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give crude compound (515, approx. 50 mg) that was used in the next step directly. MS (ESI) [M+H+f = 460.5.
Step 6 - 3,5-Dιmethyl-4-(lH-pyrrolo[2,3-h]pyridin-3-ylmethyl)-pyra∑ole-l-carhoxylic acid benzylamide (P-0084)
[0631] To 3-(l -benzylcarbamoyl-3,5-dimethyl-l H-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine- 1 -carboxylic acid tert-butyl ester (515, 50.0 mg, 0.1 1 mmol) in dichloromethane (6.0 mL) was added trifluoroacctic acid (0.20 mL, 2.6 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 20 minutes. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give a white solid (P-0084, 1 1.0 mg, 28.1 %). MS (ESI) [M+HY = 360.5.
[0632] 3-(3,5-Dimethyl-lH-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridme P-0l24
Figure imgf000257_0001
was prepared from 3-(3,5-Dimethyl-lH-pyrazol-4-ylmethyl)-pyrrolo[2,3-b]pyridine-l -carboxylic acid tert-butyl ester (514, 15.0 mg, 0.046 mmol) by dissolving in dichloromethane (10.0 mL) to which trifluoroacetic acid (0.10 mL, 1.3 mmol) was added. The reaction was stirred at room temperature for 1 hour, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate in hexane to give an off-white solid (P-0124, 7.5 mg,
72.0%). MS (ESI) [M+H+]* = 227.3. [0633| Additional compounds were prepared following the protocol of Scheme 158, replacing benzyl isocyanate with an appropriate electrophile in Step 5. The following compounds were made following this procedure:
3,5-Dimethyl-4-(lH-pyrrolo[2.3-bJpyridin-3-ylmethyl)-pyrazole-l -carboxylic acid phenylamide (P-0085),
[3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazol- l ->'l]-phenyl-methanone
(P-0086), l-f3,5-Dimethyl-4-(lH-pyrrolo[2.3-b]pyridin-3-ylmcthyl)-pyτazol-l -yl]-3-phenyl-propan- l-one (P-0087),
3-(3,5-Dimethyl-l-phenylmethanesulfonyl-lH-pyrazol-4-ylmethyl)-lH-pyrrolof2,3- bjpyridme (P-0088),
3-[l-(Butane-l-sulfonyl)-3,5-dimethyl-lH-pyrazol-4-ylmcthylJ-l H-pyiTolof2,3-b]pyridine
(P-0089),
3,5-Dimethyl-4-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid butylamide (P-0090), and
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid phenethyl-amide (P-0091).
[0634] The electrophile used in place of benzyl isocyanate in Step 5 is indicated in Column 2 of the following table, with the compound structure given in Column 3. Column 1 provides the compound number and Column 4 the experimental mass spectrometry result.
Figure imgf000258_0001
Figure imgf000259_0001
[0635] Additional compounds were prepared following the protocol of Scheme 158, replacing dimethyl-(lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-amine 2 with (5-chloro-lII-pyrrolo[2,3- b]pyridin-3-ylmethyl)-dimethyl-aminc (prepared as described in Example 107, Scheme 164, isolated after step 1 ) in Step 1 and replacing benzyl isocyanate with an appropriate electrophile in Step 5. The following compounds were made following this procedure:
4-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazolc-l -carboxylic acid [2-(4-fluoro-phenyl)-ethyl]-amide (P-0157),
4-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-yimethyl)-3,5-dimethyl-pyrazole-l-carboxylic acid 4-fluoro-benzylamide (P-0158),
4-(5-Chloro-l H-pyπOlo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-l-carboxylic acid 4-chloro-bcnzylamide (P-0159), and
4-(5-Chloro-lH-pyrrolo[2,3-b]pjτidin-3-ylmethyl)-3,5-dimethyl-pyrazole-l-carboxylic acid [(S)-l-(4-fluoro-phenyl)-ethyl]-amide (P-0160).
[0636] The electrophile used in place of benzyl isocyanate in Step 5 is indicated m Column 2 of the following table, with the compound structure given in Column 3. Column 1 provides the compound number and Column 4 the experimental mass spectrometry result.
Figure imgf000260_0001
Example 44 Synthesis of [4-chloro-5-(1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yll- pyridin-4-ylmethyl-aniine P-Ol 68
[0637] μ-Chloro-S-ClH-pyrrolop^-blpyridin-S-ylmethyO-thiazol^-yll-pyridin^-ylmethyl- amine P-0168 was synthesized in 5 steps as shown in Scheme 159.
Scheme 159
Figure imgf000260_0002
Step 1 - Preparation of4-chloro-2-[(pyridin-4-ylmethyl)-amino]-thiazole-5-carbaldehyde (517), [0638] To a solution of 4-(aminomethyl)pyridine (516. 1.16 mL. 1 1 ,5 mmol) and N,N- diisopropylethylamine (3.8 mL. 22 mmol) in tetrahydrofuran (50 mL) was added 2.4-dichloro- thiazole-5-carbaldehyde (93, 2.0 g, 1 1 ,0 mmol) in tetrahydrofuran (5 mL) at room temperature. The reaction mixture was stirred at roam temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. The crude compound 4-chloro-2-[(pyridin-4~ylmethyl)-amino]-thiazole-5-carbaldehyde (517) was used for the next step without purification,
Step 2 - Preparation of(4-chloro-5-fυrmyl-thiazol-2-yl)-pyridin-4-ylmethyl-carbamic acid tert- butyl ester (518):
[0639| A mixture of 4-chloro-2-[(pyridin-4-ylmethyl)-amino]-thiazole-5-carbaldehyde (517, 3.28 g, 1 1.0 mmol), di-tert-butyldicarbonate (4.0 g, 18 mol) and triethylamine (10 mL, 74 mmol) in dichloromethane (120 mL) was stirred at room temperature for 6 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid (518, 564 mg, 15%). MS (ESI) [M MIT= 354.1.
Step 3 - Preparation of {4-chloro-5-[hydroxy-(l-triisopropylsdanyl-lH-pyrrolo[2,3-b]pyridin-3- yl)-methyl]-thiazol-2-yl}-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (519) ' [0640] To a solution of 3-iodo-l -triisopropylsilanyl-l H-pyrrolo[2,3-b]pyridine (96, 0.44 g, 1.1 mmol) in tetrahydrofuran (20 mL) at -20 0C, isopropylmagnesium chloride (2 M in tetrahydrofuran, 0.6 mL, 1.2 mmol) was added dropwise. The reaction mixture was allowed to warm to 0 0C in 10 minutes. The reaction mixture was then cooled to -40 0C A solution of (4- chloro-5-foπnyl-thiazol-2-yl)-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (518, 0.26 g, 0.73 mmol) in tetrahydrofuran (4 mL) was added to the reaction mixture. The reaction mixture was allowed to warm to -10 0C over 30 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid (519, 397 mg, 86%). MS (ESI) [M+HT - 628.3.
Step 4 — Preparation of[4-chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmelhyl)-thiuzυl-2-yl]-pyridin- 4-ylmethyl-carbamic acid tert-butyl ester (520):
[0641] A mixture of {4-chloro-5-[hydroxy-(l -triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridin-3- yl)-methyl]-thia2ol-2-yl}-pyridin-4-ylmethyl-carbamic acid tert-butyl ester (519, 0.397 g, 0.57 mmol), triethylsilane (1.0 niL, 6.3 mmol), and trifluoroacetic acid (0.5 mL, 6 mmol) in acetonitrile (10 mL) was stirred at 40 0C for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with sodium bicarbonate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chiomatography eluting with methanol in dichloromethane to provide the desired compound as a yellow solid (520, 126 mg. 49%). MS (ESI) [MfH"]f = 456.2.
Step 5 Preparation of[4-chloro-5-(lH-pyrrolo[2,3-h]pyridin-3-yhnethyU-ihiazol-2-ylJ-pyridin- 4-ylmethyl -amine (P-Ol 68):
[0642] To a solution of [4-chloro-5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]- pyridin-4-ylmethyl-carbamic acid tert-butyl ester (520, 126 mg, 0.000276 mol) in dichloromethane (2 mL) was added hydrogen chloride (4 M in 1,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into cold sodium bicarbonate solution, extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. After removal of solvents, the residue was washed with ethyl acetate to provide the desired compound as a light yellow solid (P-0168, 68.4 mg, 70%). MS (ESI) [M+H+]* = 356.2.
[0643] Additional compounds were prepared following the protocol of Scheme 159, replacing 4-(aminomethyl)pyridine 516 with an appropriate amine. The following compounds were made following this procedure:
[4-Chloro-5-(l H-pyrrolo[2,3-6]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl-amine
(P-0164),
[4-ChIoro-5-(l H-pyrrolo[2,3-^]pyridin-3-yImethyl)-thiazoI-2-yl]-pyridin-2-ylmethyl-amine
(P-0167),
[4-Chloro-5-(l H-pyrrolo[2,3-έ]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2- ylmethyl)-amine (P-Ol 71),
[4-Chloro-5-(lH-pyrrolo[2,3-6]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl-p>τidin-3- ylmethyl)-amine (P-Ol 73),
[4-Chloro-5-(l H-pyrrolo[2,3-/7]pyridin-3-ylmethyl)-thiazol-2-yl]-(l ,5-dimethyl-l H-pyrazol-3- ylmethyl)-amine (P-Ol 72),
[4-Chloro-5-(lH-pyrrolo[2,3-/?]pyridm-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-2H-pyrazol-3- ylmethyl) -amine (P-0175), and t4-Chloro-5-(lH-pyrrolot2,3-ό]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-ben2yl)-amine (P-
0156).
The following table indicates the amine (Column 2) used in Scheme 159 to provide the compounds (Column 3). Column 1 provides the compound number and Column 4 the observed mass.
Figure imgf000263_0001
Example 45 Synthesis of [4-ethyl-5-(lH-pyrroloI2,3-blpyridin-3-ylmethyI)-thiazol-2-yl]-(4- fluoro-benzyl)-amine P-0162 and (4-fluoro-beπzyl)-[4-methyl-5-(lH-pyrrolo[2,3-b]pyridin-3- ylmethyl)-thiazol-2-yl]-amine P-0162
10644] L4-Ethyl-5-(lH-pytTolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine P-0162 was synthesized in 1 step from [4-chloro-5-(lH-pyrrolo[2, 3-b] pyridin-3-ylmethyl)- thiazol-2-yl]-(4-fluoro-benzyl)-amine P-0156 as shown in Scheme 160
Scheme 160
Figure imgf000263_0002
Step I - Preparation of[4-ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro- benzyl)-amine (P-OJ 62):
[0645] Into a round bottom flask, under an atmosphere of nitrogen, [l , l '-bis(diphenyl phosphmo) ferrocene] dichloro palladium (II), complex with dichloro methane (1 : 1 ). was placed with toluene (15 mL, 140 mmol). [4-Chloro-5-(lH-pyrrolo[2,3-b] pyτidin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro- benzyl)-amine (P-0156,145 mg, 0.4 mmol) was added in 5 ml of toluene at room temperature. The mixture was stirred for 10 minutes. To the stirring reaction, a solution of 3.13 M ethyl magnesium bromide in ether (1.86 mL) was added dropwise at room temperature. The opaque solution was heated to 60 0C. Tetrahydrofuran (10 mL) was added to the warm solution. The mixture was heated to reflux for an additional two hours. After cooling to 0 0C, the reaction was quenched with a solution of citric acid at pH 4-5 in ice-water and stirred to room temperature. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Purification with flash chromatography, eluting with a gradient of ethyl acetate:hexanes (20: 100), gave a yellow solid that was further washed with ethyl acetate to give P- 0162 (15 mg,10%) as an off-white solid. MS (ESI) [M+H"]+ = 367.2.
10646) (4-Fluoro-benzyl)-[4-methyl-5-(lH-p yrrolo[2,3-b]p>τidin-3-ylmethyl)-thiazol-2-yl]- amine P-O ϊ 63
Figure imgf000264_0001
was prepared using the protocol of Scheme 160, substituting the 3.13 M ethyl magnesium bromide in ether solution with 1.4 M of methylmagnesium bromide in tetrahydrofuran. MS (ESI) [M+H ]+ = 353.2.
Example 46 Synthesis of (4-Chloro-benzyl)-|6-(lH-pyrrolo[2,3-b]pyridin-3-yImethyl)- pyridaziπ-3-yI]-amine P-0092
[0647] (4-Chloro-benzyl)-[6-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridazin-3-yl]-amine P- 0092 was synthesized in 3 steps as shown in Scheme 161 , Scheme 161
Figure imgf000265_0001
Step 1 - Synthesis of(6-bromo-pyridazin-3-yl)-(4-chloro-ben∑yl)-amine (522): |0648] To 6-bromo-pyridazin-3-ylamine (521, 0.85 g, 0,0049 mol) in acetonitrile (30.0 mL) were added 4-chlorobenzaldehyde (40, 0.82 g, 0.0058 mol), triethylsilane (4.0 mL, 0.025 mol) and trifluoroacetic acid (2.0 mL, 0.026 mol). The reaction was heated to reflux for 4 hours, then poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and washed with ethyl acetate to give a white solid (522, 1.0 g). MS (ESI) [M+FTf - 298.3, 300.2.
Step 2 - Preparation of3-[6-(4-chloro-benzylamino)-pyridazin-3-ylmethyl]-pyrrolo[2,3- b] pyridine- 1 -carboxy Hc acid tert-butyl ester (523):
[0649] To (6-bromo-pyridazin-3-yl)-(4-ch]oro-benzyi)-amine (522, 0.560 g, 1.88 mmol) in tetrahydrofuran (45.0 mL), under an atmosphere of nitrogen at -78 0C, was added n-butyllithium (2.50 M in hexane, 0.760 mL) slowly. After 10 minutes, l ,2-bis-(chloro-dimethyl-silanyl)-ethane (0.201 g, 0.94 mmol) in tetrahydrofuran (5.0 mL) was added to the reaction. The reaction mixture was allowed to stir at room temperature for 3 hours. The reaction was cooled to -78 0C, followed by addition of 1.70 M of tert-butyllithium in hexane (1.20 mL) slowly. The reaction was stirred for 20 minutes, followed by addition of a solution of CuCN.2LiCl (0.6 M in tetrahydrofuran, 3.00 mL) and 3-chloromethyl-pyrrolo[2,3-b]pyridine-l -carboxylic acid tert-butyl ester (512, 0.47 g, 1.8 mol) in tetrahydrofuran (10.0 mL). After 30 minutes, the reaction was allowed to warm to room temperature for 10 minutes. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was treated with trifluoroacetic acid (1.0 mL) dissolved in dichloromethane (10.0 mL) for 10 minutes. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified with silica gel column chromatography eluting with 60% ethyl acetate in hexane to give the desired compound (523, 0.10 g, 23.8%). MS (ESI) [M+HT - 450.1.
Step 3 - Preparation af(4-chloro-benzyl)-[6-(lII-pyrrolo[2,3-h]pyridin-3-ybnethyI)-pyridazin-3- ylj -amine (P-0092):
[0650] To 3-[6-(4-chloro-benzylamino)-pyridazin-3-ylmethyl]-pyrrolo[2,3-b]pyridine-l- carboxylic acid tert-butyl ester (523, 50.0 rag, 0.1 1 1 ramol) in dichloromethane (10.0 niL) was added trifluoroacetic acid (0,30 mL, 0.0039 mol). The reaction was stirred at room temperature overnight. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give an off-white solid (P- 0092, 7.3 mg, 19.0%). MS (ESI) [M+H~]+ = 350.1.
Example 47 Synthesis of [l-ethyl-5-(lH-pyrroloI2,3-b]pyridin-3-ylmethyl)-lH-pyrazol-3- yl]-(4-fhioro-benzyl)-amine P-0165
[0651 ] [l-Ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-lH-pyrazol-3-yl]-(4-fluoro-bcnzyl)- amine P-0165 was synthesized in 7 steps as shown in Scheme 162.
Scheme 162
Figure imgf000266_0001
Step 1 - Preparation of5-nitro-2H-pyrazole-3~carbo?cylic acid methyl ester (525):
[0652] To 5-nitro-2H-pyrazole-3-carboxylic acid (524, 10.0 g, 0.0637 mol) in methanol (100 0 mL) was added concentrated sulfuric acid (1.00 mL, 0.0180 mol). The reaction was stirred at room temperature overnight. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give a white solid (525, 1.5 g. 13.8%).
Step 2 - Preparation of2-ethyl-5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (526): [0653] To 5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (525, 2.50 g, 0.0146 mol) in N,N- dimethylformamide (62.5 niL) were added iodocthanc (1 ,2 mL, 0.016 mol) and potassium carbonate (4.17 g, 0.0301 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (526, 1 ,3 g, 44.7%).
Step 3 — Preparation of 5-amino-2-ethyl-2H-pyrazυle-3-carbυxylic acid methyl ester (527): [0654] To 2-efhyl-5-nitro-2II-pyrazole-3-carboxylic acid methyl ester (526, 1.30 g, 6.53 mmol) in methanol (60.0 mL) was added 20% Pd(OH)2/C (0.1 g). The reaction was stirred under an atmosphere of hydrogen overnight. The reaction was filtered and concentrated to give a light yellow solid (527, 1.0 g, 90.ό0/-
Step 4 - Preparation of2-ethyi-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carboxylic acid methyl ester (529):
[0655] To 5-amino-2-ethyI-2H-pyrazole-3-carboxylic acid methyl ester (527, 1.00 g, 5.91 mmol) in acetonitrile (27.5 mL) were added 4-fluorobenzaldehyde (528, 0.660 mL, 6.26 mmol), triethylsilane (4.77 mL, 0.0298 mol) and trifluoroacetic acid (2.38 mL, 0,0310 mol). The reaction was stirred at 80 °C for 4 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (529, 1.00 g, 61 %).
Step 5 Preparation of2-ethyl-5-(4-fluow-benzylamino)-2H-pyrazole-3-carbaldehyde (530): [0656] To 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carboxylic acid methyl ester (529, 1.00 g, 3.61 mol) in tetrahydrofuran (70.0 mL) under an atmosphere of nitrogen at room temperature, lithium tetrahydroaluminate (1.00 M of in tetrahydrofuran, 10.00 mL) was slowly added. The reaction was stirred at room temperature overnight, followed by slowly adding sodium sulfate decahydrate (15.0 g). After 2 hours, the reaction was filtered, concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a yellow oil (530, 0.16 g, 18%). MS (ESI) [M+ϊT]+ = 248.2. Step 6 - Preparation of l-ethyl-5-[methoxy-(lH-pyrrυlυ[2,3~b]pyridin-3-yl)-methyl]-lIl-pyrazol- 3-yl-(4-fluoro-benzyl)-amine (531):
[0657] To lH-Pyrrolo[2,3-b]pyridine (1, 54.0 mg, 0.46 mmol) in methanol (15.0 mL) were added 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 1 10.0 mg, 0.44 mmol) and potassium hydroxide (0.60 g, 0.01 1 mol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give a white solid (531, 0.12 g, 71.1%). MS (ESI) [M-IF]' = 378.2.
Step 7 ~~ Preparation of[l-ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-lH-pyrazol-3-v!]-(4- fluoro-benzyt)-amine (P-Ol 65):
[0658] To l -ethyl-5-[melhoxy-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-1 H-pyrazol-3-yl-(4- fluoro-benzyl)-amine (531, 0.12 g, 0.32 mmol) in acctonitrilc (I U.0 mL, 0, 191 mol) were added tricthylsilane (0.60 mL, 0.0038 mol) and trifmoroacetic acid (0.30 mL, 0.0039 mol). The reaction was stirred at 80 0C for 2 hours. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give crude compound. 1H NMR indicated that the reaction was incomplete. The crude compound was dissolved in dichloromethane ( 15.0 mL), trifluoroacetic acid (0.30 mL) and triethylsilane (0.60 mL). The reaction was stirred at 43 0C for 72 hours. The reaction was concentrated, poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexane to give an off-white solid (P-0165, 18.7 mg, 17%). MS (ESI) [M+H"]+ = 350.3.
[0659] (4-Fluoro-benzyl)-[l-methyl-5-( lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l H-pyrazol-3-yl]- amine P-0169
Figure imgf000268_0001
was prepared using the protocol of Scheme 162, substituting iodoethane with iodomethane in Step 2. MS (ESI) [M4 II T = 336.3.
1066UJ [5-(5-Chloro-lH-pyrrolo[2>3-b]pyridin-3-ylmethyl)-l -methyl-lH-pyrazol-3-yl]-(4-fluoro- benzyl)-amine P-0170
Figure imgf000269_0001
was prepared using the protocol of Scheme 162, substituting iodoethane with iodomethane in step 2 and l H-pyrrolo[2,3-b]pyridine 1 with 5-chloro-lH-pyrrolo[2,3-b]pyπdme in step 6. MS (ESI) [M+H T = 370,3
[0661] (4-Fluoro-benzyl)- { l-methyl-5-[5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyτidin- 3-ylmethyl]- lH-pyrazol-3-yl} -amine P-0180
Figure imgf000269_0002
was prepared using the protocol of Scheme 162, substituting iodoethane with iodomethane in step 2 and l H-Pyrrolo[2,3-b]pyridine 1 with 5-(l-Methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine (prepared as described in Example 1 15, Scheme 172) in step 6. MS (ESI) [M+H+]+ =- 416.2.
|0662] 3-[5-(4-Fluoru-benzylamino)-2-methyl-2H-pyrazol-3-ylmethyl]-lII-pyrrolo[2,3- b]pyridine-5-carbonitrile P-0191
Figure imgf000269_0003
was prepared using the protocol of Scheme 162, substituting l H-Pyrrolo[2,3-b]pyridine 1 with IH- Pyrrolo[2,3-b]pyridine-5-carbuniιrile in Step 6. MS (ESI) [M+H+]+ = 361.5.
Example 48 Synthesis of [4-chloro-l-ethyI-5-(lII-pyrroIoI2,3-b]pyridin-3-ylmethyI)-lH- pyrazoI-3-yIl-Il-(4-fluoro-phcnyl)-mcth-(E)-ylidene]-amine P-0166
[0663] [4-chloτO-l -ethyl-5-(lH-pytτolot2,3-b]pyridin-3-ylmethyl)-lH-pyra2θl-3-yl]-[l -(4- fluoro-phenyl)-meth-(E)-ylidene]-amine P-0166 was synthesized in 1 step as shown in Scheme 163. Scheme 163
Figure imgf000270_0001
Step 1 — Preparation of[4-chloro-l-ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylnιethyl)-lH-pyra∑ol-3- yl] -[ 1 -(4-fluoro-phenyl)-meth-(E)-ylidene] -amine (P-0166):
[0664] To [l -ethyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-lH-pyrazol-3-yl]-(4-fluoro-benzyl)- amine (P-0165, 10.1 mg, 0.0289 mmol, prepared as described in Example 105, Scheme 162) in acetonitrile (8.0 mL) was added N-chloro-succinimide (4.18 mg, 0.0318 mmol). The reaction was stirred at room temperature for 2 hours. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-0166, 1.1 mg). MS (ESI) [M+HT = 382.1.
Example 49 Synthesis of 5-chloro-3-chloromethyI-pyrroIo|2,3-b]pyridine-l-carboxylic acid tert-butyl ester
[0665] 5-chloro-3-chlororaethyl-pyrrolo[2,3-b]pyridine-l -carboxylic acid tert-butyl ester was synthesized in 3 steps as shown in Scheme 164.
Scheme 164
Figure imgf000270_0002
Step 1 - Preparation of(5-chloro-lH-pyrrolol2,3-b]pyridin-3-ylmethyl)-dimethyl-amine (533): [0666] To 5-Chloro-lH-pyrrolo[2,3-b]pyridine (532, 8.00 g, 0.0524 mol) in isopropyl alcohol (250.0 mL) were added dimethylamine hydrochloride (4.79 g, 0.0587 mol) and formaldehyde (1.77 g. 0,0589 mol). The reaction was stirred at room temperature overnight, followed by refluxing for 4 hours. The reaction was concentrated, poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound (533, 10.0 g, 91 %), that was used directly in the next step.
Step 2 and 3 -- Preparation of 5-chloro-3-chloromethyl-pyrrolo[2,3-b] pyridine- 1 -carboxylic acid tert-butyl ester (535): [0667] 5-Chloro-3-chloromethyl-pynOlo[2,3-b]pyridine- l-carboxylic acid tert-butyl ester 535 was prepared following the protocol of Scheme 158 (Example 101) steps 1 and 2, substituting dimethyl-(l H-pyττolo[2,3-b]pyridin-3-ylmethyl)-amine 2 with (5-chloro-lH-pyrrolo[2,3- b]pyπdin-3-ylmethyl)-dimethyl-amine 533 m step 1.
Example 50 Synthesis of (4-chloro-benzyl)-|5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3- ylmethyl)-6-fluoro-pyridin-2-yl]-amine P-0132
[0668] (4-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2- yl]-amine P-0132 was synthesized in 3 steps as shown in Scheme 165.
Scheme 165
Figure imgf000271_0001
Step 1 — Preparation of (4-chloro-henzvl)-(6-fluoro-pyridin-2-yl)-amine (536): [0669] To 2,6-difluoropyridinc (58, 9.85 g. 0.0856 mol) in N-methylpyrrolidinone (50.0 mL) were added p-chlorobenzylamine (61, 10.5 mL, 8.63 mmol) and N,N-diisopropylethylamine (30.0 mL. 0.172 mol). The reaction was stirred at 90 °C overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane, then washed with ethyl acetate/hexane to give a white solid (536, 1 O g, 50%).
Step 2 - Preparation of(5-hromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-anune (537): [0670] To (4-chloro-benzyl)-(6-fluoro-pyridin-2-yl)-amine (536, 1.03 g, 4.35 mmol) in acetonitrile (30.0 mL), under an atmosphere of nitrogen, N-bromosuccinimide (0.820 g, 4.61 mol) was added slowly. After 2 hours, the reaction was poured into a solution of sodium thiosulfate and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and crystallized with ethyl acetate and hcxaπe to give a white solid (537, 1.10 g, 80.1 %).
Step 3 - Preparation of(4-chlυrυ-benzyl)-[5-(5-chlaro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6~ fluoro-pyridin-2-yl] -amine (P-Ol 32):
10671] To (5-bromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-aminc (537, 2,76 g, 8.75 mol) in tetrahydrofuran (90.0 mL), under an atmosphere of nitrogen at -78 0C, n-butyllithium (2.50 M in hcxane, 3.64 mL) was added slowly. After 60 minutes, l,2-bis-(chloro-dimcthyl-silanyl)-ethane (0.942 g, 4.38 mol) in tetrahydrofuran (8.0 mL) was added to the reaction. The reaction mixture was allowed to stir at room temperature for 2 hours. The reaction was cooled to -78 0C, followed by addition of tert-butyllithium (1.70 M in hexane, 10.50 mL). The reaction was stirred for 30 minutes, followed by addition of 0.65 M of CuCN.2LiCl in tetrahydrofuran (14.0 mL). The reaction was stirred at -35 0C for 10 minutes, followed by addition of 5-chloro-3-chloromethyl- pyrrolo[2,3-b]pyridine-l -carboxylic acid tert-butyl ester (535, 1.70 g, 5,64 mol, prepared as described in Example 49, Scheme 164) in tetrahydrofuran (10.0 mL), The reaction was allowed to warm to room temperature for 1 hour and 2 N HCl (30 mL) was added to the reaction mixture, then stirred for 30 minutes. The reaction was poured into aqueous ammonia and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The Filtrate was concenlrated and purified with silica gel column chromatography eluting with 30% ethyl acetate in hexane to give the desired compound (P-0132, 0.75 g, 33.1 %). MS (ESI) [M+HT = 401.1.
Example 51 Synthesis of 5-chloro-3-(2,6-difluoro-pyridin-3-ylmethyl)-lH-pyrrolo[2,3- b]pyridiπe P-0155
[0672] 5-Chloro-3-(2,6-difluoro-pyridm-3-ylmethyl)-l H-pyrrolo[213-b]pyridine P-0155 was synthesized in 1 step as shown in Scheme 166.
Scheme 166
Figure imgf000272_0001
Step 1 — Preparation υf5-chlorυ-3-(2, 6-diflunro~pyridin-3-ylmethyl)- 1 H-pyrrolo[2, 3 -b] pyridine
(P-0155):
[0673] To 2,6-Difluoropyridine (58, 3.40 g, 0.0295 mol) in tetrahydrofuran (200.0 mL), under an atmosphere of nitrogen at -78 0C, 2.50 M of n-bulyllithium in hexane (12.0 mL) was added slowly. After 60 minutes, CuCN,2LiCl (0.75 M in tetrahydrofuran, 40,0 mL) was added to the reaction mixture. After 5 minutes, 5-chloro-3-chloromethyl-pvrτolo[2,3-b]pyridine-l-carboxylic acid tert- butyl ester (535, 4,20 g, 0.0139 mol, prepared as described in Example 49, Scheme 164) in tetrahydrofuran (20 mL) was added to the reaction. The reaction was stirred at -78 0C overnight, then poured into water and ammonia (10 mL), and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 15% ethyl acetate in hexane to give a white solid (P-0155, 300 mg, 7.7%). MS (ESI) [M-H+]" = 278.1.
Example 52 Synthesis of 3-(2,6-difluoro-pyridin-3-yImethyl)-lH-pyrrolo[2,3-b]pyridine P- 0154
[0674] 3-(2,6-difluoro-pyridin-3-ylmethyl)-lH-pyrrolo[2,3-b]pyridinc P-0154 was synthesized in 1 step as shown in Scheme 167.
Scheme 167
Figure imgf000273_0001
536 P-0154
Step 1 - Preparation of 3-(2, 6-difluoro-pyridin-3-ylmethyl)~lH-pyrrolo[2,3-b] pyridine (P-0154): [0675] To 3-(2,6-difluoro-pyridin-3-ylmethyl)-pyrrolo[2,3-b]pyridine-l -carboxylic acid tert- butyl ester (536, 0.35 g, 1.0 mmol, prepared as described in Example 49, Scheme 164, replacing 5- chloro-lH-pyrrolo[2,3-b]pyridine 532 with lH-pyrrolo[2,3-b]pyridine in step 1) in N- methylpyrrolidinone (3.00 mL) were added p-chlorobenzylamine (0.20 mL, 1.6 mmol) and N,N- diisopropylethylamine (0.30 mL, 0.0017 mol). The reaction was stirred at 50 0C for 72 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and the crude intermediate was dissolve in dichloromethane (15.0 mL) and trifluoroacetic acid (0.5 mL). The reaction was stirred at room temperature for 2 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 35% ethyl acetate in hexane to give a white solid (P-0154, 0.18 g. 72%). MS (ESI) [M+HT = 246.2. Example 53 Synthesis of 5-((lH-pyrrolo[2,3-b]pyridin-3-yl)methyl)-N-(4-chluroben/yl)-6- chloropyridin-2-amiπe P-0161
10676] 5-((lII-p>τrolo[2,3-b]pyridin-3-yl)methyl)-N-(4-chlorobenzyl)-6-chloropyridin-2-amine P-0161 was synthesized in 6 steps as shown in Scheme 168.
Scheme 168
Figure imgf000274_0001
Step 1 - Preparation υf(4-chlυrυ-benzyl)-(6-chlaro-pyridin-2-yl)-amine (53H): [0677] To 6-chloro-pyridin-2-ylamine (537, 5.60 g, 0.0436 mol) in acetonitrile (300 mL) were added 4-chlorobenzaldehyde (40, 6.7 g, 0.048 mol), trifluoroacetic acid (13 mL, 0.17 mol) and triethylsilane (21 mL, 0.13 mol). The reaction was heated to reflux for 4 hours, then concentrated, poured into water, extracted with ethyl acetate, and washed with sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The filtrate was purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (538, 6.5 g, 59%). MS (FSI) [M+H+]+ = 255.1.
Step 2 - Preparation of(5-bromo-6-chloro-pyridin-2-yl)-(4-chloro-benzyl)-amirιe (539): [0678] To (4-chloro-bcnzyl)-(6-chloro-pyridin-2-yl)-amine (538, 4.00 g, 0.0158 mol) in acetonitrile (66.7 mL, 1.28 mol) under an atmosphere of nitrogen, N-bromosuccinimide (2.81 g, 0.0158 mol) in acetonitrile (20 mL) was added slowly. The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and crystallized with ethyl acetate in hexane to give a white solid (539, 2.60 g, 95.3%).
Step 3 - Preparation of2-chloro-6-(4-chloro-henzykιmino)-pyridine-3-carbaldehyde (540): [0679] To (5-bromo-6-chloro-pyπdin-2-yl)-(4-chloro-benzyl)-amine (539, 2.60 g, 7.83 mmol) in tetrahydrofuran (60.0 rnL) under an atmosphere of nitrogen at -78 0C, isopropylmagnesium chloride (2.00 M in tetrahydrofuran, 4.20 mL) was added over 10 minutes. The reaction was stirred at -78 0C for 20 minutes, then allowed to warm to room temperature for 10 minutes. The reaction was cooled to -78 0C. tert-Butyllithium (1.70 M in hexane. 10.2 mL) was added to the reaction over 10 minutes. After 40 minutes, N,N-dimefhylfonnamide (1.80 mL, 0.0232 mol) was added to the reaction. The reaction was stirred at -78 0C for 40 minutes, then allowed to warm to room temperature for another 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in hexane to give a light yellow solid (540, 1.0 g, 45.4%). MS (ESI) [M-LTp = 279.0.
Step 4 - Preparation of (4-chloro-ben∑yl)-(6-chloro~5-formyl-pyriώn-2-vl)-carbamic acid tert- butyl ester (541):
[0680] To 2-chloro-6-(4-chloro-benzylamino)-pyridine-3-carbaldehyde (540, 0.40 g, 1.42 mmol) in dichloromethane (10.0 mL) were added 4-dimcfhylaminopyridine (10.0 mg, 0.082 mmol). di- tert-butyldicarbonate (0.693 g, 3.17 mmol) and triethylamine (0.50 mL, 0.0036 mol). The reaction was stirred at room temperature overnight, then concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (541, 0.45 g, 83.0%).
Step 5 - Preparation of (4-chloro-benzyl)-6-chloro-5-[hydroxy-(l H-pyrrolo[2, 3-bj ' pyridin-3-yl)- methyl] -pyridin-2-yl-carbamic acid tert-butyl ester (542):
[0681] To lH-Pytτolo[2,3-b]pyridine (1, 465 mg, 3.93 mmol) in methanol (50 mL) were added sodium hydroxide (0.630 g, 0.0157 mol) and (4-chloro-benzyl)-(6-chloro-5-formyl-pyridiii-2-yl)- carbamic acid tert-butyl ester (541, 1.5 g, 0.0039 mol). The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (542, 1.Og, 51 %). MS (ESI) [M+H+]+= 499.1.
Step 6 - Preparation of 5-((l H-pyrrυlo[2,3-b] pyridin-3-yl)methyI)-N-(4-chlombenzyl)-6- chlυrυpyridin-2-amine (P-Ol 61):
[0682] To (4-chloro-benzyl)-6-chloro-5-[hydroxy-(l H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]- pyridin-2-yl-carbamic acid tert-butyl ester (542, 1.00 g, 2.00 mmol) in acetonitrile (130.0 mL) were added triethylsilane (1 1 5 mL, 0.0720 mol) and trifluoroacetic acid (5.5 mL, 0.071 mol). The reaction was heated to reflux for 2 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate and hexanc to give a light yellow solid (P-0161, 480 mg, 62%). MS (ESI) [M+ETf = 383,1 , 385, 1 ,
[0683J [6-Chloro-5-(lII-pγrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluorometh3'l- pyridin-3-ylmethyl) -amine P-0174
Figure imgf000276_0001
was prepared following the protocol of Scheme 168, substituting 4-chloro-benzaldehyde 40 with 6-trifluoromethyl-pyridine-3-carbaldehyde in step 1. MS (ESI) [M+ET]~ = 418.2,
[0684] [6-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6- trifluoromcthyl-pyπdin-3-ylmethyl)-amine P-0176
Figure imgf000276_0002
was prepared following the protocol of Scheme 168, substituting 4-chloro-benzaldehyde 40 with ό-trifluoromethyl-pyridine-S-carbaldehyde in step 1 and lH-Pyrrolo[2,3-b]pyridine 1 with 5- chloro-lH-pyrrolo[2)3-b]pyridine in step 5. MS (ESI) [M+H+]+ = 452.0.
[0685] {6-Chloro-5-[5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl]- pyridin-2-yl}-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine P-0179
Figure imgf000276_0003
was prepared following the protocol of Scheme 168, substituting 4-chloro-benzaldehyde 40 with 6-trifluoromethyl-pyridine-3-carbaldehyde in step 1 and lH-Pyrrolo[2,3-b]pyridine 1 with 5-(l - Methyl-lH-pyrazol-4-yl)-l H-pyrrolo[2,3-b]pyridine (prepared as described m Example 57, Scheme 172) in step 5. MS (ESl) [M+HT ^ 498.0.
Example 54 Synthesis of (3-chloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yll-amine P-0129
[0686] (3-Chloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyridin-2-yl]-amine P-0129 was synthesized in 1 step as shown in Scheme 169, Scheme 169
Figure imgf000277_0001
Step I - Preparation of(3~chlυrυ-benzyl)-[5-(lH-pyrrolo[2,3~b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0129):
[0687] 3-(6-bromo-pyridin-3-ylmethyl)-l -triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (6a, 10 rag, 0.023 mmol, prepared as described in Example 2, Scheme 4) was combined with 3- chlorobenzyl amine (543, 13 mg, 0.093 mmol) in dioxane (0.3 mL). Tris(dibenzylideneacetone)- dipalladium(O) (3 mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos, 3 mg) and sodium fert-butoxide (15 mg) were added. The mixture was heated at 100 0C overnight. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in DMSO and purified by reverse phase HPLC on a YMC-Pack ODS-A C-18 column (50mm x 10mm ID), eluting with water with 0.1 % trifluoroacetic acid and 5-40% acetonitrile with 0.1 % trifluoroacetic acid over 13 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0129. MS (ESI) [M+HT = 349.1.
[0688] Additional compounds were prepared following the protocol of Scheme 169. replacing 3-chlorobenzyl amine 543 with an appropriate amine. The following compounds were made following this procedure:
(4-Morpholin-4-ylmethyl-ben7.yl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]- amine (P-0093),
Pyridin-3-ylmethyl-[5-(lH-p>τrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0094),
(5-Methyl-isoxazol-3-ylmethyl)-[5-(lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0095),
(2-Pyrrolidin-l -yl-ethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0096), ri -(4-Methanesulfonyl-phenyl)-ethyl]-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0097),
(2-Methoxy-ethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0098).
(2-Morpholin-4-yl-ethyl)-r5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pvridin-2-yl]-amine (P-
0099),
((R)-l -Phenyl-ethyl)-[5-(lH-pyπOlo[2,3-bJpyridin-3-ylmethyl)-p>τidin-2-yl]-amine (P-0125), (3-Moφholin-4-yl-benzyl)-[5-(lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0126),
[l -(2-Fluoro-phenyl)-cthyl]-[5-(lH-pyπ"olo[2,3-b]pyτidin-3-ylmethyl)-pyi idin-2-yl]-amine (P-
0127),
[2-(.3-Fluoro-phenyl)-cthyl]-[5-(lH-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0128),
(l -Methyl-l II-imidazol-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0130), and
(l,5-Dimethyl-lH-pyrazol-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-)'lmethyl)-pyridm-2- yl]-amine (P-0l31 ).
[0689] The following table indicates the amine (Column 2) used in Scheme 169 to provide the compounds (Column 3), Column 1 provides the compound number and column 4 the observed mass.
Figure imgf000278_0001
Figure imgf000279_0002
Example 55 Synthesis of 3-chloro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylraethyl)-pyridin-2- yll-beπzamide P-OlIl
[0690] 3-Chloro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>τidin-2-y]]-benzamide P-0111 was synthesized in 1 step as shown in Scheme 170.
Scheme 170
Figure imgf000279_0001
Step 1 - Preparation of3-chloro-N-[5-(lH-pγrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- benzamide (P-OUl) [0691] 3-(6-Bromo-pvridin-3-ylmethyl)-l-triisopropylsilanyl-lH-p>τrolo[2,3-b]pyridine (6a, 10 mg, 0.023 mmol, prepared as described in Example 2, Scheme 4) was combined with 3-chloro- benzamide (544, 15 mg, 0.096 mmol) in dioxane (0.4 niL). Tris(dibenzylideneacetone)- dipalladium(O) (3 mg), 4,5-bis(diphenylphosphino)-9.9-dimethylxanthenc (Xantphos, 3 mg), and sodium rert-butoxide (15 mg) were added. Cesium carbonate (20 mg) was added and the mixture was heated at 100 0C overnight. Acetic acid (0.1 inL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in DMSO (0.2 niL) and purified by- reverse phase HPLC on a YMC-Pack ODS-Λ C-18 column (50mm x 1 Omm ID), elutmg with water with 0.1 % trifluoroacetic acid and 5-40% acetonitrile with 0.1 % trifluoroacetic acid over 13 minutes at a flow rate of 6 mL/minute to provide the desired compound P-OH l. MS (ESI) [M+H"]+ = 363.1.
[0692] Additional compounds were prepared following the protocol of Scheme 170, replacing 3-chloro-benzamide 544 with an appropriate amide. The following compounds were made following this procedure:
3,4-Dichloro-N-[5-(lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-pyridin-2-ylJ-bcnzamide (P-OlOO),
2-Chloro-4-fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide (P-
0101),
2,5-Dimcthyl-2H-pyrazole-3-carboxylic acid [5-(lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl] -amide (P-Ol 02),
Thiophene-2-carboxylic acid [5-( lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide
(P-Ol 03),
2-Methoxy-N-[5-(lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide (P-
0104),
N-[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide (P-0105),
Pyrazine-2-carboxylic acid [5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide (P-
0106),
Pyridine-2-carboxylic acid [5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amide (P-
0107),
6-Methyl-N-[5-(l H-p>τrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-nicotinamide (P-0108),
4-Fluoro-3-methyl-N-[5-( lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyridin-2-yl]-benzamide (P-
0109),
5-Methyl-pyτazine-2-carboxylic acid [5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amide (P-OI lO),
4-Fluoro-N-[5-( lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromcthyl- benzamide (P-0112), N-[S-(I H-Pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethoxy-benzamide (P- 0113),
N-[5-(lH-Pyrrolo[2,3-b]p>τidin-3-ylmethyl)-p>τidin-2-yl]-3-trifluoromethyl-benzamide (P- 0114),
3-Chloro-4-fluoro-N-[5-(IH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-beπzamide (P- 0115),
3,4-Difluoro-N-[5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyridin-2-yl]-benzamidc (P-0116), 2-Chloro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide (P-0117), 5-Fluoro-2-methyl-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-ben2amide (P- 0118),
2-Fluoro-N-[5-(lH-pyrrolo[2,3-bJpyridin-3-ylmethyl}-pyridin-2-yl]-bcnzamidc (P-0119), 3-Methoxy-N-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-beπzamide (P-0120), 3-Fluoro-N-[5-( l H-pyrrolo[2,3-b]pyridin-3-ylπiethyl)-pyridm-2-yl]-benzamide (P-0121), 3-Methyl-N-[5-(lII-ρyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide (P-0122), and 2-Chloro-N-[5-(lH-pyrrolo[2,3-b]ρyridin-3-ylmethyl)-pyridin-2-yl]-isonicotinamide (P-0123).
[0693] The following table indicates the amide (Column 2) used in Scheme 170 to provide the compounds (Column 3). Column 1 provides the compound number and column 4 the observed mass.
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Example 56 Synthesis of 3,5-dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazoIe- 1-carboxylic acid 4-methoxy-benzylamide P-0135
[0694] 3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyra7oIe-l -carboxyhc acid 4- methoxy-benzylamide P-0135 was synthesized in 1 step as shown in Scheme 171.
Scheme 171
Figure imgf000283_0002
Step 1 - Preparation of3,5~dimethyl~4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazo!e-l- carboxylic add 4-methoxy-benzylamide (P-0135):
[0695] 3~(3.5~dimethyl-lH-pyrazol-4-ylmethyl)-pyτrolo[2,3-b]pyridine-l -carboxylic acid tert- butyl ester (514, 10 rπg, 0.03 mmol) was dissolved in dichloromethane (0,5 mL), 1 ,8- Diazabicylo[5.4.0]unde-7-ene (6 mg, 0.04 mmol) was added. l-Isocyanatomethyl-4-methoxy- benzene (545, 6.5 mg, 0.04 mmol) was added. The reaction was allowed to proceed at room temperature for 30 minutes. Acetic acid (0.2 mL) was added to the reaciton. The solvents were removed under reduced pressure. The residue was dissolved in dimethyl sulfoxide (0,2 mL) and purified by reverse phase HPLC on a Phenomenex column (50mm x 10mm ID), eluting with water with 0.1 % trifiuoroacetic acid and 20-100% acetonitrile with 0.1% trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0135. MS (ESI) [M+H+]' = 390.3.
[0696] Additional compounds were prepared following the protocol of Scheme 171 , replacing 1 -isocyanatomethyl-4-methoxy-benzene 545 with an appropriate isocyanatc or bromide. The following compounds were made following this procedure:
3-( 1 -Benzy 1-3 ,5 -dimethyl- 1 H-pyrazol-4-ylmethyl)- 1 H-pyrrolo [2 ,3-b]pyridine (P-0133),
2-[3,5-Dimethyl-4-(lII-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyrazol-l -yl]-l -phenyl-ethanone
(P-0134),
3,5-Dimethyl-4-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 2-chloro- benzylamide (P-0136),
3, 5-Dimethyl-4-(l H-pyrrolo [2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 2-fluoro- benzylamide (P-0137),
3-[3,5-Dimethyl-l -(5-trifluoromethyl-furan-2-ylmethyl)-lH-pyrazol-4-ylmethyl]-lH- pyrrolo[2,3-bjpyridine (P-0138),
3 - [3 ,5 -Dimethyl- 1 -(5 -mcthyl-isoxazol-3 -ylmethyl)- 111-pyrazol-4-ylmethyl] - 111-pyrrolo [2,3- b]pyridine (P-0139),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 4-chloro- benzylamide (P-0140),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid [2-(4- ethoxy-phenyl)-ethyl]-amide (P-0141),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 3-methoxy- benzylamide (P-0142),
3-{3,5-Dimethyl-l -[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmcthyl]-lH-pyrazol-4- ylmethyl}-lH-pyrrolo[2,3-b]pyridine (P-0143), 3-[3,5-Diraethyl-l -(4-methyI-2-phenyl-thiazol-5-ylmethyl)-lH-pyrazol-4-ylmethyl]-lH- pyrτolo[2,3-b]pyridine (P-0144),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 2-methoxy- benzylamide (P-0145),
3,5-Dimethyl-4-(lH-p>τrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid [2 -(2,4- dichloro-phenyl)-ethyl]-amide (P-Ol 46),
3,5-Dimethyl-4-(l H-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyrazole-l -carboxylic acid [2-(4- fluoro-phenyl)-ethyl] -amide (P-0147),
3,5-Dimethyl-4-(lH-pyrrolϋ[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid [2-(2- fluoro-phenyl)-ethyl]-amide (P-0148),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazolc-l -carboxylic acid ((S)-I - phenyl-ethyl)-amide (P-0149),
3,5-Dimethyl-4-(l H-pyπτ>lo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 3-fluoro- benzylamide (P-0150),
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyrazole-l -carboxylic acid 4-fluoro- benzylamide (P-0151),
3,5-Dimethyl-4-( lH-pyrrolo[2,3-b]pyridm-3-ylrnethyl)-pyrazole-l -carboxylic acid 4-methyl- benzylamidc (P-0152), and
3, 5-Dimethyl-4-(lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 2-methyl- benzylamide (P-0153).
[0697] The following table indicates the isocyanate or bromide (Column 2) used in Scheme 171 to provide the compounds (Column 3), Column 1 provides the compound number and Column 4 the observed mass.
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
Example 57: Synthesis of 5-(l-methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridinc 547.
[0698] 5-(l -Methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2,3-b]pyridine 547 was synthesized in 1 step from 5-bromo-l H-pyrrolo[2,3-b]pyridine 44 as shown in Scheme 172.
Scheme 172
Figure imgf000287_0002
Step 1 - Preparation of 5-( 1 -Methyl- 1 H-pyrazol-4-yl)- 1 H-pyrrolo[2 ,3-b] pyridine (547): [0699] To 5-bromo-7-azaindole (44, 1.04 g, 5.28 mmol) in 1.00 M potassium carbonate in water (15.8 mL) and tetrahydrofuran (50.0 ml) were added l -mefhyl-4-(4,4.5,5-tetramethyl- [ l,3,2]dioxaborolan-2-yl)-l H-pyrazolc (546, 1.65 g, 7.92 mmol),
Tetrakis(triphcnylphosphine)palladium(0) (0.305 mg, 0.26 mmol) and tetra-n-butylammonium iodide (0.20 g, 0.53 mmol). The reaction mixture was stirred at 70 0C overnight. The reaction mixture was poured into water and the organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography eluting with 25% ethyl acetate in hexane to provide a light yellow solid (547, 670 mg, 64.0%). MS(ESI) [M+HT = 199.4.
Example 58: Synthesis of [2-(4-fluoro-benzyIamino)-thiazoI-5-yl]-(lH-pyrroIoI2,3-b]pyridin- 3-yl )-methaπoπe P-Ol 77.
[0700] [2-(4-Fluoro-benzylamino)-thiazol-5 -yl]-(l H-pyrrolo[2,3-b]pyridin-3-yl )-methanone P- 0177 was synthesized in 2 steps as shown in Scheme 173.
Scheme 173
Figure imgf000288_0001
Step 1 - Preparation of(4-fluoro-benzyl)-[5-(lH-pyrrolo[2, 3-b]pyridine-3-carbonyl)-thiazol-2- ylj-carbamic acid tert-butyl ester (549):
[0701] A mixture of {4-chloro-5-[hydroxy-(l -triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridin-3- yl)-methyl]-thiazol-2-yl} -pyridin-4-ylmethyl-carbamic acid tert-butyl ester (548, 0.397 g, 0.57 mmol, prepared according to the protocol of Scheme 159, Example 44, replacing 4- (aminomethyl)pyridine 516 with 4-fluoro-benzylamine in step 1, isolated after step 3), triethylsilane (1.0 mL, 6.3 mmol), and trifluoroacetic acid (0.5 mL, 6 mmol) in acetonitrile (10 mL) was stirred at 40 0C for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with sodium bicarbonate and brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the desired compound as a yellow solid (549, 0.1 1 g, 9%). MS (ESI) [M-H*]" - 451.10.
Step 2 - Preparation of[2-(4-fluoro-benzylamino)-thiazol-5-yl]-(IH-pyrrolo[2,3-b]pyridin-3-yl J- methanone (P-0177): [0702] To a solution of (4-fhioro-benzyl)-[5-(l H-pyrrolo[2, 3-b]pyridine-3-carbonyl)-thiazol-2- yl]-carbamic acid tert-butyl ester (549, 0.1 I g. 0.2 mmol) in dichloromethane (2 mL) was added hydrogen chloride (4 M in 1 ,4-dioxane, 2 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into cold sodium bicarbonate solution, extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. After removal of solvents, the residue was washed with ethyl acetate to provide the desired compound as a yellow solid (P-0177, 9 mg, 10%). MS (ESI) [M+H+f = 353.12.
Example 59: Synthesis of {2-[(4-chlυro-benzyl)-methyl-amino]-thiazol-5-yl}-(lH-pyrroIo[2,3- b]pyridin-3-yl)-methanone P-0178.
[07031 {2-[(4-Chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(lH-pyrrolof2,3-b]pvridin-3-yl)- methanone P-Ol 78 was synthesized in 3 steps as shown in Scheme 174.
Figure imgf000289_0001
Step I — Preparation of4-chloro-2-[(4-chloro-henzyl)-methy l-amino]-thiazυIe-5-carbaldehyde (SSl) -
[0704] To a solution of (4-chloro-benzyl)-methyl-amine (550, 2 g, 0.01 mol) and N,N-diisopropylethylamine (4 mL, 0.03 mol) in tetrahydrofuran (50 mL) was added 2,4-dichloro- thiazole-5-carbaldehyde (93, 3 g, 0.01 mmmol) in tetrahydrofuran (20 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was collected by filtration and washed with hexanes to provide the desired compound as a light-yellow solid (551, 3.6 g, 90%).
Step 2 - Preparation of{4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}- (I-triisopropyisilanyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-methanol (552): [0705] To a solution of 3-iodo-l4riisopropylsilanyl-lH-pyrτolo[2,3-b]pyridine (96, 0.82 g, 2.0 mmol) in tetrahydrofuran (5 mL) at -20 0C, isopropylmagnesium chloride (2 M in tetrahydrofuran, 1.1 mL, 2.2 mmol) was added dropwise. The reaction mixture was allowed to warm to 0 °C in 10 minutes. The reaction mixture was then cooled to -40 0C. To the reaction mixture was added a solution of 4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazole-5-carbaldehyde (551, 0.41 g, 1.4 mmol) in tetrahydrofuran (10 mL). The reaction mixture was allowed to warm to -10 0C in 30 minutes. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexanes to provide the desired compound as a yellow solid (552, 0.5 g, 60%). MS (ESI) [M+H'J 1 = 575.29.
Step 3 - Preparation of{2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(lH-pyrrolo[2,3- b]pyridin-3-yt)-methanone (P-Ol 78):
10706) A mixture of {4-chloro-2-[(4-chloro-benzyl)-methyl-amino]-thiazol-5-yl}-(l - triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-methanol (552, 1 g, 2 mmol), triethylsilane (2 mL, 12 mmol), and trifluoroacetic acid (1 mL, 13 mmol) in acetonitrile (10 mL) was stirred at 40 0C for 2 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with sodium bicarbonate and brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with methanol in dichloromethane to provide the desired compound as a yellow solid (P-0178, 0.17 g, 30%). MS
Figure imgf000290_0001
Example 60: Synthesis of aldehyde intermediates.
10707] (3-Chloro-pyridin-4-ylmethyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 558 was synthesized in 4 steps from 6-amino-nicotinic acid methyl ester 553 as shown in Scheme 175. Scheme 175
Figure imgf000290_0002
Step 1 — Synthesis of 6-[(3-chlυro-pyrhliπ-4-ytmethyl)-amino] -nicotinic acid methyl ester (555): [0708] To 6-amino-nicotinic acid methyl ester (553, 2.15 g, 0.014 mol) in acetonitrile (60.0 ml.) were added 3-chloro-pyridine-4-carbaldehyde (554, 2.00 g, 0.014 mol), tricthylsilane (11.00 mL, 0.069 mol) and trifluoroacetic acid (5.00 mL, 0.065 mol). The reaction was stirred at 80 0C overnight. The reaction was concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (555, 1.5 g, 38.2%). MS (ESI) [M+IT]+ = 278.9.
Step 2 - Synthesis of6-[(3-Chloro-pyridin-4-ybnethyl)-amino]-pyridin-3-yl-methanol (556): [0709] To 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-nicotinic acid methyl ester (555, 1.00 g, 3.60 mmol) in tetrahydrofuran (120 mL) was added a solution of lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 5.00 mL) under an atmosphere of nitrogen at room temperature. The reaction was stirred at room temperature overnight, followed with addition of sodium sulfate decahydrate. After 1 hour, the reaction mixture was filtered, concentrated, and purified with silica gel column chromatography eluting with 2% to 20% methanol in dichloromethane to give the desired compound as a white solid (556, 0.5 g, 56%). MS (ESI) [M+HT = 250.1.
Step 3 - Synthesis of6-[(3-ch!oro-pyridin-4-ylmethyl)-amino]-pyridine-3-carbaldehyde (557): (0710) To 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-yl-methanol (556, 0.50 g, 2.00 mmol) in tetrahydrofuran (20,0 mL) was added Dess-Martin periodinane (1.02 g, 2.40 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound (557, 0.45 g, 91%) that was used in the next step without further purification.
Step 4 - Synthesis υf(3-chlυro-pyridin-4-ylmethyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert- hutyl ester (558):
|0711] To 6-[(3-chloro-pyridin-4-ylmethyl)-amino]-pyridine-3-carbaldehyde (557, 0.45 g, 1.80 mmol) in dichloromethane (20.0 mL) were added di-tert-butyldicarbonale (0.65 g, 3.00mmol), 4-dimethylaminopyridine (0.012 g, 0.010 mmol) and triethylamine (0.28 mL, 2.00 mmol). The reaction was stirred at room temperature overnight, then concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (558, 250 mg, 40.0%).
[0712] (2-Difluαromemoxy-benzyl)-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 559
Figure imgf000292_0001
was prepared following the protocol of Scheme 175, substituting 3-chloro-p>τidine-4-carbaldehyde 554 with 2-difluoromethoxy-benzaldehyde in Step 1 ,
[0713] [2,6-Difluoro-3-(propane-l-sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 560
Figure imgf000292_0002
was prepared following the protocol of Scheme 175, substituting 3-chloro-pyridine-4-carbaldehyde 554 with propane- 1 -sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide in Step 1. MS (ESI) [M+HT = 470.3.
[0714] (6-Fluoro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester 565 was synthesized in 4 steps from 2,6-Difluoro-nicotinic acid methyl ester 60 as shown in Scheme 176. Scheme 176
Figure imgf000292_0003
Step 1 - Synthesis of 2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino] -nicotinic acid methyl ester (562):
[0715] To 2,6-difluoro-nicotinic acid methyl ester (60, 1.82 g, 0.0105 mol, prepared as described in Example 22, Scheme 24, Step 2) in N,N-dimethylformamide (20,0 mL), under an atmosphere of nitrogen at -40 0C, C-(6-trifluoromethyl-pyridin-3-yl)-methylamine (561, 1.00 g, 5.68 mmol) was added. The reaction was stirred at -40 0C, then allowed to warm to room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in hexane to give a white solid (562, 1.40 g, 74.9), MS (ESI) [M+H"T = 330.1.
Step 2 - Synthesis of2-βιιoro-6-[(6-trifluoromethy1-pyridiπ-3-ylmethyl)-amino]-pyridin-3-yl- methanol (563):
[0716] To 2-fluoro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-nicotinic acid methyl ester (562, 1.40 g, 4.25 mxnol) in tetrahydrofuran (100.0 inL) under an atmosphere of nitrogen at room temperature, a solution of lithium tetrahydroaluminate (1.00 M in tetrahydrofuran, 10.0 mL) was added slowly. The reaction was stirred at room temperature overnight, followed by addition of an appropriate amount of sodium sulfate decahydrate. After 1 hour, the reaction mixture was filtered and concentrated to give crude compound (563, 1 .2 g, 93.7%) that was used in the next step without further purification.
Step 3 - Synthesis of 2-fluoro-6-[ (6-trifluoromethyl-pyridin-3-ylmethyl)-aminoJ -pyridine-3- carbaldehyde (564):
[0717] To 2-fluoro-6-t(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-yl-methanol (563, 1.20 g, 3.98 inmol) in dichloromethane (40.0 mL) was added Dcss-Martin periodinane (1.86 g, 4,38 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into aqueous sodium thiosulfate and potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (564, 0.28 g, 23.5%).
Step 4 Synthesis of(6-fluoro-5-formyl-pyridin-2-yl)-(6-trifluoromethyI-pyridin-3-ylmethyl)- carbamic acid tert-butyl ester (565):
[0718] To 2-fluoro-6-[(6-trifluoromethyl-p)τidin-3-ylmethyl)-amino]-pyridine-3 -carbaldehyde (564, 0.28 g, 0.94 mmol) in tetrahydrofuran (10.0 mL) were added di-tert-butyldicarbonate (0.245 g, 1.12 mmol) and 4-dimethylaminopyridine (0.050 g, 0.41 mmol). The reaction was stirred at room temperature overnight, then concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (565, 0,22 g, 59%).
[0719] (6-Chloro-5-formyl-pyridin-2-yl)-(6-trifluoromethyl-pyridiπ-3-ylmethyl)-carbamic acid tert-butyl ester 570 was synthesized in 4 steps from 6-chloro-pyridin-2-ylamine 537 as shown in Scheme 177. Scheme 177
Figure imgf000294_0001
Step 1 - Synthesis of(6-chloro-pyridin-2-yl)~(6-triβuυrυmethyl-pyridin-3-ylmethyl)-amine (567): 10720) To 6-chloropyridin-2-ylamine (537, 0.760 g, 5.91 mmol) in acetomtrile (30.0 niL), ό-trifluoromethyl-pyridine-S-carbaldehyde (566, 1.06 g, 6.05 mmol), trifluoroacetic acid (3.00 tnL, 0,0389 mol) and triethylsilane (6.00 mL, 0.0376 mol) were added. The reaction was heated to reflux for 4 hours. The reaction was concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated and purified with silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (567, 1.60 g, 94.1 %).
Step 2 - Synthesis of (5-bromυ-6-chlora-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyI)- amine (568):
[0721] To (6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridm-3-ylmethyl)-amine (567, 4.50 g, 0.0156 mol) in acetonitrile (120.0 mL) under an atmosphere of nitrogen, N-bromosuccinimide (3.03 g, 0.0170 mol) in acetonitrile (50 mL) was added slowly. The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and purified with silica gel column chromatography eluting with 25% to 100% ethyl acetate in hexane to give a white solid (568, 6.20 g, 80.2%).
Step 3 — Synthesis υf2-chloro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3- carbaldehyde (569):
[0722] To (5-bromo-6-chloro-pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (568, 4.60 g, 0.0125 mol) in tetrahydrofuran (60.0 mL) under an atmosphere of nitrogen at -78 0C, isopropylmagnesium chloride (2.00 M in tetrahydrofuran, 6.44 mL) was added over 10 minutes. The reaction was stirred at -78 0C for 20 minutes, and then allowed to warm to room temperature for 10 minutes. The reaction was cooled to -78 °C, followed by adding tert-butyllilhium (1.70 M in hexane, 15.3 mL) over 10 minutes. After 40 minutes, N,N-dimethylformamide (1.23 mL, 0,0158 mol) was added and the reaction was stirred at -78 0C for 40 minutes, then allowed to warm to room temperature for 30 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 35% to 100% ethyl acetate in hexane to give a light yellow solid (569, 2,84 g, 71 ,7%).
Step 4 - Synthesis of(6-chlorn-5-formyl-pyridin-2-yl)-(6-trifluoromethyi-pyridin-3-ylmcthvl)- carbamic acid tert-butyl ester (570)
[0723] To a solution of 2-chloro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridine-3- carbaldehyde (569, 0.545 g, 1.73 mmol) in tetrahydrofuran (10 mL), N,N-diisopropylcthylamine (0.60 mL, 3.40 mmol), 4-dimcthylaminopyπdine (20 mg, 0.10 mmol), and a solution of di-tert- butyldicarbonate (0.41 g, 0.0019 mol) were added. The reaction mixture was stirred at room temperature overnight, then concentrated, poured into water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (570, 0.60 g, 83.6%).
[0724] (5-Bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine 571
Figure imgf000295_0001
was prepared following the protocol of Steps 1 and 2 of Scheme 177, substituting 6-chloro- pyridin-2-ylamine 537 and 6-trifluorornethyl-pyridine-3-carbaldehyde 566 with 6-fluoro-pyridin- 2-ylamine and 2-chloro-benzaldehyde, respectively in Step 1.
[0725] (6-Fluoro-5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert- butyl ester 572
Figure imgf000295_0002
was prepared following the protocol of Scheme 177, substituting 6-chloropyridin-2-ylamine 537 and 6-trifluoromcthyl-pyridine-3-carbaldehyde 566 with 6-fluoro-pyridin-2-ylamine and 6- methoxy-pyridine-3-carbaldehyde, respectively in step 1.
[0726] (5-bromo-6-fluoro-pyridin-2-yl)-(5-fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester 631 was prepared following the protocol of Scheme 177, substituting 6-chloro-pyridin-2-ylamine 537 and ό-trifluoromcthyl-pyridine-S-carbaldehyde 566 with 6-fluoro-pyridin-2-ylamine and 5-fluoro- pyridine-3-carbaldehyde, respectively in Step 1 , without Step 3 (i.e. the product of Step 2 is reacted according to Step 4).
[0727] (5-Dromo-6-fluoro-pyridin-2-yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester 637
Figure imgf000296_0002
was prepared following the protocol of Scheme 177, substituting 6-chloro-pyridin-2-ylamine 537 and 6-trifluoromethy]-pyridine-3-carbaldehyde 566 with 6-fluoro-pyridin-2-ylaminc and 5-chloro- benzaldehydc, respectively in Step 1 , without Step 3 (i.e. the product of Step 2 is reacted according to Step 4).
Example 61: Synthesis of propane-1-sulfonic acid (2,4-difluoro-3-[5-(lH-pyrrolo[2,3- b]pyridin-3-ylmethyl)-pyridin-2-ylarnino]-methyl-phenyl)-aπiide P-0258
[0728] Propane-1-sulfonic acid (2,4-difluoro-3-[5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)- pyridin-2-ylamino]-methyl-phenyl)-amide P-0258 was synthesized in 2 steps from 3-Iodo-l- triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine 96 as shown in Scheme 178.
Scheme 178
Figure imgf000296_0003
Step 1 - Synthesis of [2,6-difluoro-3-(propane- 1 -mlfonyiamino)-benzyl] -5 -[hydroxy-(l - tnisopropylsilanyl-lH-pyrrolo[2,3-b]pyr idin-3-yl)-methyl]-pyridin-2-yl-carbamic acid ten-butyl ester (574):
[0729] To a solution of 3-Iodo-l-tnisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (96, 0,644 g, 1 ,61 mmol) in tetrahydrofuran (10.0 mL) at -40 0C under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.80 mL) was added slowly. The reaction was allowed to warm to 15 °C over 100 minutes, then cooled to -40 0C, followed by adding [2,6-difluoro-3-(propanc-l- sulfonylamino)-benzyl]-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester (560, 0.100 g, 0.21 mmol, prepared as described in Example 60, Scheme 175) in tetrahydrofuran (2.0 mL). The reaction was allowed to warm to 5 0C over 2 hours, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a yellow solid (574, 75 mg, 47%). MS (ESI) [M+H+]+ = 744.7.
Step 2 - Synthesis of Propane- 1 -sulfonic acid (2,4-difluoro-3-[5-(IH-pyrrolo[2,3-b]pvrιdin-3- ylmethyl)-pyridin-2-y!amino]-methyI-phcnyl)-amide (P-0258):
[0730] To [2,6-difluoro-3-(propane-l-sulfonylamino)-benzyl]-5-[hydroxy-(l -triisopropylsilanyl- lH-pyrrolo[2,3-b]pyr idin-3-yl)-methyl]-pyridin-2-yl-carbamic acid tert-butyl ester (574, 75.0 mg, 0.10 mmol) in acetonitrile (10.0 mL) were added triethylsilane (0.40 mL, 2.5 mmol) and tπfluoroacetic acid (0.20 mL, 2.6 mmol). The reaction was stirred at 80 °C for 4 hours. The reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 15% methanol in dichloromethane to give an off-white solid (P-0258, 29.3 mg, 61.6%). MS (ESI) [M+H+]+ - 472 4.
[0731] Propane- 1 -sulfonic acid (3-{[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin- 2-ylamino]-methyl}-2,4-difluoro-phenyl)-amide (P-0259), [6-Fluoro-5-(lH-pyrrolo[2,3-b]pyridin- 3-ylmethyl)-p>τidin-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (P-0378), and [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridin-3- ylmethyl)-amine (P-0379),
Figure imgf000297_0001
respectively, were prepared following the protocol of Scheme 178. P-0259 was prepared by replacing 3-iodo-l- triisopropylsilanyl-lH-pyiτolo[2,3-b]pyridine 96 with 5-chloro-3-iodo-l-tπisopropylsilanyl-lH- pyrrolo[2,3-b]pyridine in Step 1 (MS [M+H+]+ = 506.1). P-0378 was prepared by replacing [2.6- difluoro-3-(propane-l -sulfonylaniino)-bcnzyl]-(5-formyl-pyridin-2-yl)-carbamic acid tert-butyl ester 560 with (ό-Fluoro-S-formyl-pyridm-Z-ylMδ-methoxy-pyridinO-ylmethy^-carbamic acid tert-butyl ester 572 (prepared as described in Example 60, Scheme 177) in Step 1 (MS [M+H']' - 364.1 ). P-0379 was prepared by replacing both azaindole 96 with 5-chloro-3-iodo- 1 - triisopropylsilanyl-lll-pyrrolo[2,3-b]pyridinc and aldehyde 560 with aldehyde 572 in Step 1 (MS [M+HT - 400.0).
Example 62: Synthesis of [6-fluoro-5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine P-0187
[0732] [6-Fluoro-5-(5-mcthoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6- trifluoromethyl-pyridin-3-y]methyl)-amine P-0187 was synthesized in 3 steps from l -benzenesulfonyl-3-iodo-5-methoxy- lH-pyrrolo[2,3-b]pyridine 575 as shown in Scheme 179.
Scheme 179
Figure imgf000298_0001
Step 1 - Synthesis af5-[(l-benzenesulfonyl-5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy- methyl] -6-fluoro-pyridin-2-yl-(6-trifluoromethyl-pyridin-3-ylmethyl )-carbamic acid tert-butyl ester (576):
[0733] To l-benzenesulfonyl-3-iodo-5-methoxy-lH-pyrrolo[2,3-b]pyridine (575, 0.326 g, 0.000788 mol) in tetrahydrofuran (3.00 mL) at -45 QC under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.380 mL) was added slowly. The reaction was allowed to warm to -25 0C in 30 minutes, and then cooled to -45 0C followed by adding (6-fluoro-5-foiτnyl- pyridin-2-yl)-(6-trifluoromethyl-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (565, 80.0 mg, 0.20 mmol, prepared as described in Example 60, Scheme 176) in tetrahydrofuran (1.0 mL). The reaction was allowed to warm to room temperature over 2 hours. The reaction was poured into aqueous ammonium chloride, and extracted with ethyl acetate The organic layer was dried o\er anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography cluting with 20% to 100% ethyl acetate in hexane to give the desired compound (576, 0,080 g, 60%), MS (ESI) [M+HT = 688.1.
Step 2 - Synthesis of[5-(l-Benzenesulfonyl-5-methυxy-lH-pyrrulϋ[2,3-b]pyridin-3-ylmethyl)-6- fluoro-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (577):
[0734] To 5-[(l -benzenesulfonyl-5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-6- fluoro-pyridin-2-yl-(6-trifluoromethyl-pyridin-3-ylmethyl )-carbamic acid tert-butyl ester (576, 0.100 g, 0.15 mmol) in acetonitrile (12.6 mL) were added triethylsilane (0.34 ml, 2.10 mmol) and trifluoroacetic acid (0.17 mL, 2.20 mmol). The reaction was heated to 80 UC for 2 hours. The reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give the crude compound (577, 90 mg, 100%) that was used in the next step without further purification.
Step 3 Synthesis of[6-Fluoro-5-(5-methoxy-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- (6-trifluoromethyl-pyridin-3-ylmcthyl)-amine (P-0187):
[0735] To [5-(l -benzenesulfonyl-5-methoxy-l II-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-6-fluoro- pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)-amine (577, 0.08 g, 0.13 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.1 10 g, 0.35 mmol). The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give an off-white solid (P-0187. 8.1 mg, 10%). MS (ESI) [M+HT = 431.9.
[0736] [6-Fluoro-5-(5-chloro-lH-pyrrolo[2,3-bJpyridm-3-ylmethyl)-pyridin-2-yl]-(6- tπfluoromethyl-pyridin-3-ylmethyl)-amine P-0186 and [6-Fluoro-5-(lH-pyrrolo[2.3-b]pyridin-3- ylmethyl)-pyτidin-2-yl]-(6-trifluoromethyl-pyτidin-3-ylmethyl)-amine P-0188,
Figure imgf000299_0001
were prepared following the protocol of Scheme 179, substituting l-benzenesulfonyl-3-iodo-5- mcthoxy-lH-pvrro]o[2,3-b]pyridine 575 with l-benzenesulfonyl-3-iodo-5-chloro-lH-pyrrolo[2,3- b]pyridine or l -Benzenesulfonyl-3-iodo-l H-pyrrolo[2,3-b]pyridirie, respectively, in Step 1. MS (ESI) [M+H+f = 435.7 and 401.6, respectively. Example 63: Synthesis of [6-(2-fluoro-benzylamino)-pyridin-3~yll-(lH-pyrroIo[2,3-b[pyridin- 3-yl)-methanone P-0403
[0737] [6-(2-fluoro-benzylamino)-pyridin-3-yl]-(lII-p>τrolo[2,3-b]pyridin-3-yl)-methanoπe P- 0403 was synthesized in 2 steps from 3-Iodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridinc 96 as shown in Scheme 180.
Scheme 180
Figure imgf000300_0001
Step 1 - (2-Fluoro-ben∑yl)- / 5-( 1 H-pyrrolo [2 ', 3-b]pyriduιe-3-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (580):
10738] To 3-iodo-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (96, 0.550 g, 1.37 mmol) in tetrahydrofuran (15.0 niL) at -40 0C under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.65 mL) was added slowly. The reaction was allowed to warm to 5 0C over 70 minutes, then cooled to -40 0C, followed by adding (2-fluoro-benzyl)-(5-formyl-pyridin-2-yl)- carbamic acid tert-butyl ester (579, prepared according to the protocol of Example 17, Scheme 19, Steps 1-3, replacing 4-chlorobenzaldehyde 40 with 2-fluoro-benzaldehyde in Step 1 ) in tetrahydrofuran (4.0 mL). The reaction was allowed to warm to room temperature over 1 hour, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (580, 0.14 g, 26%). MS (ESI) [M+H*]+ = 447.0.
Step 2 - Synthesis υf [6-(2-Fluoro-ben∑ylamino)-pyridin-3-yl]-(lH-pyrrolo[2,3-b]pyridin-3-yl)- methanone (P-0403):
[0739] To (2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-carbamic acid tert-butyl ester (580, 0.080 g, 0.18 mmol) in dichloromethane (3.0 mL) was added trifluoroacetic acid (1.0 mL. 0.013 mol). The reaction was stirred at room temperature overnight, then concentrated, poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 15 % methanol in dichloromethane to give the desired compound (P-0403, 15.0 mg, 23.0%). MS (ESI) [M+ITf = 347.5. Example 64: Synthesis of (5-chloro-lH-pyrroIo[2,3-b]pyridin-3~yI)-[6-(2-fluoro- benzylamino)-pyridin-3-yI]-methanonc P-0404
[0740) (5-Chloro-l H-p>τrolo[2,3-b]p>τidin-3-yl)-[6-(2-fluoro-benzylamino)-pyridin-3-yl]- methanune P-0404 was synthesized in 4 steps from l -benzencsulfonyl-5-chloro-3-iodo-IH- pyrrolo[2,3-b]pyπdme 581 as shown in Scheme 181 ,
Scheme 181
Figure imgf000301_0001
Step 1 - Synthesis of5-[(l-benzenesulfony!-5-chloro-lH-pyrrυlo[2,3-bjpyridin-3-yl)-hydroxy- methyl] -pyridin-2-yl -(2-βuorn-ben∑yl)-carbamic acid tert-butyl ester (582) [0741] To a solution of l -benzenesulfonyl-5-chloro-3-iodo-lH-pyrrolo[2,3-b]pyτidine (581, (J.420 g, 1.00 mmol) in tetrahydrofuran (15.0 mL) at -40 0C under nitrogen, isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.49 mL) was added slowly. The reaction was allowed to warm to 5 0C over 70 minutes, then cooled to -40 0C, followed by adding (2-fluoro-benzyl)-(5-formyl- pyridin-2-yl)-carbamic acid tert-butyl ester 579 in tetrahydrofuran (6,0 mL). The reaction was allowed to warm to room temperature over 1 hour, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (582, 0.25 g, 41 %). MS (ESI) [M+HT = 623.1.
Step 2 — Synthesis of [5-(l-Bemenemlfυnyl-5~chIυru-lH-pyτrolo[2,5-b]pyήdine-3-carbonyU~ pyridin-2-yl] -(2-βuoro-henzyl)-carbamic acid tert-butyl ester (583):
(0742] To 5-[(l-benzenesulfonyl-5-chloro-lH-pyτro]o[2,3-b]pyridin-3-yl)-hydroxy-methyl]- pyridin-2-yl-(2-fluoro-benzy])-carbamic acid tert-butyl ester (582, 0.25 g, 0.40 mmol) in dichloromethane (5.0 mL) was added Dess-Martin periodinanc (0.20 g, 0.48 mmol). The reaction was stirred at room temperature for 10 minutes, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (583, 0.060 g., 24%),
Step 3 Synthesis of [5-(5-Chloro-lH-pyrrolo[2,3-h]pyridine-3-carbonyl)-pyridin-2-}i]-(2-fluoro- benzyl)-carhamic acid tert-butyl ester (584):
[0743] To [5-(l-benzenesulfonyl-5-chloro-lH-p>τrolo[2,3-b]pyridine-3-carbony])-pyridin-2-yl]- (2-iluoro-benzyl)-carbamic acid tcrt-butyl ester (583, 60.0 mg, 0,097 mmol) in letrahydrofuran (1.0 mL) was added aqueous potassium carbonate (1.0 M, 1.0 mL). The reaction was irradiated with microwave on 300 watts, 1000C for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to give crude compound (584, 0.040 g, 64%) that was used in the next step without further purification.
Step 4 - Synthesis (jf(5-Chloro-lII-pyrrolo[2,3-b]pyridin-3-yl)-[6-(2-fluoro-henzylamino)- pyridin-3-yi] -methanone (P-U4U4):
[0744] To [5-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(2-fiuoro-benzyl)- carbamic acid tert-butyl ester (584, 0.030 g, 0.062 mmol) in dichloromethane (1.0 mL) was added trifluoroacetic acid (1.0 mL, 0.013 mol). The reaction was stirred at room temperature overnight, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 15% methanol in dichloromethane to give the desired compound (P-0404, 2.8 mg, 12%). MS (ESI) [M+H"T = 381.0.
Example 65: Synthesis of (5-chloro-lH-pyrrolo[2,3-b]pyridiπ-3-yl)-6-[(6-methϋxy-pyridiπ-3- ylmethyl)-amiπo]-pyridiπ-3-yl-methaπone P-0405
[0745] (5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-6-[(6-mcthoxy-pyridin-3-ylmethyl)-amino]- pyridin-3-yl-methanone P-0405 was synthesized in 3 steps from 5-Chloro-lH-pyrrolo[2,3- bjpyridine 532 as shown in Scheme 182.
Scheme 182
Figure imgf000302_0001
Step 1 - Synthesis υf5-[(5-chloro-lH-pγrrolo[2,3-b]pyrιdin-3-yl)-hydroxy-methyl]-pyridin-2-yl- (6-methoxy-pyndin-3-ylmethyl)-carbamic acid tert-butyl ester (586):
[07461 To 5-chloro-lH-pyrrolo[2,3-b]pyridine (532, 0.092 g. 0.60 mmol) in methanol (15.0 mL) ■were added (5-formyl-pyridin-2-yl)-(6-methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (585, 0,240 g, 0.70 mmol, prepared according to the protocol of Example 17, Scheme 19, Steps 1- 3, replacing 4-chlorobenzaldehyde 40 with 6-methoxy-pyridine-3-carbaldehyde in Step 1 ) and potassium hydroxide (1.2 g, 0.021 mol). The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (586, 0.1 10 g, 37%).
Step 2 - Synthesis of[5-(5-chloro-lH-ρyrrolo[2,3-b]pyridiτie-3-carbonyl)-pyridm-2-yl]-(6- methoxy-pvridin-3-ylmethyl)-carbamic acid tert-butyl ester (587):
[0747] To 5-[(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-pyridin-2-yl-(6- methoxy-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (586, 0.060 g, 0.12 mmol) in dichloromethane (10.0 mL) was added Dess-Martin periodinane (0.062 g, 0.15 mmol). The reaction was stirred at room temperature for 10 minutes. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hcxanc to give the desired compound (587, 0.020 g, 33%).
Step 3 - Synthesis of(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-6-[(6-methoxy-pyridin-3-ylmethyl)- amino] -pyridin-3-yl-methanone (P-0405):
[0748] To [5-(5-chloro-lH-pyτrolo[2,3-b]pyridine-3-carbonyl)-pyridin-2-yl]-(6-methoxy- pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (587, 0.020 g, 0.040 mmol) in dichloromethane (2.0 mL) was added trifluoroacetic acid (0.30 mL, 0.0039 mol). The reaction was stirred at room temperature for 2 hours, then poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (P-0405, 5.5 mg, 34%). MS (ESI) [M+H+]+ = 394.3.
[0749] {6-[(6-Methoxy-pyridin-3-ylmethyl)-amino]-pyridin-3-yl}-(lH-pyrrolo[2,3-b]pyridin-3- yl)-methanone P-0406
Figure imgf000303_0001
was prepared following the protocol of Scheme 182, substituting 5-chloro-lH-pyrrolo[2.3- b]pyridine 532 with 5-methoxy-lH-pyτrolo[2,3-b]pyridine in step 1. MS (ESI) [M+HT = 390.1.
Example 66; Synthesis of intermediate S-fl-benzenesulfonyl-S-chloro-lH-pyrrolo [2,3- b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine 592
[0750] 5-(l -Benzenesulfonyl-5-chloro-l H-p>τrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol- 2-ylamine 592 was synthesized in 4 steps from 2-amino-4-chloro-thia/ole-5-carbaldehyde 588 as shown in Scheme 183.
Scheme 183
Figure imgf000304_0001
Step I - Synthesis of(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-hutyl ester (589): [0751] To 2-amino-4-chloro-thiazole-5-carbaldehyde (588, 5.00 g, 0.0308 mol) in tetrahydrofuran (122 ml) were added di-tert-butyldicarbonate (7.38 g, 0.0338 mol) and 4-dimethylaminopyπdine (0.35 g, 0,0029 mol). The reaction was stirred at 58 0C for 2 hours, then concentrated and purified with silica gel column chromatography eluting with 20% to 80% ethyl acetate in hexane to give a yellow solid (589, 7.0 g, 87%).
Step 2 - Synthesis of5-[(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy- methylJ-4-chloro-thiazol-2-yl-carbamic acid tert-butyl ester (590):
[0752] To a solution of l-benzenesulfonyl-5-chloro-3-iodo-lH-pyrrolo[2,3-b]pyridine (581, 4.40 g, 10.5 mmol) in tetrahydrofuran (30.0 mL) at -45 °C under nitrogen, a solution of isopropylmagπesium chloride (2.0 M in tetrahydrofuran, 5.4 mL) was added slowly over 10 minutes. The reaction was allowed to warm to -25 0C over 30 minutes. The reaction was cooled to -65 0C, followed by adding the cold deprotonated (4-chloro-5-forrayl-thiazol-2-yl)-carbamic acid tert-butyl ester 589, which was prepared in situ by adding isopropylmagnesium chloride (2,0 M in tetrahydrofuran, 5.0 mL) to (4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (589. 2.51 g, 9.55 mmol) in tetrahydrofuran (23.0 mL) at -78 0C under an atmosphere of nitrogen. The reaction was allowed to warm to room temperature in 2 hours, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25%to 100% ethyl acetate in hexane to give the desired compound (590, 3.70 g. 60.3%). MS (ESI) [M+tT]+ = 554.2.
Step 3 - Synthesis of [5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3~h]pyridin-3-vlmethyl)-4~ chlorυ-thiazol-2-yl] -curbamic acid tert-butyl ester (591):
[0753] To 5-[(l -benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]p>Tidin-3-yl)-hydroxy-methyl]-4- chloro-thiazol-2-yl-carbamic acid tert-butyl ester (590, 0.200 g, 0.32 mmol) in dichloromethane (15.0 mL) were added triethylsilane (0.600 ml, 376 mmol) and trifluoroacetic acid (0.300 ml, 3.89 mmol). The reaction was stirred at room temperature for 3 hours, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% to 100% ethyl acetate in hexane to give the desired compound (591, 0.155 g, 88.7%). MS (ESI) [M+H 'J 1 = 538.9.
Step 4 - Synthesis of5-(l-Ben∑enesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyrιdin-3-ylmethyl)-4- chloro-thiazol-2-ylamine (592):
[0754] To [5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyi"idin-3-ylmethyl)-4-chloro- thiazol-2-yl]-carbamic acid tert-butyl ester (591, 4.30 g, 7.97 mmol) in dichloromethane (70.0 mL) was added a solution of hydrogen chloride (4.00 M in 1 ,4-dioxane, 42.0 mL), The reaction was stirred at room temperature for 2 days, then concentrated, and triturated with ethyl ether and ethyl acetate to give the desired compound (592, 2.60 g, 74.2%). MS (ESI) [M+H1 J 1 = 439.0.
[0755] 5-(l -Benzenesulfonyl-lH-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-4-chloro-thiazol-2-ylamine 593
Figure imgf000305_0001
was prepared following the protocol of Scheme 1 83, substituting l -benzenesulfonyl-5-chloro-3- iodo-lH-pyrrolo[2,3-b]pyridine 581 with l-benzcncsulfonyl-3-iodo-lH-pyrrolo[2,3-b]pyπdine in Step 2. MS (ESI) [M+H+]+ = 404.4. Example 67: Synthesis of [4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)- thiazol-2-yll-(5-fluoro-pyridiπ-3-ylmethyI)-amine P-0231
10756] [4-Chloro-5-(5-chlϋro-lH-p>τrolo[2,3-b]pyridin-3-ylmethyl)-thia7ol-2-yl]-(5-fluoro- pyridin-3-ylmcthyl)-amine P-0231 was synthesized in 2 steps from 5-(l-benzenesulfonyl-5-chloro- lH-p)τrolo[2.3-b]pyridin-3-yImι3thyl)-4-chIoro-thiazol-2-yIamine 592 as shown in Scheme 1 84.
Scheme 184
Figure imgf000306_0001
Step I - Synthesis of [5-(l-henzenesiiifonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4- chloro-thia∑ol-2~yl]-(5-flιιoro-pyridin-3-ylmethyl)-amine (595).
[0757] To 5-(l-ben2enesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro- thiazol-2-ylamine (592, 50.0 mg, 0.1 1 mmol, prepared as described in Example 66, Scheme 183) in ethanol (1.60 mL) and acetic acid (0.08 mL) were added 5-fluoro-pyridine-3-carbaldehyde (594, 43 mg, 0.34 mmol) and silica supported cyanoborohydride (1.21 mmol/g, 0.180 g). The reaction was irradiated with microwave on 300 watts, 1000C for 7 minutes. The reaction was poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the desired compound (595, 0.030 g. 48%).
Step 2 - Synthesis of [4-chloro~5~(5-chloro-lII-pyrrolo[2,3-b]pyridin-3-ylmeth}i)-thia:ol-2-yl]-(5- fluoro-pyridin-3-ylmethyl)-amine (P-0231):
[0758] To [5-(l -benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-4-chloro- thiazol-2-yl]-(5-lluoro-pyridin-3-ylmethyl)-amine (595, 0.030 g, 0,055 mmol) in tetrahydrofuran (6.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.034 g, 0, 1 1 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compυund (P-0231, 1.5 mg, 6.7%). MS (ESI) [M+HT = 408.1. Example 68: Synthesis of 5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3- ylniethyl)-pyridiπ-2-ylamine 599
[0759] 5-(l-Benzenesulfonyl-5-chlϋro- lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>τidin-2-yIamine 599 was synthesized in 4 steps from 5-chloro-lH-p>τrolo[2,3-b]pyridine 532 as shown in Scheme
185,
Scheme 185
Figure imgf000307_0001
Step 1 - Synthesis υf 5-chloro-l H-pyrrolo[2,3-b]pyridine-3-carbaldehyde (596): [07601 To 5-chloro-lH-pyrrolo[2,3-b]pyridine (532, 10.0 g, 65.5 mmol) in acetic acid (28.3 mL) were added hexamethylenetetramine (11.9 g, 85.2 mmol) and water (56.7 mL). The reaction was refluxed overnight, followed by addition of 200 mL of water. After 30 minutes, the reaction was filtered to recover the solid, then dried under air to give the desired compound (596, 7.0 g. 59%).
Step 2 - Synthesis of l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbaldehyde (597):
[0761] To 5-chloro-lH-pyrrolo[2,3-b]ρyridine-3-carbaldehyde (596, 3.60 g, 0.0199 mol) in dichloromethane (100 mL) were added a solution of potassium hydroxide (9 M in water, 50 mL), tctrabutylammonium hydrogen sulfate (400 mg, 0.001 mol) and benzenesulfonyl chloride (2.9 mL, 0.023 mol). The reaction was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate to give a white solid (597, 2.3 g, 36.0%).
Step 3 - Synthesis of(6-amino-pyridin-3-yl)-(l-benzenesulfonyl-5-chlorυ-lH-pyrrυio[2l 3- b]pyridin-3-yl)-meιhanol (598):
[0762] To 2-amino-5-bromopyridine (15, 3.10 g, 17.9 mmol) in tetrahydrofuran (80.0 mL) under an atmosphere of nitrogen at -78 0C, a solution n-butyl lithium (2.50 M in hexane, 7.10 mL) was added slowly. After 30 minutes, l ,2-bis-(chloro-dimethyl-silanyl)-ethane (3.90 g dissolved in tetrahydrofuran 20.0 mL, 18.1 mmol) was added to the reaction mixture slowly, and then allowed to warm to room temperature for 1 hour. The reaction was cooled to -78 0C followed by adding a solution of n-butyllithium (2.50 M in Hexane, 7.10 mL). The reaction mixture was stirred at -78 0C for 30 minutes, then allowed to warm to room temperature for 60 minutes. The reaction mixture was cooled to -78 0C, followed by adding a solution of n-butyllithium (2.50 M in Hexane. 7.50 mL) slowly. After 60 minutes, l-benzenesulfonyl-5-chloro-lH-pyrτolo[2,3-b]pyridine-3- carbaldehyde (597, 1 .90 g in 30 mL tetrahydrofuran, 5.92 mmol) was added to the reaction mixture. The reaction mixture was stirred at -78 0C for 2 hours, then allowed to warm to room temperature for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 20% methanol in dichloromethane to give the desired compound (598, 1.25 g, 50.9%). MS (ESI) [M+H~f = 415.2.
Step 4 - Synthesis of5-(l-benzenesιdfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyhdw- 2-ylamine (599):
[0763J To (6-amino-pyridin-3-yl)-(l -bcnzcncsulfonyl-5-chloro-lH-pvrrolo[2,3-b]pyridin-3-yl)- methanol (598, 1.00 g, 0.00241 mol) in dichloromethane (25.0 mL) were added triethylsilane (3.00 mL, 0.0188 mol) and trifluoroacetic acid (1.50 mL, 0.0195 mol). The reaction was stirred at room temperature overnight, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (599, 0.70 g, 73%).
[0764] 5-(l -Ben7enesulfonyl-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylaminc 600
Figure imgf000308_0001
was prepared following the protocol of Scheme 185, substituting 5-chloro-lH-pyrrolo[2,3- bjpyridine 532 with lH-pyrrolo[2,3-b]pyridine in Step 1. MS (ESI) [M+H'f = 365.2.
Example 69; Synthesis of [5-(5-chloro-lH-pyrrolo[2,3-blpyridin-3-ylmethyl)-pyridin-2-yl]-(5- fluoro-pyridin-3-ylmethyl)-amine P-0324
[0765J [5-(5-Chloro-l H-p>τrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3- ylmethyl)- amine P-0324 was synthesized in 2 steps from 5-(l -benzenesulfonyl~5~chloro-lH- pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine 599 as shown in Scheme 186. Scheme 186
Figure imgf000309_0001
Step 1 - Synthesis of [5~(l-benzenesulfonyl-5-chloro-lH-pyrrυlo[2,3-b]pvridin-3~ylnιethyl)- pyridin-2-yl]-(5-βuυrυ-pyridin-3-ylmethyl)-amine (601):
(0766] To 5-(l-benzenesulfonyl-5-chloro4 Hφ>τrolo[2,34)]pyridin-3-ylmethyl)-p>-τidin-2- ylamine (599, 80.0 mg, 0.20 mmol, prepared as described in Example 68, Scheme 185) in ethanol (2.0 niL) and acetic acid (0.10 mL, 0.0018 mol) were added 5-fluoro-p>τidine-3-carbaldehydc (594, 62.7 mg, 0.50 mmol) and sodium cyanoborohydridc on silica gel (1.200 mmol/g loading; 0.251 g, 0.30 mmol). The reaction was irradiated with microwave on 300 watts, 100 0C for 10 minutes. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (601, 0.060 g, 59%).
Step 2 - Synthesis of [5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro- ρyridin-3-ylmeιhyl) '-amine (P-0324):
[0767] To [5-(l -benzcncsulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- (5-fluoro-pyridin-3-ylmethyl)-amine (601, 0.060 g, 0.12 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.1 1 g, 0.35 mmol). The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (P-0324, 13.5mg, 31 %). MS (ESI) [M+H+]+ = 368.0.
Example 70: Synthesis of (3-ChIoro-pyridm-4-ylmethyl)-I5-(lII-pyrroloI2,3-b]pyridin-3- ylmethyI)-pyridin-2-yl]-amine P-0183
[0768] (3-Chloro-pyridin-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyτidin-3-ylmethyl)-pyridin-2-yl]- amine P-0183 was synthesized in 2 steps from 5-(l-benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3- ylmethyl)-pyridin-2-ylamine 600 as shown in Scheme 187. Scheme 187
Figure imgf000310_0001
Step I - Synthesis of [5-( 1 -benzenesulfonyl- 1 H-pyrrolo [2 ', 3-b] pyridin-3-ylmethvl)-pyridin-2-yl] - (4-chloro-pyridin-3-ylmethyl)-amine (602):
[07691 To 5-(l-ben2enesulfonyl-lH-pyπυlo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (600, 120.0 mg, 0.33 mmol, prepared as described in Example 68, Scheme 185) in acetonitrile (10.0 mL) were added 3-chloro-pyridine-4-carbaldehyde (554. 51 ,3 mg, 0.36 mmol), trifluoroacetic acid (0.30 mL, 0.0039 mol) and triethylsilane (0.60 mL, 0.0038 mol). The reaction was heated to reflux overnight, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 30% to 100% ethyl acetate in hexane to give the desired compound (602, 80 mg, 49.6%). MS [M+H+]+ = 490.2.
Step 2 - Synthesis of(3-chlorυ-pyridin-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyήdin-2-yl] -amine (P-0183):
[0770] To [5-(l-benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(4-chloro- pyridin-3-ylmethyl)-amine (602, 0.08 g. 0.16 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.240 g, 0.76 mmol). The reaction was stirred at room temperature overnight. The reaction was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a yellow solid (P-0183, 4.0 mg, 7%), MS (ESI) [M+HT]+ = 350.2.
Example 71: Synthesis of [5-(5-Chloro-lH-pyrroIo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yI]- [6-(2,2,2-trifluoro-ethoxy)-pyridin-3-ylmethyl]-aminc P-0409
|0771] [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(5-fluoro-pyridin-3- ylmethyl)-amine P-0409 was synthesized in 1 step from 5-(l -benzenesulfonyl-5-chloro-lIl- pyrrolo[2,3-b]pyridiii-3-ylmethyl)-pyridin-2-ylamine 599 as shown in Scheme 188. Scheme 188
Figure imgf000311_0001
Step 1 ~ Synthesis of [5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-[6-(2,2,2- trifluoro-ethoxy)-pyridin-3-ylmethyl] -amine (P-0409):
[0772] To 5-(l -benzenesulfoπyl-5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2- ylamine (599, 124.1 mg, 0.31 mmol, prepared as described in Example 68, Scheme 185) in ethanol (3.00 mL) and acetic acid (0.2 mL) were added 6-(2,2,2-trifluoro-ethoxy)-pyridine-3- carbaldehyde (603, 164.0 mg, 0.80 mmol) and silica supported cyanoborohydπde (1.21 mmol/g. 0,700 g). The reaction was irradiated with microwave on 300 watts, 1000C for 150 minutes. To the reaction was added a solution of potassium hydroxide (9.0 M in water, 1.0 mL). The reaction was irradiated with microwave on 300 watts, 100 0C for 10 minutes. The reaction was poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (P-0409, 10.6 mg, 7.6%). MS ESI) [M+HT = 448.4.
Example 72: Synthesis of l-(3-fluoro-phenyl)-3-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl]-urea P-0412
[0773] l-(3-Fluoro-phenyl)-3-[5-(HI-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-urea P-0412 was synthesized in 2 steps from 5-(l-benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3- ylmethyl)-pyridin-2-ylamine 600 as shown in Scheme 189.
Scheme 189
Figure imgf000311_0002
Step 1 — Synthesis ofl-[5-(l-henzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-
3-(3-fluoro-phenyl)-urea (605):
[0774] To 5-(l -benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (600, 150,0 mg, 0.41 mmol, prepared as described in Example 68, Scheme 185) in acetonitrile (12.5 mL) were added 3-fluoro-isocyanato-benzene (604, 61.6 mg, 0.45 mmol), 4-dimethylaminopyridine (10.0 mg, 0.082 mmol) and triethylaminc (0.25 mL, 0.0018 mol). The reaction mixture was heated at 70 0C overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (605, 0.100 g, 48.4%).
Step 2 ■■- Synthesis of I -(3-Fluoro-phenyl)-3-[ '5-(I H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2- ylj-urea (P-0412):
[0775] To l -[5-(l -benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-(3- fluoro-phenyl)-urea (605, 0.100 g, 0.20 mmol) in tetrahydrofuran (10.0 mL) was added tetrabutylammonium fluoride, trihydrate (0.240 g, 0.76 mmol). The reaction was stirred at room temperature for 5 hours, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-0412, 17.9 mg, 24.8%). MS (ESI) [M+H+]+ = 362.2.
Example 73: Synthesis of (2-chloro-benzyl)-[6-fluoro-5-(lH-pyrrolo[2,3-blpyridin-3- ylmethyI)-pyridin-2-yl]-amine P-0335
[0776] (2-Chloro-benzyl)-[6-fluoro-5-(lH-pyrrolo[2,3^b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine P-0335 was synthesized in 2 steps from (5-bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)- amine 571 as shown in Scheme 190.
Scheme 190
Figure imgf000312_0001
Step 1 - Synthesis of[6-(2-chloro-benzylamino)-2-fluoro-pyridin-3-yl]-(l-triisopropylsilanyl-lH- pyrrolo[2,3-b]pyridin-3-yl)-methanol (606):
[0777] To (5-bromo-6-fluoro-pyridin-2-yl)-(2-chloro-benzyl)-amine (571, 0.635 g, 2.01 mmol, prepared as described in Example 60, Scheme 177) in tetrahydrofuran (25.0 mL) under an atmosphere of nitrogen at -78 0C, a solution of n-butyllithium (2.50 M in hexane, 0.80 mL) was added slowly. After 20 minutes, tert-butyllithium (1.7 M in hexane, 2.40 mL) was added to the reaction and after 30 minutes, I-triisopropylsilanyl-lH-pyrrolo[2(3-b]pyridine-3-carbaldehyde (47, 0.575 g, 1 ,90 minol, prepared as described in Example 18) in tetrahydrofuran (8.0 ml.) was added to the reaction. The reaction mixture was stirred at -78 0C for 60 minutes, then allowed to warm to room tempci ature for another 10 minutes. The reaction mixture was poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (606, 0.180 g, 17.6%). MS (ESI) [M+irT = 539.2.
Step 2 - Synthesis of(2-chloro-benzyl)-[6-fluoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin- 2-vl] -amine (P-0335):
[0778] To [6-(2-chloro-benzylamino)-2-fluoro-pyridin-3-yl]-(l -triisopropylsilanyl- 1 H- pyrrolo[2,3-b]pyridin-3-yl)-methanol (606, 180.0 mg, 0.33 mmol) in acetonitrile (15,0 mL) were added triethylsilane (1.00 mL, 6.26 mmol) and trifluoro acetic acid (0.50 mL, 6 50 mmol). The reaction was heated to reflux for 2 hours, then poured into aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-0335, 24.9 mg, 19.4%). MS (ESI) PVMT]+ = 367.0.
Example 74: Synthesis of l-benzenesuIfonyl-5-chIoro-3-(2-methanesuIfonyI-pyrimidin-5- ylmethyI)-lH-pyrroIoI2,3-b]pyridine 610
[0779] l-Benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-lH- pyrτolo[2,3-b]pyridine 610 was synthesized in 3 steps from l -benzenesulfonyl-5-chloro-3-iodo- l H-pyrrolo[2,3-b]pyridinc 581 as shown in Scheme 191 , Scheme 191
Figure imgf000313_0001
Step I - Synthesis of (l-benzenesulfonyl-5-chloro-l H-pyrrolo[2,3-b]pyridin-3 -yl)-(2- methylsulfanyl-pyrimidin-5-yl)-methanol (608):
[0780) To a solution of ] -Benzenesulfonyl-5-chlorυ-3-iodo-lH-pyrrolo[2.3-b]pyridine (581, 4,36 g, 10.4 mmol) in tetrahydrofuran (100.0 mL) at -40 0C under nitrogen, isopropylmagnesium chloride (2,0 M in tetrahydrofuran, 5.06 mL) was added slowly. The reaction was allowed to warm to 5 0C over 60 minutes, then cooled to -40 0C, followed by adding 2-methylsulfanyl-pyrimidiπe- 5-carbaldehyde (607, 1.30 g, 8.43 mmol, dissolved in tetrahydrofuran 15.0 mL). The reaction was allowed to warm to 10 0C over 2 hours. The reaction was poured into aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 15% methanol in dichloromethane to give the desired compound (608, 3.00 g, 79.6%). MS (ESI) [M+HT = 447.2.
Step 2 - Synthesis of I -benzenesulfonyl -5 chloro-3-(2-methylsιdfanyl-pyrimidin-5-ylmethyl)-lH- pyrrolo[2, 3-b] pyridine (609):
[0781] To (1 -benzenesulfonyl-5-chloro-lH-pyrrolo[2.3-b]pyridin-3-yl)-(2-methylsulfanyl- pyrimidin-5-yl)-methanol (608, 0.35 g, 0.78 mmol) in dichloromethane ( 15.0 mL) were added triethylsilane (2.00 mL, 12.52 mmol) and trifluoroacetic acid (1.00 mL, 13.0 mmol). The reaction was stirred at 35 0C overnight, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (609, 0.25 g, 74%). MS (ESI) [M+IT]+ = 430.9.
Step 3 - Synthesis of l-henzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-lH- pyrrolo[2 , 3-b] pyridine (610) and 1 -benzenesulfonyl -5 chloro-3-(2-methanesιdfinyl-ρyrimidin-5- ylmethyl)-l H-pyrrolo[2, 3-b] pyridine (611):
[0782] To l-benzenesulfonyl-5-chloro-3-(2-methylsulfanyl-pyrimidin-5-ylmethyl)-lH- pyrrolo[2,3-b]pyridine (609, 0.500 g, 1.16 mmol) in dichloromethane (15.0 mL) was added meta- chloroperoxybcnzoic acid (max. 77%, 0,572 g, 2.55 mmol) at 0 0C. The reaction was stirred at 0 JC for 70 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compounds (610. 0.310 g, 57.7%), MS (ESI) [M+HT = 463.1; and (611, 0.200 g, 38.6%), MS (ESI) [M+HT = 447.2. [0783] l-Benzenesulfonyl-3-(2-methanesulfoπyl-pyrimidin-5-ylmethyl)-lH-pyrrolo[2,3- blpyridine 612
Figure imgf000315_0001
was prepared following the protocol of Scheme 191 , substituting l -benzenesulfonyl-5-chloro-3- iodo-lH-pyrrolo[2,3-b]pyπdme 581 with l-benzenesulfonyl-3-iodo-lH-ρyrrolo[2,3-b]pyridine in Step 1.
Example 75: Synthesis of (4-chloro-benzyl)-[5-(5-chloro-lH-pjrrolo[2,3-b]pyridin-3- ylinethyl)-pyriniidin-2-yl]-amine P-0260
[0784] (4-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine P-0260 was synthesized in 2 steps from l-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl- pyπmidin-5-ylmethyl)-lH-pyrrolo[2,3-b]pyridine 610 as shown in Scheme 192. Scheme 192
Figure imgf000315_0002
Step 1 - Synthesis of [5-(l-benzenesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyrimidin-2-yl]-(4-chloro-benzyl)-amine (613):
[0785] To 1 -benzenesulfonyl-5-ch]oro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-lH- pyrrolo[2,3-b]pyridine (610, 0.060 g, 0.13 mmol, prepared as described in Example 74, Scheme 191) m N-methylpyrrolidinone (1.80 ml) was added p-chlorobcnzylamme (61, 0.20 g, 1.4 mmol). The reaction was irradiated with microwave on 300 watts, 150 0C for 15 minutes, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (613, 0.05 g, 74%). MS (ESI) [M+H'J * = 524.3.
Step 2 — Synthesis of(4-chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyrιmidin-2-yl] -amine (P-0260):
[0786] To [5-(l -ben7enesulfonyl-5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2- yl]-(4-chloro-bcnzyl)-amine (613, 0.050 g, 0.095 mmol) in tetrahydrofuran (10.0 ml) was added tetrabutylammonium fluoride, trihydrate (0.20 g, 0,63 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight, then poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and washed with ethyl acetate in hcxane to give an off-white solid (P-0260, 16,9 mg, 46%). MS (ESI) [M+HT = 385,9.
|0787] Additional compounds were prepared following the protocol of Scheme 192, substituting p-chlorobenzylamine 61 with a suitable amine in Step 1 , The following compounds were prepared following this protocol:
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pvrimidin-2-yl]-(2,6-difluoro-ben2yl)-amine
(P-0261),
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidm-2-yl]-(2-trifluoromethyl-benzyl)- amine (P-0262),
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl] -amine
(P-0263),
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylJ-(2-fluoro-benzyl)-amine
(P-0264),
[5-(5-Chloro-lH-pyτrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,4-difluoro-ben7yl)-amine
(P-026S),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)- amine (P-0266).
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2)5-difluoro-benzyl)-amine
(P-0267), and
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-trifluoromethyl-benzyl)- amine (P-0268).
The following table indicates the amine (Column 2) used in Scheme 192 to provide the compounds
(Column 3), Column 1 provides the compound number and Column 4 the experimental mass spectrometry result.
Figure imgf000316_0001
Figure imgf000317_0001
Example 76: Synthesis of (Z-fluoro-S-trifluoromcthyl-benzylHS-ClH-pyrrololZjS-bJpyridin- 3-ylmethyl)-pyrimidin-2-yl] -amine P-0291
[0788] (2-Fluoro-5-tπfluoromethyl-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridm-3-ylmcthyl)- pyπmidm-2-yl]-amine P-0291 was synthesized in 1 step from l-benzenesulfon>l-3-(2- methanesulfonyl-pynmidin-5-ylmethyl)-lH-pyrrolo[2,3-b]pyndine 612 as shown in Scheme 193 Scheme 193 3
Figure imgf000317_0002
Step 1 - Synthesis of (2-fluoro-5-trifliioromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridw-3- ylmethy l)-pyrιmιdιn-2-yl] -amine (P-0291)
[0789] To l -benzenesulfonyl-3-(2-methanesulfonyl-pyrimidm-5-ylmeth\l)-lH-pyrrolo[2,3- b]pyridine (612, 0.080 g, 0.19 mmol, prepared as described in Example 74, Scheme 191) in N- inethylpyrrolidinone ( 1.00 mL) was added 2-fluoro-5-trifluoromethyl-benzylamine (614, 0.20 g, 1.0 mmol). The reaction was irradated with microwave on 300 watts. 1500C for 15 minutes. Potassium hydroxide in water (1.00 M, 2.00 mL) was added to the reaction. The reaction was irradiated with microwave on 300 watts, 900C for 10 minutes, then poured into water and extracted with ethyl acetate, The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexanc to give a white solid (P-0291. 37.4 mg, 50%). MS (ESI) [M+H'V = 402.6.
[0790] Additional compounds were prepared following the protocol of Scheme 193, substituting 2-fluoro-5-trifluoromethyl-benzylamine 614 with a suitable amine. The following compounds were prepared following this protocol:
C2,5-Difluoro-benzyl)-[5-(l H-pyτrolo[2)3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0292), (2-Chloro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0293),
(3-Fluoro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0294),
(3,5-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl] -amine (P-0295), (2-Fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0300), (2-Chloro-bcnzyl)-[5-(lH-pyrrolo[2,3-b]pyτidin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0301), [5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine (P-0302),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-benzyl)-amine (P-0303),
(5-Chloro-2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyτimidin-2-yl]-amine (P-0304),
(2,4-Dichloro-benzyl)-[5-(l I[-pyrrolo[2>3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0305), (2,4-Difiuoro-benzyl)-[5-( lH-pyrrolo [2,3 -b]pyridin-3-ylmethyl)-pyrimidin-2-yl] -amine (P-0306), (4-Chloro-benzyl)-[5-(lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0307), [5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trilluoromcthyl-benzyl)-amine (P-0308),
(2-Fluoro-3-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2)3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0309),
(2,5-Dichloro-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-yl]-amine (P-0310), (3-Chloro-2-fluoro-bcnzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl] -amine (P-0311),
(2-Difluoromethoxy-beπzyl)-f5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0312),
(2,3-Dichloro-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-yl]-amine (P-0313),
(4-Chloro-2-fluoro-bcnzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyriinidin-2-yl]-amine
(P-0314),
(5-Fluoro-2-tπfluoromethyl-benz;yl)-[5-(lH-pyrrolo[2,3-b]p>τidin-3-ylmethyI)-pyrimidin-2-yl]- amine (P-0315),
(2-Chloro-4-fluoro-benzyl)-[5-(lH-pyrrolof2,3-b]pyridm-3-ylmethyl)-p>τimidin-2-yl]-amiπe
(P-0316),
(5-Chloro-2-methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-yl]-amine
(P-0317),
(5-Fluoro-2-methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine
(P-0318),
(2-Fluoro-4-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0319),
(4-Fluoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyπmidiπ-2-yl]- amine (P-0320), and
(2-ChJuro-5-fluoro-benzyl)-[5-(lII-pyrrolo[2.3-b]pyridm-3-ylniethyl)-p>τimidin-2-yl]-amine
(P-0407).
The following table indicates the amine (Column 2) used in Scheme 193 to provide the compounds
(Column 3). Column 1 provides the compound number and Column 4 the experimental mass spectrometry result.
Figure imgf000319_0001
Figure imgf000320_0001
Figure imgf000321_0001
Example 77: Synthesis of [5-(5-Chlorα-lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyriinidin-2- yl] -(2-difluoromcthoxy-benzyl)-aπiine P-0390
|0791| ^-(S-Chloro-lH-pyrrolotl.S-blpyridin-S-ylmethyO-pjTimidin^-ylJ-CI-difluoromcthoxy- bcnzyl)-amine P-0390 was synthesized in 1 step from l-bcnzenesulfonyl-5-chloro~3-(2- methanesulfonyl-p>τimidin-5-ylmethyl)-lH-pyrrolo[2,3-b]p>τidine 610 as shown in Scheme 194, Scheme 194
Figure imgf000322_0001
Step 1 - Synthesis of [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yll-(2- difluoromethoxy-benzyl)-amine (P-0390)
[0792] To l-benzenesulfonyl-5-chloro-3-(2-methanesulfonyl-pyrimidin-5-ylmethyl)-lH- pyrrolo[2,3-b]pyridine (610, 0,060 g, 0,13 mmol, prepared as described in Example 74. Scheme 191) in N-methylpyrrolidinone (1.40 ml) was added 2-difruoromethoxy-bcnzylamine (615, 0.200 g. 1.16 mmol). The reaction was irradiated with microwave on 300 watts, 150 0C for 15 minutes. Potassium hydroxide in water (1.00 M, 2.00 mL) was added to the reaction. The reaction was irradiated with microwave on 300 watts, 90 0C for 10 minutes, then poured into ethyl acetate and water. The organic layer was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (P-0390, 10.9 mg, 20%). MS (ESI) [M+HT = 41 8.O.
[0793] Additional compounds were prepared following the protocol of Scheme 194, substituting 2-difluoromethoxy-benzylamine 615 with a suitable amine. The following compounds were prepared following this protocol:
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-5-trifluoromethyl- benzyl)-amine (P-0289),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-trifluoromethyl- benzyl)-amine (P-0391),
(3-Chloro-2-fluoro-benzyl)-[5-(5-chloro-l H-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0392),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-3-trifluoromethy[- benzyl)-aminc (P-0393),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-4-trifluoromethyl- benzyl)-amine (P-0394), [5-(5-Chloro-l H-pyrrolo[2,3-bJp>τidin-3-ylmethyl)-pyrimidin-2-yl]-(2,3-difluoro-benzyl)-amme
(P-0395),
(2-Chloro-4-fluoro-benzyl)-[5-(5-chlϋro-lH-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyrimidin-2-ylj- amine (P-0396),
[5-(5-ChIOrO-IH-PyTToIo [2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethoxy-benzyl)- amine (P-0402),
(2-Chloro-5-fluoro-benzyl)-[5-(5-chloro-lH-ρyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylJ- amine (P-0408),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-4-ylmethyl-amine
(P-0416),
[5-(5-Chloro-lH-pyrrolo[2,3-b]ρyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-pyrrolidm-l-yl-ethyl)- amine (P-0417),
Benzyl-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine (P-0418),
Benzyl-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyrimidin-2-yl]-methyl-aminc
(P-0419),
[5-(5-Chloro-lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyπmidin-2-yl]-(4-trifluoromethoxy-benzyl)- amine (P-0420),
(3-Chloro-benzyl)-[5-(5-chloro-l H-pyrrolo[2,3-b]pyridiπ-3-ylmethyl)-pyrimidin-2-ylJ-aminc
(P-0421),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-3-ylmethyl-amine
(P-0422),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-fluoro-bcnzyl)-amine
(P-0423),
(3 -Chloro-bcnzyl)-[5 -(5 -chloro- 1 H-pyrrolo [2,3-b]pyridin-3 -ylmethyl)-pyrimidin-2-yl] -methyl- amine (P-0424),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyτimidin-2-yl]-(3,5-difluoro-benzyl)-amine
(P-0425),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>τimidin-2-yl]-[l -(2-fluoro-phenyl)-ethyl]- amine (P-0426),
[l -(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0427),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[(S)-l -(4-fluoro-phenyl)- ethyl]-amine (P-0428),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-ylJ-(6-trifluoromethyl-pyridin-3- ylmethyD-amine (P-0429),
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>τimidin-2-yl] -methyl- amine (P-0430),
[5-(5"Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyτimidin-2-yl]-(2-methyl-benzyl)-amine
(P-0431),
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-benzyl)-amine
(P-0433),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyτimidin-2-yl]-(2-moφholin-4-yl-ethy])- amine (P-0434),
[5-(5-Chloro-lII-pyrrolo[2>3-bJpyridm-3-ylmethyl)-pyrimidin-2-yl]-cyclohexylmethyl-amine
(P-0435),
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-2-ylmcthyl-amine
(P-0436),
[2-(4-Chloro-phcnyI)-cthyl]-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyτimidin-2-yl]- amine (P-0437),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyrimidin-2-yl]-(4-difluoromethoxy-benzyl)- amine (P-0438),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-y]methyl)-pyrimidin-2-y]]-(4-methoxy-benzyl)-amine
(P-0439),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylinethyl)-pyrimidin-2-yl]-(4-methyl-benzyl)-amine
(P-0440),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-ethyl)-amiπe
(P-0441),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-fluoro-benzyl)-amine
(P-0442),
(3-Chloro-4-fluoro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0443),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidm-2-yl]-(2-ethoxy-benzyl)-amine
(P-0444),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidm-2-yl]-(4-morρholin-4-yl-benzyl)- amine (P-0445),
[5-(5-Chloro-lH-pyπOlo[2,3-b]pyτidin-3-y]mcthyl)-pyrimidin-2-yl]-(3-difluoromethoxy-benzyl)- amine (P-0446),
(4-Chloro-3-fluoro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine (P-0447),
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[l -{3-fluoro-phenyl)-ethyl]- amine (P-0448), and
[5-(5-Chloro-lH-pyrτolo[2.3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-dimethylamino-bcnzyl)- amine (P-0449).
The following table indicates the amine (Column 2) used in Scheme 194 to provide the compounds (Column 3). Column 1 provides the compound number and Column 4 the experimental mass spectrometry result.
Figure imgf000325_0001
Figure imgf000326_0001
Figure imgf000327_0001
Figure imgf000328_0002
Example 78: Synthesis of (2-chloro-6-fluoro-beπzyl)-[5-(lH-pyrrolo|2,3-blpyridin-3- ylmethyl)-pyridin-2-yl]-amine P-0210
[0794] (2-Chloro-6-fluoro-benzyl)-[5-(lH-pyπ-olo[2,3-b]p>τidin-3-ylmethyl)-pyridin-2-yl]- amine P-0210 was synthesized in 2 steps from 5-(l-Benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3- ylmethyl)-pyridin-2-ylaminc 600 as shown in Scheme 195.
Scheme 195
Figure imgf000328_0001
Step 1 -- Preparation of[5-(l-benzenesulfonyl-lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2- yl]-(2-chloro-6-fliιoro-benzyl)-amine (617):
[0795] 5-(l -Benzenesulfunyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamine (600. 30 mg, 0,083 mmol, prepared as described in Example 68, Scheme 185) was combined with 2-chloro- 6-fluoro-bcnzaldehyde (616. 26,2 mg, 0.165 mmol) in a 2 mL microwave reaction vial The mixture was dissolved in ethanol:acetic acid (95:5, 0.6 mL). Silica supported cyanoborohydridc (1.0 mmoL'g, 83 mg, 0.083 mmol) was added and the mixture was irradiated with microwave on 300 watts for 5 minutes at 100 0C. The silica was separated by centrifuging and the supernatant solution was decanted, The silica residue was rinsed with ethanol (0.500 mL) and centrifuged. The solvents were combined and removed under reduced pressure to give compound 617, which was used in the next step without further purification.
Step 2 - Preparation of(2-chloro-6-fluoro-benzyl)-f5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)- pyridin-2-yl] -amine (P-0210):
[0796] [5-(l-Benzenesulfonyl-l H-pyiτolo[2,3-b]pyτidin-3-ylmethyl)-pyridin-2-yl]-(2-chloro-6- fluoro-benzyl)-amine 617 was combined with methanol :potassium hydroxide (IM) (1 : 1 , 0,5 mL). The mixture was heated at 80 0C for 2 hours. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in dimethylsulfoxide (0.4 mL) and purified by reverse phase HPLC on a Phenomenex column (50mm x 10mm ID) eluting with 0.1 % trifluoroacetic acid in water and 20-100 % acetonitrile with 0.1 % trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0210 MS (ESI) [M+H+]+ = 367.1.
[0797] Additional compounds were prepared following the protocol of Scheme 195, replacing 2-chloro-6-fluoro-benzaldchyde 616 with an appropriate aldehyde in Step 1. The following compounds were made following this procedure:
Phenethyl-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0211), (2,4-Difluoro-ben/yl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>τidin-2-yl]-amine (P-0212), (2-Fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyridin-2-yl]-amine (P-0213), (3-Bromo-pyridin-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P- 0214),
(2-Methoxy-pyridin-3-ylmethyl)-[5-(l II-pyrrolo[2,3-b]pyπdin-3-ylmethyl)-pyridin-2-yl]-amine (P-0215),
(2-Chloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0216), (2-Methyl-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-aminc (P-0217), (l-Methyl-lH-benzoirnidazol-2-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylrnethyl)-pyridin-2- yl]-amine (P-0218), (6-Methoxy-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]p\τidin-3-ylmethyl)-p\τidin-2-yl]-amine
(P-0219),
(lH-Benzoimidazol-2-ylmethyl)-[5-(lH-pyrrolo[2.3-b]pyridm-3-ylmethyl)-pyridiπ-2-yl]-aminc
(P-0220),
(2-Ch]oro-4-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>τidin-2-yl]-amiπe (P-
0221),
(5-Methoxy-pyridin-3-ylmethyl)-[5-(lH-pyrτolϋ[2,3-b]pyτidin-3-ylmethyl)-p\τidin-2-yl]-aminc
(P-0222),
(3-Fluoro-pyridin-4-ylmethyl)-[5-( lH-pyrrolo[2,3-b]pyridin-3-ylπiethyl)-pyridin-2-yl]-amine (P-
0223),
(6-Methoxy-pyridin-2-ylmethyl)-[5-(lH-ρyrrolo[2,3-b]pyridin-3-ylmcthyl)-p>τidin-2-yl]-amine
(P-0224),
(4-FLuoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0225),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine
(P-0226),
(3,5-Dichloro-pyridin-4-ylmethyl)-[5-(lH-pyrτolo[2,3-b]pyridin-3-ylme(hyl)-pyridin-2-yl]-amiπe
(P-0227),
(6-Morpholin-4-yl-pyridin-2-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0228),
(3-Fluoro-pyridin-2-ylmethyl)-r5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-ρyridin-2-yl]-aminc (P-
0229),
(5-Fluoro-pyτidin-3-ylmethyl)-[5-(UI-p}τrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine
(P-0230),
(2,4-Dichloro-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0342),
(3-Fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amme (P-0343),
(2-Fluoro-4-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0344),
(4-Chloro-2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-aminc (P-
0345),
(3-Fluoro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyridin-2-yl]- amine (P-0346),
(2-Morpholin-4-yl-pyridiri-3-ylmethyl)-[5-(lH-pyrτolo[2,3-b]pyridin-3-ylincthyl)-pyridin-2-yl]- amine (P-0347),
(4-Chloro-3-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0348), (2-ChloiO-5-trifluoromethyl-ben2yl)-[5-(lH-p>τrolo[2,3-b]p>τidin-3-ylmethyl)-pyridin-2-yl]- amine (P-0349),
(2-Fluoro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrυlo[2,3-b]pyτidin-3-ylmethyl)-pyridin-2-yl]- amine (P-0350),
(2,3-Dichloro-benzyl)-[5-( 1 H-p>τrolo[2,3-b]pyridin-3-ylmethyl)-pyπdm-2-yl]-amme (P-0351),
(2-FIuoro-3-methoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyτidin-2-yl]-amine (P-
0352),
Dimethyl-(5- {[5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyridin-2-ylamino]-methylf-pyrirnidin-2- yl)-amine (P-0353),
(3-Chloro-2-fluoro-benzyI)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amiπe (P-
0354),
(5-Fluoro-pyridin-2-ylmethyl)-[5-( lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0355),
(3,5-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]-amine (P-0356),
(2-Proρoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0357),
(2-Morpholin-4-yl-benzyl)-f5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethy])-pyτidin-2-yl]-amine (P-
0358),
(2-Chloro-3-methoxy-benzyl)-[5-(lH-pyτrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0359),
(2-Fluoro-6-trifluoromcthyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0360),
[2-(2-Moipholin-4-yl-ethoxy)-benzyl]-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]- amine (P-0361),
(2,3-Difluoro-bcnzyI)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyτidm-2-yl]-ainiπe (P-0362),
(2-Chloro-3-trifluoromethyl-benzyl)-[5-(lH-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0363),
(2-Chloro-5-fluoro-benzyl)-[5-(lH-pyπOlo[2)3-b]pyridin-3-ylmetliyl)-pyτidin-2-yl]-amine (P-
0364),
(2-Fluoro-3-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0365),
(5-Fluoro-2-methoxy-benzyl)-[5-(lII-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0366),
(2-DJfluoromethoxy-ben2y])-[5-( 1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-aminc (P-
0367),
(2-Fluoro-4-methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]-amine (P-
0368), [2-(3-Dimethylamino-propoxy)-benzyl]-[5-(lH-pyrrolo[2,3-b]pvτidm-3-ylmethyl)-p>τidin-2-yl]- amine (P-0369),
(2,6-Dimethoxy-p\τidin-3-ylmethyl)-[5-(lH-ρyrrolo[2,3-b]pyridin-3-ylmethyl)-p>τidin-2-ylJ- amine (P-0370),
(2-Fluoro-5-mcthoxy-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]-amine (P-
0371),
(4-Fluoro-2-methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyτidin-2-yl]-amme (P-
0372),
(3-Chloro-5-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0373),
(6-Cyclopenlyloxy-pyridin-3-ylmcthyl)-[5-(lH-pyπOlo[2,3-bJpyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0374),
(5-Fluoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0375),
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylJ-L2-(2,2.2-trifluoro-ethoxy)-pyridin-3- ylmethyl] -amine (P-0376),
Propane- 1 -sulfonic acid (2-fluoro-3-{[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2- ylaminoj-methyl} -phenyl)-amide (P-0377),
(2,5-Dichloro-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0380),
Pyrimidin-5-ylmcthyl-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0381),
(5-Chloro-2-fluorθ-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0382),
(2-Ethyl-benzyl)-[5-(l II-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0383),
2,2-Dimcthyl-N-(3-{[5-(lH-pyrrolo[2)3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino] -methyl} - pyridin-2-yl)-propionamide (P-0384),
Methyl-(3-{[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylaminoJ-methyl}-pyridin-2-yl)- amine (P-0385),
Mcthyl-(5-{[5-( lH-pyrrolo[2,3-b]pyridin-3-ylraethyl)-pyridin-2-ylamino]-methyl}-pyrimidin-2- yl)-amine (P-0386),
(2-Chloro-4-methanesulfonyl-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine (P-0387),
(5-Fluoro-2-methyl-ben2yl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-
0397),
(2,2-Difluoro-bcn/o[l,3]dioxol-4-ylmethyl)-[5-(lH-pyrrolol2,3-b]pyridin-3-ylmethyl)-pyridin-2- yl]-amine (P-0398),
Dimethyl-(3-{[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-ylamino]-rriethyl}-pyridin-2- yl)-amine (P-0399),
(5-Chloro-pyridin-3-ylmethyl)-[5-(lH-pyrrolof2,3-b]p>τidin-3-ylmethyl)-pyridin-2-yl]-amine (P- 0400), and
(2-Melhϋxy-ρyrirnidin-5-ylmethyl)-[5-(lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine (P-0401).
The following table indicates the aldehyde (Column 2) used in Step 1 of Scheme 195 to provide the compounds (Column 3). Column 1 provides the compound number and Column 4 the experimental mass spectrometry result.
Figure imgf000333_0001
Figure imgf000334_0001
Figure imgf000335_0001
Figure imgf000336_0001
Figure imgf000337_0001
Figure imgf000338_0001
Figure imgf000339_0001
Example 79: Synthesis of [4-Chloro-5-(5-chloro-1H-pyrrolo [2,3-b]pyridin-3-ylmethyl)- thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine P-0190
[0798] [4-Chloro-5-(5-chloro-l H-pyrroloP^-bJpiTidin-S-ylmethy^-thiazol-Z-y^-Cό-methoxy- pyridin-3-ylmethyl)-amine P-0190 was synthesized in 2 steps from 5-(l -benzenesulfbnyl-5-chloro- l H-pyrτolϋ[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine 592 as shown in Scheme 196.
Scheme 196
Figure imgf000339_0002
Step I - Preparation of [ 5 -( 1 -henzenesulfonyl-S-chloro- 1 H-pyrrolo[ 2 ,3-b] pyridin-3-ylmethyl)-4- chloro-thiazol-2-yl]-(6-methoxy-pyridin-3-ylmethyl)-amine (619);
[0799] 5-(l -Benzcnesulfonyl-5-chloro-lH-pyrrolo[2,3-b]p)τidin-3-ylmϋthyl)-4-chlϋro-thiazol- 2-ylamme (592, 30 mg, 0.083 mmol, prepared as described in Example 66, Scheme 183) was combined with ό-methoxy-pyridine-3-carbaldchyde (618, 26.2 mg, 0.165 mmol) in a 2 rriL microwave reaction vial. The mixture was dissolved in ethanol: acetic acid (95:5, 0,6 mL). Silica supported cyanoborohydride (1.0 mmol/g, 83 mg, 0.083 mmol) was added and the mixture w-as irradiated with microwave on 300 watts for 5 minutes at 100 0C. The silica was separated by centrifuging and the supernatant solution was decanted. The silica residue was rinsed with ethanol (0.500 mL) and centrifuged. The solvents were combined and removed under reduced pressure to give the desired compound 619, which was used without further purification.
Step II - Preparation of [4-chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2- yl]-(6-tnethoxy-pyridin-3-ylmethyl)-amine (P-0190):
[08001 [5-(1 -Ben7enesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-lhiazol-2-yl]-(6- methoxy-pyridm-3-ylrnethyl)-aminc 619 was combined with methanol: potassium hydroxide (I M) (1 : 1 , 0.5 mL). The mixture was heated at 80 0C for 2 hours. Acetic acid (0.1 mL) was added and the solvents removed under reduced pressure. The remaining residue was dissolved in dimethylsulfoxide (0.4 mL) and purified by reverse phase HPLC on a Phenomenex column (50mm x 10mm ID) eluting with 0.1 % trifluoroacctic acid in water and 20-100 % acetonitrile with 0.1 % trifluoroacetic acid over 16 minutes at a flow rate of 6 mL/minute to provide the desired compound P-0190. MS (ESI) [M+H+] f = 419.9.
10801] Additional compounds were prepared following the protocol of Scheme 1 96, replacing 6-methoxy-pyridine-3-carbaldehyde 618 with a suitable aldehyde in Step 1. The following compounds were made following this procedure:
[4-Chloro-5-(5-chloro-lH-pyrrolo[2!3-b]pyridin-3-ylmelhyl)-thiazol-2-yl]-thiazol-2-ylmethyl- amine (P-Ol 89),
Benzyl-[4-chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-ylJ-amine (P-0192), [4-Chloro-5-(5-chloro-lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-methoxy-benzyl)- amine (P-0193),
(4-Chloro-benzyl)-[4-chloro-5-(5-chloro-lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]- amine (P-0194),
[4-Chloro-5-(5-chloro-lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)- amine (P-0195),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5- ylmefhyl)-amine (P-0196), [4-Chloro-5-(5-chloro-l H-p>τrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethyl-5-meth>l-3H- imidazol-4-ylmethyl)-amine (P-0197),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-t;thyl-2H-pyrazol-3- >imethyl)-amine (P-0198),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-2- ylmethyl)-amine (P-0199),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-4- ylmethyl)-amine (P-0200),
[4-Ch]oro-5-(5-chloro-lH-pyrrolof2,3-b]pyridin-3-y]methyl)-thiazol-2-yl]-(2-methyl-thiazol-4- ylmethyl)-amine (P-0201),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-methyl-thiazol-5- ylmethyl)-amine (P-0202),
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-ch]oro-pyridin-2- ylmethyl)-amine (P-0203),
[4-Chloro-5-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl- amine (P-0236),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmcthyl- amine (P-0237),
[4-Chloro-5-(5-chloro-1 H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-chloro-pyridin-4- ylmethyD-aminc (P-0238),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thia2ol-2-yl]-(l -ethyl- lH-pyrazol-4- ylmethyl)-amine (P-0239),
[4-Chloro-5-(5-chloro-] II-pyπOlo[2,3-b]pyridiπ-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridiπ-2- ylmethyl)-amine (P-0240),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3- ylmethyl)-amine (P-0241),
[4-Chloro-5-(5-chIoro-l H-pyrrolo[2,3-bJpyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl- pyridin-3 -ylmcthyl) -amine (P-0242),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-6-fluoro- ben2yl)-amine (P-0243),
[4-ChIoro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-phenethyl-amiπc (P-0244),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-y]methyl)-thiazol-2-yl]-(2,4-difluoro-benzyl)- amine (P-0245),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazoI-2-yl]-(2-fIuoro-beπzyl)- amine (P-0246), [4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridm-3-ylmethyl)-thiazol-2-yl]-(2-methoxy-ρ\τidin-3- ylmethyl)-amine (P-0247),
(2-Chloro-benzyl)-[4-chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]- amine (P-0248).
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-benzyl)- amine (P-0249).
[4-Chloro-5-(5-chloro-lH-pyτrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-chloro-4-fluoro- benzyl)-amine (P-0250),
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-2- ylmethyl)-amine (P-0251),
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-morpholin-4-yl- pyridin-2-ylmethyl)-amine (P-0252),
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3,5-dichloro-pyridin-4- ylmethyl)-amine (P-0253),
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-thiazol-2-yl]-(2-tnfluoromethyl- benzyl)-amine (P-0254), and
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2- ylraethyl) -amine (P-0255).
The following table indicates the aldehyde (Column 2) used m Step 1 of Scheme 196 to provide the compounds (Column 3). Column 1 provides the compound number and Column 4 the experimental mass spectrometry result.
Figure imgf000342_0001
Figure imgf000343_0001
Figure imgf000344_0001
Figure imgf000345_0001
[0802] Additional compounds were prepared following the protocol of Scheme 196, replacing 5-(l -benzenesulfonyl-5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine
592 with 5-(l -benzenesulfonyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-4-chloro-thiazol-2-ylamine
593 (prepared as described in Example 66, Scheme 183) in addition to replacing 6-methoxy- pyridinc-3-carbaldehyde 618 with a suitable aldehyde in Step 1. The following compounds were made following this procedure:
[4-Chloro-5-(lH-p>τrolo[2,3-b]pyridin-3-ylmeth\.l>thiazol-2-yl]-(2,4-dimethyl-thiazol-5- ylmethyl)-amine (P-0204),
[4-Chloro-5-(l H-p>τrolo[2,3-b]pyridin-3-ylmeth>l)4hiazol-2-yl]-(2-ethyl-5-methyl-3H-imidazol- 4-ylmethyl)-amine (P-0205),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-2-ylmcthyl)- amine (P-0206),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-niethoxy-pyridin-3-ylmethyl)- amine (P-0207),
[4-Chloro-5-(lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4,5-dimethyl-thiophen-2- ylmethyD-aminc (P-0208),
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,5-dimethyl-thiophen-3- ylmethyl)-amine (P-0209),
The following table indicates the aldehyde (Column 2) used in Step 1 of Scheme 196 to provide the compounds (Column 3). Column 1 provides the compound number and Column 4 the experimental mass spectrometry result.
Figure imgf000346_0001
Figure imgf000347_0003
Example 80: Synthesis of 5-[l-(lH-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]-pyridin-2-yl-(4- trifluoromethyl-benzyl)-amine P-0388
|0803] 5-[l-(lH-Pyrrolo[2,3-b]pvridin-3-yl)-ethyl]-pyridin-2-y]-(4-trifluoromethyl-benzyl)- amine P-0388 was synthesized from (5-bromo-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-aniine 17 as shown in Scheme 197.
Scheme 197
Step 3
Figure imgf000347_0001
Figure imgf000347_0002
Step 1 - Preparation of 1 -[6~(4-trifluoromethyl-benzylamino)-pyridin-3-yl] -ethanone (620): [0804] (5-Bromo-pyridin-2-yl)-(4-trifluoromemyl-benzyl)-amine (17, 3.00 g, 9 06 mmol, prepared as described in Example 10, Scheme 12) was dissolved in tetrahydrofuran (80 niL). The reaction was cooled at -78 0C under an atmosphere of argon. 2.5 M n-butyllithium in hexane (10,9 mL) was added. The reaction was stirred at -78 0C for 60 minutes. N-Methoxy-N- methylacetamide (1.93 mL, 18.1 mmol) was added to the reaction, which was allowed to warm to room temperature. The reaction was poured into 1 M ammonium chloride and brine and extracted with ethyl acetate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography (ethyl acetate:hexanes) to provide the desired compound as an oil that crystallized to a white solid (620, 1.328 g, 50%), consistent with the compound structure by 1H-NMR and MS(ESI): [M+H !] '=295.3, Step 2 - Preparation of(5-acetyl-pyridin-2-yl)~(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (621):
[0805] To 1 -[ό-(44rifluoromethyl-benzylammo)-pvridin-3-yl]-ethanone (620, 1.3O g, 4.42 mmol) in tctrahydrofliran (15.0 mL) were added di-tert-butyldicarbonate (1.10 g, 5.04 mmol), 4- dimethylaminopyridine (0.0259 g, 0.21 mmol) and N,N-diisopropylethylamine (0,888 mL, 5.10 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature for 3 days. The mixture was extracted with ethyl acetate and saturated sodium bicabonate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography (0- 15% ethyl acetate:hexanes) to provide the desired compound as an oil that solidified to a white solid (621, 1 .29g, 74%), consistent with the compound structure by 1H-NMR.
Step 3 - Preparation of 1 - [6-(4-triβuoromethyl-benzylamino)-pyridin-3-yl] - 1 -( 1 - triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-ethanol (622):
[0806] 3-lodo-l -triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (96, 485.9 mg, 1.21 mmol) was dissolved in tetrahydrofuran (8 mL) at -20 0C under an atmosphere of nitrogen. 2.0 M isopropylmagnesium chloride in tetrahydrofuran (0.655 mL) was added. The reaction was stirred at -20 0C for 1 hour. Into the reaction was added (5-acetyl-pyridin-2-yl)-(4-trifluoromethyl- benzyl)-carbamic acid tert-butyl ester (621, 300.0 mg, 0.76 mmol) in tetrahydrofuran (6 mL) The reaction was allowed to warm to room temperature overnight. The mixture was extracted with ethyl acetate and saturated sodium bicabonate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography on the (ethyl acetate:hexanes), to provide the desired compound as an oil (622, 125 mg, 29%), consistent with the compound structure by 1H-NMR.
Step 4 - Preparation of5-[l-(lH-pyrrolo[2,3-b]pyridin-3-yl)-vinvl]-pyridin-2-yl-(4- triβuoromethyl-benzyl)-amine (623):
[0807] 1 -[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-yl]-l -(I -triisopropylsilanyl-1 H- pyrrolo[2,3-bJpyridin-3-yl)-ethanol (622, 125.0 mg, 0.22 mmol) was dissolved in acctonitrilc (1 1.7 mL) and trifluoroacetic acid (0.175 mL, 2,3 mmol) and triethylsilane (0.292 mL, 1.8 mmol) were added. The reaction was heated to reflux overnight. The reaction was concentrated, then washed with ethyl acetate and saturated sodium bicarbonate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography (0-60% ethyl acetate :hexanes) to provide the desired compound (623, 43 mg, 50%), consistent with the compound structure by 1H-NMR.
Step 5 - Preparation of S-[I-(I I I-pyrrolo[2,3-b]pyridin~3-yl)-ethyl]-pyridin~2-yl-(4- ιriβuυrυmethyl-benzy1)-amine (P-0388),
[0808] 5-[l-(lH-P>τrolo[2.3-b]pyridin-3-yl)-vinyl]-pyridin-2-yl-(4-trifluoromethyl-benzyl)- amine (623, 0.043 g, 0,0001 1 mol) was dissolved in tetrahydrofuran (10 mL) and methanol ( 10 niL). The reaction was shaken under an atmosphere of hydrogen (30 psi) overnight The reaction was filtered through Celite and the filtrate adsorbed onto silica and purified by silica gel column chromatography (ethyl acetate;hexanes) to provide the desired compound as a white solid (P-0388, 2.1 mg, 5%), consistent with compound structure by 1H-NMR and MS(ESI): [M+H']"=397.6.
Example 81: Synthesis of [5-(5-Chloro-lH-pyrrolo[2,3-b|pyridin-3-ylmethyl)-thiazol-2-yl]- (4-fluoro-benzyl)-amine P-0290
[0809] [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine P-0290 was synthesized in four steps from (4-fluoro-bcnzyl)-(4-chloro-5-formyl-thiazol-2-yl)- carbamic acid tert-butvl ester 624 as shown in Scheme 198.
Scheme 198
Figure imgf000349_0001
Step 1 - Preparation of(4-βuoro-henzyl)-(4-chloro-5-formyl-thiazυϊ-2-yl)-carbamic acid tert-buly! ester (625) -
|0810] To a solution of (4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert- butyl ester (624, 1 g, 2.70 mmol, prepared as described in Example 44, Scheme 159, Step 2, where 4-(aminomethyl)pyridine 516 is replaced with p-fluorobenzylamine, i.e. intermediate in preparing compound P-0156) in methanol (100 mL) was added Pd/'C (100 mg, 50% water wet) and sodium acetate (660 mg, 8.09 mmol) and the mixture was shaken under an atmosphere of hydrogen (50 psi) overnight observing -50% conversion by LC /MS. The mixture was filtered over a bed of Celite and the solvent was removed in vacuo and the residue purified by silica gel chromatography (ethyl acetate/heptane) to provide the desired compound as an off-white solid (450 me, 50 %), consistent with compound structure by 1H-NMR,
Step 2 - Preparation of{5-[(5-chhro-l-trusopropylsilanyl-lH-pyrrolo[2,3-k]pyridin-3-yl)- hydroxy-methyl]-thiazol-2-yl}-(4-βuoro-benzyl)-carbamic acid tart-butyl ester (627); [U811] To a solution of 5-diloro-3-iodυ-l -(triisopropylsilyl)-lH-pyrrolo[2.3-b]pyridine (626, 300 mg, 0,69 mmol) in tetrahydrofuran (10 mL) at -20 11C was added dropwise iso-propyl- magnesium chloride (2M in tetrahydrofuran, 0.44 mL, 0.88 mmol). The reaction mixture was allowed to warm to 0 0C over 10 minutes and then cooled to -40 0C, To this reaction mixture was added a solution of (4-fluoro-benzyl)-(4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (625, 21 1 mg, 0.63 mmol) in tetrahydrofuran (5 mL). The reaction mixture was allowed to warm to 0 0C over 30 minutes and then quenched with brine (50 mL). The mixture was transferred to a separatory funnel and the layers were separated. The organic layer was dried over sodium sulfate and evaporated in vacuo to give the crude material which was purified by silica gel column chromatography (0-30% ethyl acetate/heptane) to provide the desired compound as a foam (120 mg, 30%), consistent with structure by 1H-NMR.
Step 3 - Preparation of[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4- fluoro-benzyl)-carbamic acid tert-butyl ester (628):
10812] To a solution of {5-[(5-chloro-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridin-3-yl)- hydroxy-methyl]-fhiazol-2-yl}-(4-fluoro-benzyl)-carbamic acid tert-butyl ester (627, 120 mg, 0.186 mmol) in acetonitrile (3 mL) was added trifluoroacetic acid (0.14 mL, 1.86 mmol) and triethylsilane (0.30 mL, 1.86 mmol). The resulting mixture was stirred for 2 hours at 40 0C. The solvent was then removed in vacuo and the residue was used directly in the next step.
Step 4: Preparation of [5-(5-chloro-lH-pyrrolo[2, 3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro- benzylj-amine (P-0290):
|0813] To the solution of crude [5-(5-chloro-llI-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]- (4-fluoro-benzyl)-carbamic acid tert-butyl ester (628, 0.186 mmol theory) in dichloromethane (5 mL) at room temperature was added trifluoroacetic acid (1 mL) and the reaction was allowed to stir overnight. The solvent was removed in vacuo and the residue taken up in ethyl acetate and then washed with saturated aqueous potassium carbonate making sure basicity was reached. The layers were separated and the aqueous layer was back-extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and evaporated in vacuo to give the crude product which was purified by silica gel chromatography (0-10% methanol/ethyl acetate). The solvent was removed in vacuo and the material was triturated with dichloromethane to give the desired compound as an off-white solid (20 mg, 29 % over 2 steps) consistent with compound structure by 1H-NMR and MS(ESI); [M+IT]+=372.9.
[0814] (4-Fluoro-beπzyl)-[5-(l H-p>τrolo[2,3-b]p>τidin-3-ylmethyl)-thiazol-2-yl]-amiπe P-0389
Figure imgf000351_0001
was synthesized following the protocol of Scheme 198, replacing 5-chloro-3-iodo-l - (triisopropylsilyl)-lH-pyrrolo[2,3-b]pyridine 626 with 3-iodo-l -triisopropykilanyl-l H- pyrrolo[2,3-b]pyridine 96. to provide the desired compound, consistent with structure by I H-NMR and MS(HSI): [M+HT=339.0.
Example 82: Synthesis of (5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-|2-ethyl-5-(4-fluoro- benzylamino)-2H-pyrazol-3-yl]-methaπone P-0184
[0815] (5-Chloro-lH-pyrrolo[2,3-b]pyridin- 3-yl)-[2-ethyl-5-(4-fluoro-bcnzylamino)-2H- pyrazol-3-yl]-methanone P-0184 was synthesized from 5-chloro-lH-pyrrolo[2,3-b]pyridine 532 in 1 step as shown in Scheme 199.
Scheme 199
Figure imgf000351_0002
Step 1 - Synthesis of(5-chloro-lli-pyrrolo[2,3-b]pyridin- 3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)- 2H-pyrazol-3-yl]-methanone (P-0184):
[0816] 5-Chloro-l H-pyrrolo[2,3-b]pyridine (532, 0,068 g, 0.44 mmol) was combined with methanol (10 ml.) and potassium hydroxide (0.16 g, 2.8 mmol), The mixture was stirred for 50 minutes, then 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 0.100 g, 0,40 mmol, prepared as described in Example 47, Scheme 162, Step 5) was added and the reaction was stirred overnight at room temperature and then concentrated. Ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate the solvent was removed under reduced pressure. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (10-100%) in hexanes provided the desired compound (0.0033 g, 2%). MS (ESI) [M+H*T = 398,1 .
Example 83: Synthesis of [5-(5~chloro-lH-pyrrolo[2,3-b]pyridin-3-vlmethvl)-l-ethyl-lH- pyrazol-3-yl]-(4-fluoro-benzyl)-amine P-0185
[0817] [5-(5-Cliloro-lH-p>ττolo[2,3-b]p>τidin-3-ylmethyl)-l-ethyl-lH-pyrazol-3-yl]-(4-fluoro- benzyl)-amine P-0185 was synthesized from 5-chloro-3-iodo-l -triisopropylsilanyl-lH-pyrrolo[2,3- b]pyridine 629 in 2 steps as shown in Scheme 200.
Scheme 200
Figure imgf000352_0001
Step 1 - Synthesis υf(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)- 21 I-pyra∑ol-3-y I] -methanol (630):
[0818] 5-Chloro-3-iodo- l -triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridine (629, 0.15 g, 0.34 mmol) was dissolved in tetrahydrofiiran (3 rnL, 40 mmol) and the solution was cooled to -20 0C. 2 M isopropylmagnesium chloride in tetrahydrofuran (200 μL) was added dropwise and the reaction was stirred and allowed to warm to -5 0C. After the reaction was cooled to -20 0C, 2-ethyl-5-(4- fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 0,043g, 0.17 mmol, prepared as described in Example 47, Scheme 162, Step 5) in tetrahydrofuran (4 mL) was added to the mixture. The reaction was stirred to -5 0C, then concentrated, ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate, the solvent was removed under reduced pressure. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (5-80%) in hexanes gave the desired compound (630, 0.038 g, 40%).
Step 2 - Synthesis of5-(5-chIoro-lH-pyrrolo[2,3-b]pyrid in-3-ylmethyl)-l-ethyl~lH-pyrazol-3 -ylj- (4-fluoro-benzyl)-amine (P-0185);
[0819] (5-Chloro-l-triisopropylsilanyl-lH-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethy l-5-(4-fluoro- benzylamino)-2H-pyrazol-3-yl]-mefhanol (630, 0.045 g, 0.081 mmol) was dissolved in acetonitrile (5 mL) and tπethylsilane (0.4 mL, 2.0 mmol) was added, followed by trifluoroacetic acid (0.2 mL, 2.0 mmol). The reaction was stirred at room temperature for 45 minutes, then stirred at 60 0C for 45 minutes. The solvent was removed under reduced pressure, ethyl acetate was added and the organic was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated to dryness, Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (40-100%) in hexanes gave the isolation of the desired compound (P-0185, 0.0068 g, 22%), MS (ESI) [M+IT"f = 384.1 .
Example 84; Synthesis of 3-2-Fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-amino]-pyridin-3- ylmethyl-lH-pyrrolo[2,3-blpyridine-5-carbonitrilc P-0415
[0820] 3-2-Fluoro-6-[(5-fluoro-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl-lH-pyrrolo[2,3- b]pyridine-5-carbonitrile P-0415 was synthesized in 5 steps from lH-Pyrrolo[2,3-b]pyridme-5- carbonitrile 632 as shown in Scheme 201.
Scheme 201
Figure imgf000353_0001
Step I - Synthesis of3-dimethylaminomethyl-lH-pyrrolo[2,3-b]pyridine-5-carbonitrile (633): [0821] To lH-Pyrrolo[2,3-b]pyridine-5-carbonitrile (632, 3.00 g, 0.0210 mol) in isopropyl alcohol (120 inL) were added dimethylamine hydrochloride (1 ,91 g, 0.0235 mol) and formaldehyde (0.708 g, 0.0236 mol). The reaction was heated to reflux overnight, then concentrated, poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% to 30% methanol in dichloromcthane containing 0.3% triethyl amine to give the desired compound (633, 2,0 g, 48%).
Step 2 - Synthesis of5-cyano-3-dimethylaminomethyl-pyrrolof2,3-bJpyridine-l-carboxylic acid ten-butyl ester (634):
[0822] To 3-dimethylaminomcthyl-l H-pyrrolo[2,3-b]pyτidinc-5-carbonitrile (633, 2.0 g, 0.010 mol) in tetrahydrofuran (60.0 mL) were added di-tert-butyldicarbonate (2.62 g, 0.0120 mol). 4-dimethylaminopyridine (0.12 g, 0,0010 mol) and triethylamine (4.0 mL, 0.029 mol). The reaction was stirred at 45 °C over a weekend, then concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 2% to 30% methanol m dichloromethane in hexane to give the desired compound (634, 2.50 g, 83%).
Step 3 - Synthesis of 3-chloromethyl~5~cyano-pyrrolo[2,3-h] pyridine- 1-carhoκylic acid tert-butyl ester (635):
[0823] To 5-cyano-3-dimethylaminomethy]-pyrrolo[2.3-b]pyridine-l-carboxylic acid tert-butyl ester (634, 2,60 g, 8.66 mmol) in toluene (60.0 mL) under an atmosphere of nitrogen was added ethyl chloroformate (0.828 mL, 8.66 mmol). The reaction was stirred at room temperature for 3 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give a white solid (635, 400 mg, 16%).
Step 4 ~ Synthesis of [5-(5-cyano-lH-pyrroh[2,3-b]pyridin-3-ylmethv!)-6-fluoro-pyridin-2-yl]-(5~ fluoro-pyridin-3-ylmethyl)-carbamic acid tert-butyl ester (636);
[0824] To (5-bromo-6-fluoro-pyridin-2-yl)-(5-fiuoro-pyridin-3-yhnethyl)-carbamic acid tert- butyl ester (631, 0.600 g, 1.50 mmol, prepared as described in Example 60) in tetrahydrofuran (10.0 mL) at -25 0C under an atmosphere of nitrogen, was added a solution of isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 0.730 mL). The reaction was allowed Io warm to 5 0C over 1 hour. The reaction was cooled to -35 DC, followed by addition of a solution of CuCN.2LiCl (0.65 M in tetrahydrofuran, 2.4 mL). After 5 minutes, 3-chloromethyl-5-cyano- pyrrolo[2,3-b]p>τidine-l-carboxylic acid tert-butyl ester (635, 0.086 g, 0.29 rnmol) in tetrahydrofuran (4.0 mL) was added to the reaction. The reaction was allowed to warm to room temperature over 1 hour, then poured into a diluted ammonia solution, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexane to give the desired compound (636, 0.13 g, 92%). MS (ESI) [M+Hτ] f = 477.4.
Step 5 - Synthesis of3-2-fluoro-6-[(5-βuυro-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl-lH- pyrrol u [2, 3-b] pyridine-5-carbonitrile (P-041 S):
[0825] To [5-(5-cyano-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(5-fluoro- pyridin-3-ylmefhyl)-carbamic acid tert-butyl ester (636, 0.130 g, 0.27 nimol) in dichloromethane (10.0 mL) was added trifluoroacetic acid (1.00 mL, 0.0130 mol). The reaction was stirred at room temperature overnight. The reaction was concentrated, poured into aqueous potassium carbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% to 1 00% ethyl acetate in hcxane to give a white solid (P-0415, 85.6 mg, 83,4%), MS (ESI) [M+tr J+ = 377.0,
[0826] (5-Fluoro-p}τidin-3-ylmethyl)-[6-fluorϋ-5-(l H-pyrrolo[2,3-b]pyτidin-3-ylmethyl)- pyridin-2-yl]-amine P-0414
Figure imgf000355_0001
was prepared following the protocol of Scheme 201 , replacing lII-Pyrrolo[2,3-b]pyridine-5- carbonitrile 632 with lH-Pyrrolo[2,3-bJpyridme in Step 1. MS (ESI) [M+HT = 352.5.
[0827] 3-[6-(4-Chloro-benzylamino)-2-fluoro-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5- carbonitrile P-0432
Figure imgf000355_0002
was prepared following the protocol of Scheme 201, replacing 5-bromo-6-fluoro-pyridin-2-yl)-(5- fluoro-pyridin-3-ylmcthyl)-carbamic acid tert-butyl ester 631 with (5-Bromo-6-fluoro-pyridin-2- yl)-(4-chloro-benzyl)-carbamic acid tert-butyl ester 637 (prepared as described in Example 60) in Step 4. MS (ESI) [M-HHf]+ = 391.9.
Example 85: Synthesis of (3-chloro-benzyl)-[5-(5-chloro-lH-pyrrolo [2,3-b] pyridin-3- ylmethyl)-l-methyl-lH-pyrazol-3-yl]-amine P-0410
[0828] (3-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo [2,3-b]pyridin-3-ylmethyl)-l - methyl-lll- pyrazol-3-yl] -amine P-0410 was synthesized in 11 steps from lII-pyrazolc-3,5-dicarboxylic acid monohydrate 638 as shown in Scheme 202.
Scheme 202
Figure imgf000356_0001
Step I - Preparation of lH-pyrazole-3,5-dicarboxylic acid dimethyl ester (639): [0829] l H-Pyrazole~3,5-dicarboxylic acid monohydrate (638, 21.1 g, 121.0 mmol) was combined with methanol (350 mL) and hydrogen chloride (10 mL), The reaction was stirred at reflux overnight and then concentrated. The resulting solid was washed with ethyl acetate and hexanes and dried under reduced pressure. The obtained compound 639 was used without further purification. MS (ESI) [M+H+]+= 185.0.
Step 2 - Preparation of 1 -methyl- lH-pyrazυle-3,5-άicarhoxylic acid dimethyl ester (640): [0830] lH-Pyrazole-3,5-dicarboxylic acid dimethyl ester (639, 9.1 g, 49.0 mmol) was combined with acetone (400 mL) and potassium carbonate (10.2 g, 74.1 mmol). The mixture was stirred for 40 minutes under an atmosphere of nitrogen. To the stirring suspension, methyl iodide (3.4 mL, 54.0 mmol) was added dropwise The reaction was stirred at room temperature overnight and then the solvent was evaporated under reduced pressure. The resulting solid was washed with water and filtered. After toluene was added, the solvent was removed under reduced pressure. The resulting compound 640 was used without further purification.
Step 3 - Preparation of 1 -methyl-1 H-pyrazole-3, 5-dicarhoxylic acid 5-ιnethyl ester (641): [0831| 1 -Methyl-1 H-pyrazole-3, 5-dicarboxylic acid dimethyl ester (640, 3.7 g, 19.0 mmol) was combined with 1 ,4-dioxane (20 mL) and water (60 mL). Concentrated sulfuric acid (1.0 mL) in 2 mL of water was added to the solution. After the reaction was stirred at reflux overnight, it was cooled to room temperature and concentrated until precipitation began. The obtained mixture was left standing overnight. The resulting solid was filtered and dried under reduced pressure. The collected aqueous fractions were extracted with ethyl acetate. The organic portion was dried over anhydrous sodium sulfate and concentrated. Additional solid was crystallized from ethyl acetate to give the desired compound (641, 2.33 g, 68%). MS (ESI) [M+H*]' = 185.0, melting point 175 0C.
Step 4 Preparation of5-azidocarbonyl-2-methyl-2H-pyrazolc-3-carbυxylic acid methyl ester (642):
[0832] 1 -Methyl- lH-pyrazole-3,5-dicarboxylic acid 5-methyl ester (641, 3.2 g, 17.0 mmol) was combined with thionyl chloride (5 mL). The reaction was heated to reflux for 40 minutes and then concentrated twice from toluene. The resulting solid was dried under reduced pressure overnight. The product was dissolved into acetone (20 mL) and sodium azide (3.5 g, 54.0 mmol) was added in water (10 mL) rapidly at once. The obtained solution was stirred for one minute and then poured into ice-water (5OmL). The precipitate was filtered and dried under reduced pressure. The final compound was used without further purification (642, 2.8 g, 77%).
Step 5 — Preparation of5-benzyloxycarbonylamino-2-methyl-2H-pyrazole-3-carboxyhc acid methyl ester (643):
[0833] 5-Λzidocarbonyl-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (642, 2.8 g, 13.0 mmol) was combined with toluene (35 mL) and benzyl alcohol (2.1 mL, 20,0 mmol). The reaction was heated to reflux for 45 minutes and then the solvent was removed under reduced pressure. The compound (643, 2.4 g, 62%) was washed with methanol and dried under vacuum. MS (ESI) [M+H+]+= 290.3.
Step 6 - Preparation υf5-amino-2~methyl-2FI-pyrazole-3-carboxylic acid methyl ester (644): [0834] 5-Benzyloxycarbonylamino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (643, 2.2 g, 7.6 mmol) was combined with methanol (50 mL) and 10% palladium on carbon (500 mg). The mixture was stirred under an atmosphere of hydrogen for three hours, The mixture was filtered through Celite and the solvent was removed under reduced pressure to give the desired compound (644, 1 .2 g, 98%). (ESI) [M+H'] f = 156.1.
Step 7 - Preparation qf5-(3~chloro~benzylamino)-2~methyl-2H-pyrazole-3-carbox\ lie acid methyl ester (646):
[0835J 5-Amino-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (644, 1.3 g, 8.0 mmol) was combined with 3-chlorobenzaldehyde (645, 0.95 mL, 8.4 mmol) and acetonitrile (40 mL). Tπfluoroacetic acid (3.2 mL, 42.0 mmol) was added followed by trielhykilane (6.7 mL. 42.0 mmol). The reaction was heated to reflux overnight and then concentrated. Ethyl acetate was added and the solution was washed with IN potassium carbonate. The organic portion was dried over anhydrous sodium sulfate, filtered and concentrated. The compound (646, 0.944 g, 42%) was crystallized from a mixture of ethyl acetate: hexane. Step 8 ~ Preparation of '/ 5-(3-chlorn-benzylamino)-2-methyl-2H-pyrazol-3-yl) '-methanol (647): [0836] 5-(3-Chloro-benzylamino)-2-methyl-2 H-pyrazole-3-carboxylic acid methyl ester (.646, 0.944 g, 3.37 mmol) was combined with tetrahydrofuran (20 ml.) and the solution was cooled to -40 0C. 1.0 M lithium tetrahydroaluminate in tetrahydrofuran (3.7 mL) was added and the reaction was stirred for 45 min at -20 0C. 1 ,0 M lithium tetrahydroaluminate in tetrahydrofuran (3,7 mL) was added at -40 0C and the reaction was stirred to 10°C. Sodium sulfate decahydrate was added in small portions and the mixture was stirred for two hours at room temperature, then filtered through Celite and concentrated. The resulting compound (647, 0.821 g, 97%) was washed with a mixture of ethyl acetate: hexanes and dried under reduced pressure.
Step 9 - Preparation of5-(3-ch!oro-benzylamino)-2-methyl-2H-pyrazole-3-earbahiehyde (648): [0837] [5-(3-Chloro-benzylamino)-2-methyl-2H-pyrazol-3-yI]-methanol (647, 0.821 g, 3.26 mmol) was combined with dichloromethane (70 mL) and manganese(IV) oxide (4 g). The reaction was stirred at room temperature overnight under an atmosphere of nitrogen. The mixture was filtered through Celite and concentrated. Purification by silica gel column chromatography eluting with a gradient of ethyl acetate (10-100%) in hexane gave the desired aldehyde (648, 0.482 g, 60%).
Step I O - Preparation ofl5-(3-chloro-benzylamino) 2-methyl-2H-pyrazol-3-yl]-(5-chloro-l- triisopropylsilanyl- 1 H-pyrrolo[2,3-b] pyridin-3-yl)-methanol (649):
[0838] 5-Chloro-3-iodo-l-triisopropylsilanyl-l H-pyrrolo[2,3-b]pyridinc (629, 0.19 g, 0.44 mmol) was dissolved in tetrahydrofuran (0.9 mL). The solution was cooled to -20 0C. 2M isopropylmagncsium chloride in tetrahydrofuran (200 μL) was added dropwise to the mixture, then stirred to -5 °C. After the reaction was cooled to -20 0C, 5-(3-chloro-benzylamino)-2-mcthyl-2 H- pyrazole-3-carbaldehyde (648, 0.050 g, 0.20 mmol) in 2 mL of tetrahydrofuran was added at once to the mixture. The reaction was stirred to 0 UC and then concentrated. Ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. The organic portion was dried over anhydrous sodium sulfate and concentrated. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (5-80%) in hexane gave the desired compound (649, 0.033 g, 30%). (ESl) [M+HT - 558.3, 560.9.
Step 11 - Preparation of (3-chloro~benzyl)-j 5-(5-chloro- 1 H~pyrrolo[2 ,3-b] pyridin-3-ylmethyl)-l - methyl- 1 H-pvrazol-3-yl] -amine (P-0410):
[0839] [5-(3-Chloro-benzylamino)-2-methyl-2II-pyrazol-3-ylJ-(5-chloro-l-tπisopropylsilanyl- lH-pyiτolo[2,3-b]pyridin-3-yl)-methanol (649, 0.033 g, 0.059 mmol) was combined with dichloromethane (5 mL, 0.08 mol) and triethylsilane (200 μL, 1.0 mmol) was added, followed by trifluoroacetic acid (100 μL, 1.0 mmol). The reaction was stirred at room temperature overnight and then concentrated. Ethyl acetate was added and the organic portion was washed with 1 M potassium carbonate, dried over anhydrous sodium sulfate and concentrated. Purification with silica gel flash chromatography eluting with a gradient of methanol (2-20%) and dichloromethanc followed by washes with a mixture of ethyl acetate:hexane gave the desired compound (P-04I0, 0.0039 g. 17%). (ESI) [M+Ify = 387.30.
[0840J [5-(5-Chloro-lH-pyπ-olo[2,3-b]pyridin-3-ylmethyl)-l -methyl-lH-p\τazol-3-yl]-(2,5- difluoπ>benzyl)-amine P-0411 and [5-(5-chloro-lH-pyrro]o[2,3-b]p\τidin-3-ylmethyl)-l-mcthyl- lH-pyrazol-3-yl]-(2-fluoro-benzyl)-amine P-0413,
Figure imgf000359_0001
and , respectively, were prepared following the protocol of Scheme 202, replacing 3-chlorobenzaldehyde 645 with 2,5-difluorobcnzaldehyde and 2-fluorobenzaldehyde, respectively, in Step 7, (ESI) [M^-H+J+ = 389.95 (P-04U) and 370.20 (P-0413).
Example 86 Additional compounds
(0841] The following compounds of the invention were synthesized following the methods of the Examples above, or similar methods known to those of skill in the art: 3-(64ert-Butoxy-pyridin-3-ylmethyl)-lH-pyrτolo[2,3-b]pyridme (P-0020). 3-(6-Methoxy-pyridin-3-ylmethyl)-4-thiophen-3-yl-l H-pyrrolo[2,3-b]pyridine (P-0022), (6-Isobutylamino-pyridin-3-yl)-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methanol (P-0029),
[6-(Cyclopropylmethyl-amino)-pyridin-3-yl]-(lH-pyrrolo[2!3-b]pyridin-3-yl)-methanol (P-0034), [6-(Cyclohexylmethyl-amino)-pyridin-3-yl]-(lH-pyiτolo[2,3-b]pyridin-3-yl)-mcthanol (P-0035), (lH-Pyrrolo[2,3-b]pyridin-3-yl)-[6-(4-trifluoromethy]-bcn2ylamino)-pyridin-3-yl]-methanol (P-0036), [6-(4-Chloro-benzy]amino)-pyridin-3-yl]-(lH-pyrrolo[2,3-b]pyridin-3-y])-methanoI (P-0037),
(4-Chloro-benzyl)- {5-[methoxy-(lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-p>τidin-2-yl} -amine (P-0039),
(4-Chloro-3-trifluoromcthyl-benzyl)-{5-[methoxy-(lH-pyrrolo[2!3-b]pyridin-3-yl)-methyl]- pyridin-2-yl] -amine (P-0040),
(4-Chloro-benzyl)-{5-fmethoxy-(5-pyridin-3-yl-l H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-pyridm-2- yl}-amine (P-0041),
[6-(4-Chloro-benzylamino)-2-methyl-p>τidin-3-yl]-(lH-pyrrolo[2,3-b]p>τidin-3-yl)-methanol (P-0046), [2,6-Bis-(4-chloro-benzylamino)-pyridin-3-yl]-(lH-pyrrolo[2,3-b]p\τidin-3-yl)-methanone (P-0049), and 3-(2-Ethylsulfanyl-4,6-dimethyl-pyrimidin-5-ylmethyI)-lH-pyrrolo[2,3-b]pyridiπe (P-0052).
[0842] All patents and other references cited in the specification arc indicative of the level of skill of those skilled in the art to which the invention pertains, and are incorporated by reference in their entireties, including any tables and figures, to the same extent as if each reference had been incorporated by reference in its entirety individually.
[0843] One skilled in the art would readily appreciate that the present invention is well adapted to obtain the ends and advantages mentioned, as well as those inherent therein. The methods, variances, and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.
[0844] It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. For example, variations can be made to provide additional compounds of Formulae I, II or III, and all sub-embodiments thereof, and/or various methods of administration can be used. Thus, such additional embodiments are within the scope of the present invention and the following claims.
[0845] The invention illustratively described herein suitably may be practiced in the absence of any clement or elements, limitation or limitations which is not specifically disclosed herein. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.
[0846] In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group. [0847] Also, unless indicated to the contrary, where various numerical values are provided for embodiments, additional embodiments are described by taking any 2 different values as the endpoints of a range. Such ranges are also within the scope of the described invention,
[0848] Thus, additional embodiments are within the scope of the invention and within the following claims.
SEQUENCE LISTING
SEQ ID NO: 1 Sequence NP_000213
Met Arg GIy Ala Arg GIy Ala Trp Asp Phe Leu Cys VaI Leu Leu Leu Leu Leu Arg VaI GIn Thr GIy Ser Ser Gin Pro Ser VaI Ser Pro GIy GIu Pro Sεr Pro Pro Ser lie His Pro GIy Lys Ser Asp Leu lie VaI Arg VaI GIy Asp GIu lie Arg Leu Leu Cys Thr Asp Pro GIy Phe VaI Lys Trp Thr Phe GIu He Leu Asp GIu Thr Asn GIu Asn Lys GIn Asn GIu Trp He Thr GIu Lys Ala GIu Ala Thr Asn Thr GIy Lys Tyr Thr Cys Thr Asn Lys His GIy Leu Ser Asn Ser He Tyr VaI Phe VaI Arg Asp Pro Ala Lys Leu Phe Leu VaI Asp Arg Ser Leu Tyr GIy Lys GIu Asp Asn Asp Thr Leu VaI Arg Cys Pro Leu Thr Asp Pro GIu VaI Thr Asn Tyr Ser Leu Lys GIy Cys Gin GIy Lys Pro Leu Pro Lys Asp Leu Arg Phe He Pro Asp Pro Lys Ala GIy lie Met He Lys Ser VaI Lys Arg Ala Tyr His Arg Leu Cys Leu His Cys Ser VaI Asp GIn GIu GIy Lys Ser VaI Leu Ser GIu Lys Phe He Leu Lys VaI Arg Pro Ala Phe Lys Ala VaI Pro VaI VaI Ser VaI Ser Lys Ala Ser Tyr Leu Leu Arg GIu GIy GIu GIu Phe Thr VaI Thr Cys Thr He Lys Asp VaI Ser Ser Ser VaI Tyr Ser Thr Trp Lys Arg GIu Asn Ser GIn Thr Lys Leu GIn GIu Lys Tyr Asn Ser Trp His His GIy Asp Phe Asn Tyr GIu Arg GIn Ala Thr Leu Thr lie Ser Ser Ala Arg VaI Asn Asp Ser Gly VaI Phe Met Cys Tyr Ala Asn Asn Thr Phe GIy Ser Ala Asn VaI Thr Thr Thr Leu GIu VaI VaI Asp Lys Gly Phe He Asn He Phe Pro Met He Asn Thr Thr VaI Phe VaI Asn Asp Gly GIu Asn VaI Asp Leu He VaI GIu Tyr GIu Ala Phe Pro Lys Pro GIu His Gin Gin Trp lie Tyr Met Asn Arg Thr Phe Thr Asp Lys Trp GIu Asp Tyr Pro Lys Ser GIu Asn GIu Ser Asn He Arg Tyr VaI Ser GIu Leu His Leu Thr Arg Leu Lys Gly Thr GIu Gly Gly Thr Tyr Thr Phe Leu VaI Ser Asn Ser Asp VaI Asn Ala Ala He Ala Phe Asn VaI Tyr VaI Asn Thr Lys Pro GIu He Leu Thr Tyr Asp Arg Leu VaI Asn Gly Met Leu GIn Cys VaI Ala Ala Gly Phe Pro GIu Pro Thr He Asp Trp Tyr Phe Cys Pro Gly Thr GIu GIn Arg Cys Ser Ala Ser VaI Leu Pro VaI Asp VaI Gin Thr Leu Asn Ser Ser Gly Pro Pro Phe Gly Lys Leu VaI VaI GIn Ser Ser He Asp Ser Ser Ala Phe Lys His Asn Gly Thr VaI GIu Cys LyS Ala Tyr Asn Asp VaI Gly Lys Thr Ser Ala Tyr Phe Asn Phe Ala Phe Lys Gly Asn Asn Lys Glu GIn He His Pro His Thr Leu Phe Thr Pro Leu Leu He Gly Phe VaI He VaI Ala Gly Met Met Cys He He VaI Met He Leu Thr Tyr Lys Tyr Leu GIn Lys Pro Met Tyr Glu VaI GIn Trp Lys VaI VaI Glu Glu He Asn Gly Asn Asn Tyr VaI Tyr He Asp Pro Thr Gin Leu Pro Tyr Asp His Lys Trp Glu Phe Pro Arg Asn Arg Leu Ser Phe Gly Lys Thr Leu Gly Ala Gly Ala Phe Gly Lys VaI VaI Glu Ala Thr Ala Tyr Gly Leu He Lys Ser Asp Ala Ala Met Thr VaI Ala VaI Lys Met Leu Lys Pro Ser Ala His Leu Thr Glu Arg Glu Ala Leu Met Ser Glu Leu Lys VaI Leu Ser Tyr Leu Gly Asn His Met Asn lie VaI Asn Leu Leu GIy Ala Cys Thr lie GIy GIy Pro Thr Leu VaI lie Thr GIu Tyr Cys Cys Tyr GIy Asp Leu Leu Asn Phe Leu Arg Arg Lys Arg Aεp Ser Phe lie Cys Ser Lys GIn GIu Asp His Ala GIu Ala Ala Leu Tyr Lys Asn Leu Leu His Ser Lys GIu Ser Ser Cys Ser Asp Ser Thr Asn GIu Tyr Met Asp Met Lys Pro GIy VaI Ser Tyr VaI VaI Pro Thr Lys Ala Asp Lys Arg Arg Ser VaI Arg lie GIy Ser Tyr lie GIu Arg Asp VaI Thr Pro Ala lie Met GIu Asp Asp GIu Leu Ala Leu Asp Leu GIu Asp Leu Leu Ser Phe Ser Tyr GIn VaI Ala Lys GIy Met Ala Phe Leu Ala Ser Lys Asn Cys lie His Arg Asp Leu Ala Ala Arg Asn lie Leu Leu Thr His GIy Arg lie Thr Lys lie Cys Asp Phe GIy Leu Ala Arg Asp lie Lys Asn Asp Ser Asn Tyr VaI VaI Lys GIy Asn Ala Arg Leu Pro VaI Lys Trp Met Ala Pro GIu Ser lie Phe Asn Cys VaI Tyr Thr Phe GIu Ser Asp VaI Trp Ser Tyr GIy lie Phe Leu Trp GIu Leu Phe Ser Leu GIy Ser Ser Pro Tyr Pro GIy Met Pro VaI Asp Ser Lys Phe Tyr Lys Met lie Lys GIu GIy Phe Arg Met Leu Ser Pro GIu His Ala Pro Ala GIu Met Tyr Asp lie Met Lys Thr Cys Trp Asp Ala Asp Pro Leu Lys Arg Pro Thr Phe Lys GIn lie VaI GIn Leu lie GIu Lys GIn lie Ser GIu Ser Thr Asn His lie Tyr Ser Asn Leu Ala Asn Cys Ser Pro Asn Arg GIn Lys Pro VaI VaI Asp His Ser VaI Arg lie Asn Ser VaI GIy Ser Thr Ala Ser Ser Ser GIn Pro Leu Leu VaI His Asp Asp VaI
SEQ ID NO 2 Sequence NM_000222
1 gatcccatcg cagctaccgc gatgagaggc gctcgcggcg cctgggattt tctctgcgtt 61 ctgctcctac tgcttcgcgt ccagacaggc tcttctcaac catctgtgag tccaggggaa 121 ccgtctccac catccatcca tccaggaaaa tcagacttaa tagtccgcgt gggcgacgag 181 attaggctgt tatgcactga tccgggcttt gtcaaatgga cttttgagat cctggatgaa 241 acgaatgaga ataagcagaa tgaatggatc acggaaaagg cagaagccac caacaccggc 301 aaatacacgt gcaccaacaa acacggctta agcaattcca tttatgtgtt tgttagagat 361 cctgccaagc ttttccttgt tgaccgctcc ttgtatggga aagaagacaa cgacacgctg 421 gtccgctgtc ctctcacaga cccagaagtg accaattatt ccctcaaggg gtgccagggg 481 aagcctcttc ccaaggactt gaggtttatt cctgacccca aggcgggcat catgatcaaa 541 agtgtgaaac gcgcctacca tcggctctgt ctgcattgtt ctgtggacca ggagggcaag 601 tcagtgctgt cggaaaaatt catcctgaaa gtgaggccag ccttcaaagc tgtgcctgtt 661 gtgtctgtgt ccaaagcaag ctatcttctt agggaagggg aagaattcac agtgacgtgc 721 acaataaaag atgtgtctag ttctgtgtac tcaacgtgga aaagagaaaa cagtcagact 781 aaactacagg agaaatataa tagctggcat cacggtgact tcaattatga acgtcaggca 841 acgttgacta tcagttcagc gagagttaat gattctggag tgttcatgtg ttatgccaat 901 aatacttttg gatcagcaaa tgtcacaaca accttggaag tagtagataa aggattcatt 961 aatatcttcc ccatgataaa cactacagta tttgtaaacg atggagaaaa tgtagatttg 1021 attgttgaat atgaagcatt ccccaaacct gaacaccagc agtggatcta tatgaacaga 1081 accttcactg ataaatggga agattatccc aagtctgaga atgaaagtaa tatcagatac 1141 gtaagtgaac ttcatctaac gagattaaaa ggcaccgaag gaggcactta cacattccta 1201 gtgtccaatt ctgacgtcaa tgctgccata gcatttaatg tttatgtgaa tacaaaacca 1261 gaaatcctga cttacgacag gctcgtgaat ggcatgctcc aatgtgtggc agcaggattc 1321 ccagagccca caatagattg gtatttttgt ccaggaactg agcagagatg ctctgcttct 1381 gtactgccag tggatgtgca gacactaaac tcatctgggc caccgtttgg aaagctagtg 1441 gttcagagtt ctatagattc tagtgcattc aagcacaatg gcacggttga atgtaaggct 1501 tacaacgatg tgggcaagac ttctgcctat tttaactttg catttaaagg taacaacaaa 1561 gagcaaatcc atccccacac cctgttcact cctttgctga ttggtttcgt aatcgtagct 1621 ggcatgatgt gcattattgt gatgattctg acctacaaat atttacagaa acccatgtat 1681 gaagtacagt ggaaggttgt tgaggagata aatggaaaca attatgttta catagaccca 1741 acacaacttc cttatgatca caaatgggag tttcccagaa acaggctgag ttttgggaaa 1801 accctgggtg ctggagcttt cgggaaggtt gttgaggcaa ctgcttatgg cttaattaag 1861 tcagatgcgg ccatgactgt cgctgtaaag atgctcaagc cgagtgccca tttgacagaa 1921 cgggaagccc tcatgtctga actcaaagtc ctgagttacc ttggtaatca catgaatatt 1981 gtgaatctac ttggagcctg caccattgga gggcccaccc tggtcattac agaatattgt 2041 tgctatggtg atcttttgaa ttttttgaga agaaaacgtg attcatttat ttgttcaaag 2101 caggaagatc atgcagaagc tgcactttat aagaatcttc tgcattcaaa ggagtcttcc 2161 tgcagcgata gtactaatga gtacatggac atgaaacctg gagtttctta tgttgtccca 2221 accaaggccg acaaaaggag atctgtgaga ataggctcat acatagaaag agatgtgact 2281 cccgccatca tggaggatga cgagttggcc ctagacttag aagacttgct gagcttttct 2341 taccaggtgg caaagggcat ggctttcctc gcctccaaga attgtattca cagagacttg 2401 gcagccagaa atatcctcct tactcatggt cggatcacaa agatttgtga ttttggtcta 2461 gccagagaca tcaagaatga ttctaattat gtggttaaag gaaacgctcg actacctgtg 2521 aagtggatgg cacctgaaag cattttcaac tgtgtataca cgtttgaaag tgacgtctgg 2581 tcctatggga tttttctttg ggagctgttc tctttaggaa gcagccccta tcctggaatg 2641 ccggtcgatt ctaagttcta caagatgatc aaggaaggct tccggatgct cagccctgaa 2701 cacgcacctg ctgaaatgta tgacataatg aagacttgct gggatgcaga tcccctaaaa 2761 agaccaacat tcaagcaaat tgttcagcta attgagaagc agatttcaga gagcaccaat 2821 catatttact ccaacttagc aaactgcagc cccaaccgac agaagcccgt ggtagaccat 2881 tctgtgcgga tcaattctgt cggcagcacc gcttcctcct cccagcctct gcttgtgcac 2941 gacgatgtct gagcagaatc agtgtttggg tcacccctcc aggaatgatc tcttcttttg 3001 gcttccatga tggttatttt cttttctttc aacttgcatc caactccagg atagtgggca 3061 ccccactgca atcctgtctt tctgagcaca ctttagtggc cgatgatttt tgtcatcagc 3121 caccatccta ttgcaaaggt tccaactgta tatattccca atagcaacgt agcttctacc 3181 atgaacagaa aacattctga tttggaaaaa gagagggagg tatggactgg gggccagagt 3241 cctttccaag gcttctccaa ttctgcccaa aaatatggtt gatagtttac ctgaataaat 3301 ggtagtaatc acagttggcc ttcagaacca tccatagtag tatgatgata caagattaga 3361 agctgaaaac ctaagtcctt tatgtggaaa acagaacatc attagaacaa aggacagagt 3421 atgaacacct gggcttaaga aatctagtat ttcatgctgg gaatgagaca taggccatga 3481 aaaaaatgat ccccaagtgt gaacaaaaga tgctcttctg tggaccactg catgagcttt 3541 tatactaccg acctggtttt taaatagagt ttgctattag agcattgaat tggagagaag 3601 gcctccctag ccagcacttg tatatacgca tctataaatt gtccgtgttc atacatttga 3661 ggggaaaaca ccataaggtt tcgtttctgt atacaaccct ggcattatgt ccactgtgta 3721 tagaagtaga ttaagagcca tataagtttg aaggaaacag ttaataccat tttttaagga 3781 aacaatataa ccacaaagca cagtttgaac aaaatctcct cttttagctg atgaacttat 3841 tctgtagatt ctgtggaaca agcctatcag cttcagaatg gcattgtact caatggattt 3901 gatgctgttt gacaaagtta ctgattcact gcatggctcc cacaggagtg ggaaaacact 3961 gccatcttag tttggattct tatgtagcag gaaataaagt ataggtttag cctccttcgc 4021 aggcatgtcc tggacaccgg gccagtatct atatatgtgt atgtacgttt gtatgtgtgt 4081 agacaaatat ttggaggggt atttttgccc tgagtccaag agggtccttt agtacctgaa 4141 aagtaacttg gctttcatta ttagtactgc tcttgtttct tttcacatag ctgtctagag 4201 tagcttacca gaagcttcca tagtggtgca gaggaagtgg aaggcatcag tccctatgta 4261 tttgcagttc acctgcactt aaggcactct gttatttaga ctcatcttac tgtacctgtt 4321 ccttagacct tccataatgc tactgtctca ctgaaacatt taaattttac cctttagact 4381 gtagcctgga tattattctt gtagtttacc tctttaaaaa caaaacaaaa caaaacaaaa 4441 aactcccctt cctcactgcc caatataaaa ggcaaatgtg tacatggcag agtttgtgtg 4501 ttgtcttgaa agattcaggt atgttgcctt tatggtttcc cccttctaca tttcttagac 4561 tacatttaga gaactgtggc cgttatctgg aagtaaccat ttgcactgga gttctatgct 4621 ctcgcacctt tccaaagtta acagattttg gggttgtgtt gtcacccaag agattgttgt 4681 ttgccatact ttgtctgaaa aattcctttg tgtttctatt gacttcaatg atagtaagaa 4741 aagtggttgt tagttataga tgtctaggta cttcaggggc acttcattga gagttttgtc 4801 ttgccatact ttgtctgaaa aattcctttg tgtttctatt gacttcaatg atagtaagaa 4861 aagtggttgt tagttataga tgtctaggta cttcaggggc acttcattga gagttttgtc 4921 aatgtctttt gaatattccc aagcccatga gtccttgaaa atatttttta tatatacagt 4981 aactttatgt gtaaatacat aagcggcgta agtttaaagg atgttggtgt tccacgtgtt 5041 ttattcctgt atgttgtcca attgttgaca gttctgaaga attc
SEQ ID NO:3 Sequence NP_5202
Met GIy Pro GIy VaI Leu Leu Leu Leu Leu VaI Ala Thr Ala Trp His GIy GIn GIy lie Pro VaI lie GIu Pro Ser VaI Pro GIu Leu VaI VaI Lys Pro GIy Ala Thr VaI Thr Leu Arg Cys VaI GIy Asn GIy Ser VaI GIu Trp Asp GIy Pro Pro Ser Pro His Trp Thr Leu Tyr Ser Asp GIy Ser Ser Ser lie Leu Ser Thr Asn Asn Ala Thr Phe GIn Asn Thr GIy Thr Tyr Arg Cys Thr GIu Pro GIy Asp Pro Leu GIy GIy Ser Ala Ala lie His Leu Tyr VaI Lys Asp Pro Ala Arg Pro Trp Asn VaI Leu Ala GIn GIu VaI VaI VaI Phe GIu Asp GIn Asp Ala Leu Leu Pro Cys Leu Leu Thr Asp Pro VaI Leu GIu Ala GIy VaI Ser Leu VaI Arg VaI Arg GIy Arg Pro Leu Met Arg His Thr Asn Tyr Ser Phe Ser Pro Trp His GIy Phe Thr lie His Arg Ala Lys Phe lie GIn Ser GIn Asp Tyr GIn Cys Ser Ala Leu Met GIy GIy Arg Lys VaI Met Ser lie Ser lie Arg Leu Lys VaI GIn Lys VaI lie Pro Gly Pro Pro Ala Leu Thr Leu VaI Pro Ala GIu Leu VaI Arg lie Arg GIy GIu Ala Ala GIn lie VaI Cys Ser Ala Ser Ser VaI Asp VaI Asn Phe Asp VaI Phe Leu GIn His Asn Asn Thr Lys Leu Ala lie Pro Gin GIn Ser Asp Phe His Asn Asn Arg Tyr GIn Lys VaI Leu Thr Leu Asn Leu Asp GIn VaI Asp Phe GIn His Ala GIy Asn Tyr Ser Cys VaI Ala Ser Asn VaI GIn GIy Lys His Ser Thr Ser Met Phe Phe Arg VaI VaI GIu Ser Ala Tyr Leu Asn Leu Ser Ser GIu GIn Asn Leu He GIn GIu VaI Thr VaI GIy GIu GIy Leu Asn Leu Lys VaI Met VaI GIu Ala Tyr Pro GIy Leu GIn GIy Phe Asn Trp Thr Tyr Leu GIy Pro Phe Ser Asp His GIn Pro GIu Pro Lys Leu Ala Asn Ala Thr Thr Lys Asp Thr Tyr Arg His Thr Phe Thr Leu Ser Leu Pro Arg Leu Lys Pro Ser GIu Ala GIy Arg Tyr Ser Phe Leu Ala Arg Asn Pro GIy GIy Trp Arg Ala Leu Thr Phe GIu Leu Thr Leu Arg Tyr Pro Pro GIu VaI Ser VaI lie Trp Thr Phe He Asn GIy Ser GIy Thr Leu Leu Cys Ala Ala Ser GIy Tyr Pro GIn Pro Asn VaI Thr Trp Leu GIn Cys Ser GIy His Thr Asp Arg Cys Asp GIu Ala GIn VaI Leu GIn VaI Trp Asp Asp Pro Tyr Pro GIu VaI Leu Ser GIn GIu Pro Phe His Lys VaI Thr VaI GIn Ser Leu Leu Thr VaI GIu Thr Leu GIu His Asn GIn Thr Tyr GIu Cys Arg Ala His Asn Ser VaI GIy Ser GIy Ser Trp Ala Phe He Pro He Ser Ala GIy Ala His Thr His Pro Pro Asp GIu Phe Leu Phe Thr Pro VaI VaI VaI Ala Cys Met Ser He Met Ala Leu Leu Leu Leu Leu Leu Leu Leu Leu Leu Tyr Lys Tyr Lys Gin Lys Pro Lys Tyr Gin VaI Arg Trp Lys He He GIu Ser Tyr GIu GIy Asn Ser Tyr Thr Phe He Asp Pro Thr GIn Leu Pro Tyr Asn GIu Lys Trp GIu Phe Pro Arg Asn Asn Leu Gin Phe GIy Lys Thr Leu GIy Ala GIy Ala Phe GIy Lys VaI VaI GIu Ala Thr Ala Phe GIy Leu GIy Lys GIu Asp Ala VaI Leu Lys VaI Ala VaI Lys Met Leu Lys Ser Thr Ala His Ala Asp GIu Lys GIu Ala Leu Met Ser GIu Leu Lys He Met Ser His Leu GIy GIn His GIu Asn He VaI Asn Leu Leu GIy Ala Cys Thr His GIy GIy Pro VaI Leu VaI He Thr GIu Tyr Cys Cys Tyr GIy Asp Leu Leu Asn Phe Leu Arg Arg Lys Ala GIu Ala Met Leu GIy Pro Ser Leu Ser Pro GIy GIn Asp Pro GIu GIy GIy VaI Asp Tyr Lys Asn He His Leu GIu Lys Lys Tyr VaI Arg Arg Asp Ser GIy Phe Ser Ser GIn GIy VaI Asp Thr Tyr VaI GIu Met Arg Pro VaI Ser Thr Ser Ser Asn Asp Ser Phe Ser GIu GIn Asp Leu Asp Lys GIu Asp GIy Arg Pro Leu GIu Leu Arg Asp Leu Leu His Phe Ser Ser GIn VaI Ala GIn Gly Met Ala Phe Leu Ala Ser Lys Asn Cys He His Arg Asp VaI Ala Ala Arg Asn VaI Leu Leu Thr Asn Gly His VaI Ala Lys He Gly Asp Phe Gly Leu Ala Arg Asp He Met Asn Asp Ser Asn Tyr He VaI Lys Gly Asn Ala Arg Leu Pro VaI Lys Trp Met Ala Pro GIu Ser He Phe Asp Cys VaI Tyr Thr VaI GIn Ser Asp VaI Trp Ser Tyr Gly He Leu Leu Trp Glu He Phe Ser Leu Gly Leu Asn Pro Tyr Pro Gly He Leu VaI Asn Ser Lys Phe Tyr Lys Leu VaI Lys Asp Gly Tyr GIn Met Ala GIn Pro Ala Phe Ala Pro Lys Asn He Tyr Ser He Met GIn Ala Cys Trp Ala Leu GIu Pro Thr His Arg Pro Thr Phe GIn GIn lie Cys Ξer Phe Leu GIn GIu GIn Ala GIn GIu Asp Arg
Arg GIu Arg Asp Tyr Thr Asn Leu Pro Ser Ser Ser Arg Ser GIy GIy Ser GIy
Ser Ser Ser Ser GIu Leu GIu GIu GIu Ser Ser Ser GIu His Leu Thr Cys Cys
GIu Gin GIy Asp lie Ala GIn Pro Leu Leu GIn Pro Asn Asn Tyr Gin Phe Cys
SEQ ID NO:4 Sequence NM 00521 1
1 gaagggcaga cagagtgtcc aaaagcgtga gagcacgaag tgaggagaag gtggagaaga 61 gagaagagga agaggaagag gaagagagga agcggaggga actgcggcca ggctaaaagg 121 ggaagaagag gatcagccca aggaggagga agaggaaaac aagacaaaca gccagtgcag 181 aggagaggaa cgtgtgtcca gtgtcccgat ccctgcggag ctagtagctg agagctctgt 241 gccctgggca ccttgcagcc ctgcacctgc ctgccacttc cccaccgagg ccatgggccc 301 aggagttctg ctgctcctgc tggtggccac agcttggcat ggtcagggaa tcccagtgat 361 agagcccagt gtccctgagc tggtcgtgaa gccaggagca acggtgacct tgcgatgtgt 421 gggcaatggc agcgtggaat gggatggccc cccatcacct cactggaccc tgtactctga 481 tggctccagc agcatcctca gcaccaacaa cgctaccttc caaaacacgg ggacctatcg 541 ctgcactgag cctggagacc ccctgggagg cagcgccgcc atccacctct atgtcaaaga 601 ccctgcccgg ccctggaacg tgctagcaca ggaggtggtc gtgttcgagg accaggacgc 661 actactgccc tgtctgctca cagacccggt gctggaagca ggcgtctcgc tggtgcgtgt 721 gcgtggccgg cccctcatgc gccacaccaa ctactccttc tcgccctggc atggcttcac 781 catccacagg gccaagttca ttcagagcca ggactatcaa tgcagtgccc tgatgggtgg 841 caggaaggtg atgtccatca gcatccggct gaaagtgcag aaagtcatcc cagggccccc 901 agccttgaca ctggtgcctg cagagctggt gcggattcga ggggaggctg cccagatcgt 961 gtgctcagcc agcagcgttg atgttaactt tgatgtcttc ctccaacaca acaacaccaa 1021 gctcgcaatc cctcaacaat ctgactttca taataaccgt taccaaaaag tcctgaccct 1081 caacctcgat caagtagatt tccaacatgc cggcaactac tcctgcgtgg ccagcaacgt 1141 gcagggcaag cactccacct ccatgttctt ccgggtggta gagagtgcct acttgaactt 1201 gagctctgag cagaacctca tccaggaggt gaccgtgggg gaggggctca acctcaaagt 1251 catggtggag gcctacccag gcctgcaagg ttttaactgg acctacctgg gacccttttc 1321 tgaccaccag cctgagccca agcttgctaa tgctaccacc aaggacacat acaggcacac 1381 cttcaccctc tctctgcccc gcctgaagcc ctctgaggct ggccgctact ccttcctggc 1441 cagaaaccca ggaggctgga gagctctgac gtttgagctc acccttcgat accccccaga 1501 ggtaagcgtc atatggacat tcatcaacgg ctctggcacc cttttgtgtg ctgcctctgg 1561 gtacccccag cccaacgtga catggctgca gtgcagtggc cacactgata ggtgtgatga 1621 ggcccaagtg ctgcaggtct gggatgaccc ataccctgag gtcctgagcc aggagccctt 1681 ccacaaggtg acggtgcaga gcctgctgac tgttgagacc ttagagcaca accaaaccta 1741 cgagtgcagg gcccacaaca gcgtggggag tggctcctgg gccttcatac ccatctctgc 1801 aggagcccac acgcatcccc cggatgagtt cctcttcaca ccagtggtgg tcgcctgcat 1861 gtccatcatg gccttgctgc tgctgctgct cctgctgcta ttgtacaagt ataagcagaa 1921 gcccaagtac caggtccgct ggaagatcat cgagagctat gagggcaaca gttatacttt 1981 catcgacccc acgcagctgc cttacaacga gaagtgggag ttcccccgga acaacctgca 2041 gtttggtaag accctcggag ctggagcctt tgggaaggtg gtggaggcca cggcctttgg 2101 tctgggcaag gaggatgctg tcctgaaggt ggctgtgaag atgctgaagt ccacggccca 2161 tgctgatgag aaggaggccc tcatgtccga gctgaagatc atgagccacc tgggccagca 2221 cgagaacatc gtcaaccttc tgggagcctg tacccatgga ggccctgtac tggtcatcac 2281 ggagtactgt tgctatggcg acctgctcaa ctttctgcga aggaaggctg aggccatgct 2341 gggacccagc ctgagccccg gccaggaccc cgagggaggc gtcgactata agaacatcca 2401 cctcgagaag aaatatgtcc gcagggacag tggcttctcc agccagggtg tggacaccta 2461 tgtggagatg aggcctgtct ccacttcttc aaatgactcc ttctctgagc aagacctgga 2521 caaggaggat ggacggcccc tggagctccg ggacctgctt cacttctcca gccaagtagc 2581 ccagggcatg gccttcctcg cttccaagaa ttgcatccac cgggacgtgg cagcgcgtaa 2641 cgtgctgttg accaatggtc atgtggccaa gattggggac ttcgggctgg ctagggacat 2701 catgaatgac tccaactaca ttgtcaaggg caatgcccgc ctgcctgtga agtggatggc 2761 cccagagagc atctttgact gtgtctacac ggttcagagc gacgtctggt cctatggcat 2821 cctcctctgg gagatcttct cacttgggct gaatccctac cctggcatcc tggtgaacag 2881 caagttctat aaactggtga aggatggata ccaaatggcc cagcctgcat ttgccccaaa 2941 gaatatatac agcatcatgc aggcctgctg ggccttggag cccacccaca gacccacctt 3001 ccagcagatc tgctccttcc ttcaggagca ggcccaagag gacaggagag agcgggacta 3061 taccaatctg ccgagcagca gcagaagcgg tggcagcggc agcagcagca gtgagctgga 3121 ggaggagagc tctagtgagc acctgacctg ctgcgagcaa ggggatatcg cccagccctt 3181 gctgcagccc aacaactatc agttctgctg aggagttgac gacagggagt accactctcc 3241 cctcctccaa acttcaactc ctccatggat ggggcgacac ggggagaaca tacaaactct 3301 gccttcggtc atttcactca acagctcggc ccagctctga aacttgggaa ggtgagggat 3361 tcaggggagg tcagaggatc ccacttcctg agcatgggcc atcactgcca gtcaggggct 3421 gggggctgag ccctcacccc cccctcccct actgttctca tggtgttggc ctcgtgtttg 3481 ctatgccaac tagtagaacc ttctttccta atccccttat cttcatggaa atggactgac 3541 tttatgccta tgaagtcccc aggagctaca ctgatactga gaaaaccagg ctctttgggg 3601 ctagacagac tggcagagag tgagatctcc ctctctgaga ggagcagcag atgctcacag 3661 accacactca gctcaggccc cttggagcag gatggctcct ctaagaatct cacaggacct 3721 cttagtctct gccctatacg ccgccttcac tccacagcct cacccctccc acccccatac 3781 tggtactgct gtaatgagcc aagtggcagc taaaagttgg gggtgttctg cccagtcccg 3841 tcattctggg ctagaaggca ggggaccttg gcatgtggct ggccacacca agcaggaagc 3901 acaaactccc ccaagctgac tcatcctaac taacagtcac gccgtgggat gtctctgtcc 3961 acattaaact aacagcatta atgca

Claims

CLAIMSWhat is claimed is:
1. A compound having the chemical structure of Formula II,
Figure imgf000369_0001
all salts, prodrugs, tautomers, and isomers thereof, wherein:
D has a structure selected from the group consisting of
Q 112244 M11-O-
Figure imgf000369_0002
in which ^ indicates the attachment point of D to Ai of Formula II;
A2 is selected from the group consisting of -CR19R20-, -C(O)-, -C(S)-, -S-, -S(O)-, -S(O)2-, -NR21-, and -O-, provided, however, that when A2 is NR'1, N is not bound to a nitrogen of D; B is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH,, -NO7, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2. -C(S)NH2, -S(O)2NH2, -NR?4R2S. -NHR2I -0R2J, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR21R21, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R23, -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R2', -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR23C(S)NR23R23, -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R23, and -NR23S(O)2NR23R23;
M4 is -NR39CH2-, -NR39CH(R40)-, -NR19CH2CH2-, or -NR39C(O)-;
M5 M6 M7. M9 Mio,, M12i Mi3i Mi4, Mi5 Mi61 Mn and M]8 are selected from the group consisting of a bond, -(CR19R2V, -(CR19R20VC(O)-(CR19R2V -(CR19R20VC(S)-(CR19R20),-, -(CR1VVC(O)O-(CR19R2V,
-(CR19R2VC(S)O-(CR19R2V, -(CR19R20)t-C(O)NR26-(CR19R2V, -(CR19R20)rC(S)NR26-(CRl 9R2V -(CR19R20)t-S(O)-(CR19R2V, -(CR19R20VS(O)2-(CR19R20),-, -(CR19R20)rS(O)2NR26-(CRl 9R2V,
-(CR19R2Vo-(CR19R20),-, -(CR19R2VOC(O)-(CR19R20),-, -(CR19R2VOC(S)-(CR19R2V -(CRl 9R2VθC(O)NR26-(CR19R2V, -(CR19R20)rOC(S)NR26-(CR19R20)s-, -(CR19R20)t-S-(CR19R20)s-, -(CR19R20)rNR26-(CR19R20)s-, -(CR19R20)rNR26C(O)-(CR19R20)s-, -(CR19R20)rNR26C(S)-(CR19R20)r,
-(CR19R20)rNR26C(O)O-(CR19R20)s-, -(CR! 9R)t-NR26C(S)O-(CR19R2V,
-(CR19R20)rNR26C(O)NR26-(CR19R20)s-, -(CR19R20)rNR2('C(S)NR26-(CR19R20)b-. -(CR19R20)t-NR26S(O)2-(CR19R20)s-, and -(CR19R2VNR26S(O)2NR26-(CRI9R20)s-; M8 is selected from the group consisting of a bond, -(CR19R20),-, -(CR19R20)ι-C(O)-(CRl 9R)1-)
-(CR19R2VC(S)-(CR19R2V- -(CR19R2VC(O)O-(CR19R2V, -(CR19R2VC(S)O-(CR19R2V, -(CR1 V0),-C(O)NR26-(CR19R20)s-,
-(CR19R2VC(S)NR26-(CR19R2O)S-, -(CR19R2VS(O)-(CR19R2V, -(CR19R2Vs(O)2-(CR19R3V, -(CR19R2VS(O)2NR26-(CR19R2V -(CR19R2V-O-(CR19R20),-, -(CR19R20VOC(OHCR19R20X-, -(CR19R20V -OC(S)-(CR19R20),-, -(CRigR20)Λ-OC(O)NR26-(CR19R20)s-,
-(CR19R20V -OC(S)NR26-(CR19R2V. -(CR19R20V-S-(CR19R2V -(CR19R20)w-NR26-(CR19R20)s-, -(CRl9R20V-NR26C(OHCR19R20)s-, -(CR|t)R20)Λ-NR26C(S) -(CR19R2V , -(CR19R20V-NR26C(O)O -(CR19R20),-,
-(CR19R20V-NR26C(S)O-(CR19R2V, -(CR19R2°V-NR26C(O)NR26-(CR19R2UV, -(CRιyR2u)w-NRMC(S)NR26-(CRl9R2U)!i-, -(CR"R2n)w-NR2('S(O)2-(CR1''R2r')s-, and -(CR19R20)w-NR26S(O)2NR26-(CR19R20)s-; wherein R19 and R20 at each occurrence are independently selected from the group consisting of hydrogen, fluoro, -OH, -NH2, lower alkyl, lower alkoxy, lower alklylthio, mono- alkylamino, di-alkylamino, and ^NR27R* , wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino; or any two of R19 and R20 on the same or different carbons combine to form a 3-7 membered monocyclic cycloalkyl or 5-7 membered monocyclic heterocycloalkyl and any others of R19 and R20 are independently selected from the group consisting of hydrogen, fluoro, -OH, -NH2, lower alkyl, lower alkoxy, lower alklylthio, mono-alkylamino, di-alkylamino. and -N R2 R28, wherein the alkyl chain(s) of lower alkyl, lower alkoxy, lower alkylthio, mono-alkylamino, or di-alkylamino are optionally substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, and cycloalkylamino, and wherein the monocyclic cycloalkyl or monocyclic heterocycloalkyl are optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino;
R21 is hydrogen or optionally substituted lower alkyl;
R21 at each occurrence is independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkcnyl, provided, however, that no alkene carbon thereof is bound to any -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -0-, -S-, or -N- of any of -NHR23, -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R21, -S(O)2R21, -C(O)NHR21, -C(O)NR23R23, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R23, -NHC(S)R23, -NR23C(S)R23, -NIIS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR21C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R21, -NR23C(S)NR23R23, -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NIIR23, -NIIS(O)2NR23R23, or -NR23S(O)2NR23R23, optionally substituted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to any -C(O)-, -C(S)-, -S(O)-, -S(O)2-, -0-, -S-, or -N- of any of -NHR23, -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23,
-C(O)NHR23, -C(O)NR23R23, -C(S)NIIR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R21, -NR23C(O)R21, -NHC(S)R2', -NR23C(S)R23, -NHS(O)2R25, -NR23S(O)2R2', -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR21C(S)NHR23, -NHC(S)NR33R23, -NR23C(S)NR23R23, -NHS(O)2NHR23. -NR23S(O)2NH2, -NR23S(O)2NHR21, -NHS(O)2NR23R23, or -NR23S(O)2NR23R23, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl. optionally substituted aryl. and optionally substituted heteroaryl;
R24 and R25 at each occurrence are independently selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that no alkene carbon thereof is bound to the nitrogen Of -NR24R25, optionally substituted lower alkynyl, provided, however, that no alkyne carbon thereof is bound to the nitrogen of -NR24R23, optionally substituted cycloalkyl. optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or
R24 and R23 together with the nitrogen to which they are attached form a monocyclic 5-7 membered optionally substituted heterocycloalkyl or a monocyclic 5 or 7 membered optionally substituted nitrogen containing heteroaryl;
R26 at each occurrence is independently selected from the group consisting of hydrogen, lower alkyl, and lower alkyl substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkyllhio, mono-alkylamino, fluoro substituted mono- alkylamino, di-alkylamino, fluoro substituted di-alkylammo, and -NR27R28, provided, however, that when R26 is substituted lower alkyl, any substitution on the lower alkyl carbon bound to the -N- of -NR2"- is fluoro;
R27 and R28 combine with the nitrogen to which they are attached to form a 5-7 membered heterocycloalkyl or 5-7 membered heterocycloalkyl substituted with one or more substituents selected from the group consisting of fluoro, -OH, -NH2, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy. lower alkylthio, and fluoro substituted lower alkylthio;
Q1 is aryl or heteroaryl, wherein aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHS(O)2R43, -NHC(O)R43, -NHR41, -NR41R43, -OR43, SR41, S(O)R43, and -S(O)2R43;
Q", O21, O31, Q41, O51, Q61, Q71, Q81, Q9', O101, Q1 ", Q121, Q131, and Q141 are selected from the group consisting of optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl and optionally substituted heteroaryl; Q12 is fluoro, chloro or -CF3;
Q 3 and Q 4 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl;
Q22, Q24, Q32, Q33, O43, O44, 0S2 » O54, O102 and Qm are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, and -SR44, provided, however, that at least one of Q22 and Q24, at least one of Q3i and Q33, at least one of Q43 and Q44, at least one of Q52 and Q54, and at least one of Q102 and Q104 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl;
Q52, Q74, Q1 12, Q124, Qπ2, Q144, and Q152 are hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44;
Q64, Q72, Q82, and QM are hydrogen, lower alkyl or fluoro substituted lower alkyl;
R43 at each occurrence is independently optionally substituted lower alkyl, optionally substituted cyeloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl or optionally substituted hctcreoaryl;
R39 is hydrogen or lower alkyl;
R40 is lower alkyl or fluoro substituted lower alkyl; each R44 is independently hydrogen, lower alkyl or fluoro substituted lower alkyl; w is 1, 2, or 3; u is 1 -6; t is 0-3; and s is 0-3; provided, however, that the compound is not
Figure imgf000373_0001
Figure imgf000374_0001
2. The compound of Claim 1, wherein:
D has a structure selected from the group consisting of
Figure imgf000374_0002
in which ? indicates the ttttachment point of D to A2 of Formula II; B is selected from the group consisting of hydrogen, -CN, -OR41, -SR41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, -C(O)NR3V, -C(O)R41, -S(O)2NR39R41, -S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl. heterocycloalkyl, aryl. and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as B, or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO7, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR14C(O)R42, -NRWS(O)2R4J, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
Q , Q , Q , Q , and Q are aryl or heteroaryl, wherein aryl or hcteroaryl are optionally substituted with one or more substituents selected from the group consisting of , -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q1, Q1 !, O41. Q61, or Q14', or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R4' is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di- alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R41 or as substituents of lower alkyl arc optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR^C(O)R42, -NR10S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and
R42 at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino. di-alkylamino, and cycloalkylamino, and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.
3. The compound of Claim 2, wherein
M4 is -NHCH2- or -NHC(O)-; M3. M10, and M18 are a bond, -NR39-, -S-, -O-, -NR39CH2-, -NR39CH2CH2-, -NR^CH(R4")-, -SCH2-, -OCH2-, -C(O)NR39-, -S(O)2NR39-, -CH2NR39-, -CH(R40)NR39-. -NR39C(O)-, or -NR39S(O)2-;
M8 is a bond, -CH2-, -CH7C(O)-, -S(O)2-, -S(O)2CH2-, -S(O)2CH(CH3)-, -S(O)2CH2CH2-, -S(O)2NR39-, -S(O)2NR3VH2-, -S(O)2NR1VH(CH3)-, -S(O)2NR^CH2CH2-, -C(O)-, -C(O)CH2-, -C(O)CH(CH3)-, -C(O)CH2CH2-, -C(O)NR39-, -C(O)NR39CH2-. -C(O)NR19CH(CH3)-, or -C(O)NR39CH2CH2-.
4. The compound of Claim 3, wherein
M5, M10, andM18 are -NR19CH2-, -NR39CH(R40)- or -NR39C(O)-; and M8 is -C(O)NR39CH2-, -C(O)NR39CH(R40)- or -C(O)NR39CII2CH2-.
5. The compound of Claim 1 having the chemical structure of Formula Ha,
Figure imgf000376_0001
all salts, prodrugs, tautomers, and isomers thereof, wherein:
A1 is -CH2- or -C(O)-;
Qla is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41;
Q5 is hydrogen, -OR43, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl. heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR43, -NR43R43, -OR43 and -S(O)2R41;
R41 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di- alkylamino, cycloalkyl, heterocycloalkyl, aryl. and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R41 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NHi, -CN, -NO:, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and
R42 at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, and cycloalkylamino, and heterocycloalkyl and heleroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy.
6. The compound of Claim 5, wherein A3 is -CH2-.
7. The compound of Claim 6, wherein Q s is -OR41, -CN, C,_3 alkyl, fluoro substituted Ci.j alkyl, fluoro, chloro, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; and Q13 and Q14 are hydrogen.
8. The compound of Claim 7, wherein M4 is -NHCH2- or -NHC(O)-.
9. The compound of Claim 5, wherein A3 is -CH2-;
M4 is -NHCH2-;
Q5 is -CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy, trifluoromethoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; and QIa is phenyl or pyridinyl, wherein phenyl or pyridinyl are substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, methoxy, trifluoromethyl, difluoromethoxy and trifluoromethoxy.
10. The compound of Claim 9, wherein Q la is phenyl mono substituted at the -posilion with chloro.
11. The compound of Claim 9, wherein Qi a is pyridin-3-yl mono substituted at the-position with methyl, methoxy, trifluoromethyl, difluoromethoxy or trifluoromethoxy.
12. The compound of Claim 5, selected from the group consisting of (4-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-6-fluoro-p>τidin-2-yl]- amine,
(4-Chloro-benzyl)-[6-chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>τidin-2-yl]-amine, [6-Chloro-5-(lH-pyrτolo[2,3-b]pyridm-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3- ylmcthyl)-aminc,
[6-Chloro-5-(5-chloro-lH-pyn"olo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl- pyridin-3 -ylmethyl)-amine,
{6-Chloro-5-[5-(l -methyl-lH-pyrazol-4-yl)-lH-pyrrolo[2>3-b]pyridin-3-ylmethyl]-pyridin-2-yl}- (6-trifluoromethyl-pyridin-3-ylmethyl)-amme,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-trifluoromethyl- pyridin-3 -ylmethyl) -amine,
[6-Fluoro-5-(5-methoxy-lH-pyrrolo[2,3-b]pyτidin-3-ylmethyl)-p>τidin-2-yl]-(6-trifluoromethyl- pyridin-3-ylmethyl)-amine,
[6-Fluoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trif]uoromethyl-pyridin-3- ylmethyl)-amine,
3-{2-Chloro-6-[(6-trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl} -l H- pyrrolo[2,3-b]pyridine-5-carbonitrilc,
[6-Chloro-5-(5-methyl-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl- pyridin-3 -ylmethyl)-amine,
[6-Chloro-5-(5-methyl-l H-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-(6-trifluoromethyl- pyridin-3 -ylmcthyl)-amine,
[6-Fluoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-methoxy-pyτidin-3-ylmethyl)- amine,
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-6-fluoro-pyridin-2-yl]-(6-methoxy-pyridm-3- ylmethyl)-aminc,
(5-Fluoro-pyridin-3-ylmethyl)-[6-fluoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine,
3-{2-Fluoro-6-[(5-fluoro-pyridin-3-ylmcthyl)-amino]-pyridin-3-ylmethyl}-lH-pyrrolo[2,3- b]pyridinc-5-carbonitπle,
3-[6-(4-Chloro-benzylamino)-2-fIuoro-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5- carbonitrile; and all salts, prodrugs, tautomers, and isomers thereof.
13. The compound of Claim 1 having the chemical structure of Formula Ub.
Figure imgf000379_0001
all salts, prodrugs, tautomers, and isomers thereof, wherein:
Q15 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, - NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR2\ -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR23R23, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R23, - NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR21R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR23C(S)NR23R23, -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23. -NHS(O)2NR23R23, and -NR23S(O)2NR23R23.
14. The compound of Claim 13, wherein
Q1 1 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR'3, -NR23R23, -OR23 and -S(O)2R23; and
Q15 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR2" , -NR23R23, -OR23 and -S(O)2R23.
15. The compound of Claim 14, wherein M5 is -NR2(1(CRl9R2ll)a- or -NR26C(O)(CR19R20),-; and A2 is -CR19R20- or -C(O)-.
16. The compound of Claim 13, wherein A2 is -CH2- or -C(O)-; Q11 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR4i. -NR41R41, -NR39C(O)R41, -NR39S(O)2R41. halogen, lower alkyl. cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di- alkylamino, cycloalkyL heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q1 1, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NII2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
Q15 is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl. aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41;
M5 is a bond, -NR39-, -S-, -0-, -NR39CH2-, -NR39CH2CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, -C(O)NR39-, -S(O)2NR39-, -CH2NR39-, -CH(R40)NR39-, -NR39C(O)-, or -NR39S(O)2-; and
Q2", and Q24 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44, provided, however, that at least one of Q22 and Q24 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
17. The compound of Claim 16, wherein A2 is -CH2-;
M5 is -NR39CH2-, -NR39CH2CH2-, or -NR39CH(R40)-; Q11 is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, di-alkylamino, and heterocycloalkyl; Q15 is hydrogen. -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; and Q72, and Q * are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that at least one of
Q22 and Q24 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
18. The compound of Claim 13, wherein
A2 is -CH2-;
M3 is -NHCH2-;
Q" is phenyl or heteroaryl, wherein phenyl or heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
QH is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy. and fluoro substituted lower alkoxy; and
Q22 and Q24 arc independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl.
19, The compound of Claim 13, selected from the group consisting of (4-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine, [5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,6-difluoro-benzyl)-amine, [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-trifluoromethyl-benzyl)- amine,
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine, [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-benzyl)-amine, [5-(5-Chloro-lH-p>τrolθ[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,4-difluoro-benzyl)-aminc> [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromethyl-benzyl)- amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2,5-difluoro-benzyl)-amine, [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-trifluoromethyl-benzyl)- amine,
[5-(5-Chloro-llI-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidm-2-yl]-(2-fluoro-5-trifluoromethyl- benzyl)-amine,
(2-Fluoro-5-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine,
(2,5-Difluoro-bcnzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pjτimidin-2-yl]-amine, (2-Chloro-54rifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine,
(3-Flιioro-5-trifluoromethyl-bεnzyl)-[5-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyrimidin-2-yl]- amine, (3,5-Difluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidm-2-yl]-amine,
(2-Fluoro-ben2yl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(2-Chloro-benzyl)-f5-(lH-pyrrolo[2,3-b]pyridin-3-yltTiethyl)-pyrimidin-2-yl]-amine,
[5-(l H-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>τimidin-2-yl]-(2-trifluoromethyl-benzyl)-amine,
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>τimidin-2-yl]-(2-trifluoromethoxy-benzyl)-aπiine,
(5-Chloro-2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(2,4-Dichloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl] -amine,
(2,4-Difluoro-benzyl)-[5-(l H-pyπ"θlo[2,3-bJpyridin-3-ylmethyl)-p>τimidin-2-yl]-amine,
(4-Chloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyτidin-3-ylmethyl)-pyrimidin-2-yl]-amine,
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-trifluoromcthyl-benzyl)-amine,
(2-Fluoro-3-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyπmidin-2-yl]- amine,
(2(5-Dichloro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(3-Chloro-2-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(2-Difluoromethoxy-benzyl)-[5-(lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl] -amine,
(2,3-Dichloro-benzyl)-[5-(lH-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(4-Chloro-2-fluoro-benzyl)-[5-(lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(5-Fluoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine,
(2-Chloro-4-fluoro-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-amine,
(5-Chloro-2-methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridiπ-3-ylmethyl)-pyrimidin-2-yl]-amine,
(5-Fluoro-2-methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>τimidin-2-yl] -amine,
(2-Fluoro-4-trifluoromethyl-bcnzyl)-[5-(l H-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine,
(4-Fluoro-2-trifluoromethyl-benzyl)-[5-(lH-pyrτϋlo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-difluoromethoxy-benzyl)- amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(5-fluoro-2-trifluoromethyl- benzyl)-amine,
(3-Chloro-2-fluoro-benzyl)-[5-(5-chloro-l H-pyrrolo[2<3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine,
[5-(5-Chloro-lH-pyrrolo[2)3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-3-trifluoromethyl- benzyl)-amine, f5-(5-Chloro-lH-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-fluoro-4-trifluoromethyl- benzyl)-amine, [5-(5-Chloro-lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyπmidin-2-yl]-(2,3-difluoro-benzyl)-amme»
(2-Chloro-4-fluoro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyπdin-3-ylmethyl)-pyπmidm-2-yl]- amine,
[5-(5-Chloro-l H-p\τrolo[2,3-b]pyndin-3-ylmethyl)-pyrimidin-2-yl]-(2-tπfluoromethoxy-benzyl)- amine,
(2-Chloro-5-fluoro-benzyl)-[5 -( 1 H-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyπmidin-2-yl] -amine,
(2-Chloro-5-fluoro-ben2yl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyπdm-3-ylmethyI)-pyπmidin-2->l]- amine,
[5-(5-Chloro-lH-pyπ"olo[2,3-b]pyridm-3-ylmethyl)-pyπmidm-2-yl]-pyπdin-4-ylmethyl-amine, f5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyπmidm-2-yl]-(2-pyrrolidm-l -yl-ethyl)- amine,
Benzyl-[5-(5-chloro-lH-pyπ"olo[2,3-b]pyridin-3-ylmcthyl)-pyrimidm-2-ylJ-amine, Benzyl-[5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-methyl-amine,
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyπmidm-2-yl]-(4-tπfluoromethoxy-benzyl)- amine,
(3-Chloro-benzyl)-[5-(5-chloro-lII-pyn"olo[2,3-b]pyridin-3-ylniethyl)-pynmidin-2-yl]-aminc,
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyπmidm-2-yl]-pyridm-3-ylmethyl-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyπmidm-2-yl]-(4-fluoro-benzyl)-amine,
(3-Cliloro-benzyl)-[5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidm-2-yl]-methyl- amine,
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyπdm-3-ylmethyl)-pyrimidin-2-yl]-(3,5-difluoro-benzyl)-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyπdm-3-ylmethyl)-pyπmidin-2-yl]-[l-(2-fluoro-phenyl)-ethyl]- amine,
[l-(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-lH-pyrrolo[2)3-b]pyπdin-3-ylmcthyl)-pyπmidin-2-yl]- amine,
[5-(5-Chloro-lH-pyrrolo[2 3-b]pyπdin-3-ylmelhyl)-p>nmidm-2-yl]-[(S)-l-(4-fluoro-phcnyl)- ethyl] -am me,
[5-(5-Chloro-lH-pyrrolo[2,3-bJpyπdm-3-ylmethyl)-pyrimidin-2-yl]-(6-tπfluoromcthyl-pyridm-3- ylmethyl)-amine,
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyπdin-3-ylmethyl)-pyrimidm-2-yl]-methyl- amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methyl-benzyl)-amme,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-methoxy-benzyl)-amme,
[5-(5-Chloro-lH-pyττolo[2,3-b]pyπdin-3-ylmethyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)- amine,
[5-(5-Chloro-lH-pyπ"olo[2,3-b]pyridin-3-ylmcthyl)-pyπmidin-2-yl]-cyclohexylmethyl-amme, [5-(5-Chloro-lH-pyrrOlo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-pyridin-2-ylmcthyl-aminc,
[2-(4-Chloro-phenyl)-ethyl]-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p>τimidin-2-yl]- amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-difluoromethoxy-ben7.yl)- amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methoxy-benzyl)-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(4-methyl-benzyl)-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-yl]-(2-methoxy-cthyl)-amine,
[5-(5-Chloro-lH-pyπ"θlo[2,3-b]pyridin-3-ylmcthyl)-pyrimidin-2-yl]-(3-fluoro-benzyl)-amine,
(3-Chloro-4-fluoro-benzyl)-[5-(5-chloro-lH-pyrrolof2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine,
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyritnidin-2-yl]-(2-ethoxy-benzyl)-aminc,
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyτimidin-2-yl]-(4-moφholm-4-yl-benzyl)- amine,
[5-(5-Chloro-l H-pyττϋlo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(3-difluoromethoxy-benzyl)- amine,
(4-Chloro-3-fluoro-benzyl)-[5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]- amine,
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-[l -(3-fluoro-phenyl)-ethyl]- amine,
[5-(5-Chloro-] H-pyττolo[2,3-b]pyridin-3-ylmethyl)-pyrimidin-2-yl]-(2-dimethylamino-benzyl)- amine; and all salts, prodrugs, tautomers, and isomers thereof.
20. The compound of Claim 1 having the chemical structure of Formula Hc,
Figure imgf000384_0001
all salts, prodrugs, tautomers, and isomers thereof, wherein.
Q25 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl. optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2. -NR24R", -NHR21, -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R21, -S(O)2R2I -C(O)NHR23, -C(O)NR23R23, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R23, -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R2', -NHC(O)NHR21, -NR23C(O)NII2, -NR23C(O)NIIR23, -NHC(O)NR23R23, -NR23C(O)NR23R2', -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R2', -NR23C(S)NR23R2', -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R23, and -NR23S(O)2NR23R23,
21. The compound of Claim 1 having the chemical structure of Formula Hd,
Figure imgf000385_0001
all salts, prodrugs, tautomers, and isomers thereof, wherein:
Q'5 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR23, -OR2', -SR2', -C(O)R2'. -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR21R23, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R2', -NR23C(O)R23, -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR23C(S)NR23R23, -NHS(O)2NHR2'. -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R2', and -NR23S(O)2NR23R23.
22. The compound of Claim 1 having the chemical structure of Formula He,
Figure imgf000385_0002
all salts, prodrugs, tautomers, and isomers thereof, wherein:
Q45 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH. -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR7+R2', -NHR^, -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R23. -S(O)2R23, -C(O)NHR23, -C(O)NR21R21, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R23, -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R2', -NHC(S)NHR23, -NR23C(S)NIl2, -NR23C(S)NIIR23, -NHC(S)NR23R23, -NR23C(S)NR23R23, -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)7NR23R23, and -NR23S(O)2NR23R2'.
23. The compound of Claim 22, wherein
Q41 is aryl or heteroaryl, wherein aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; and
Q45 is hydrogen, -OR23, -CN, fluoro, chloro. lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23.
24. The compound of Claim 23, wherein M8 is -C(O)NR31)CRSV°- or -C(O)NR39(CRR80)r; A6 is -CR19R20- or -C(O)-; and
R80 is hydrogen, lower alkyl or fluoro substituted lower alkyl.
25. The compound of Claim 22, wherein A6 is -CH2- or -C(O)-;
Q41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl. cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q41, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN. -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
Q45 is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl arc optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41;
M8 is -C(O)NR39CH2-, -C(O)NR39CH(R40)-, or -C(O)NR39CH2CH2-; and Q52, and Q54 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44, provided, however, that at least one of Q52 and Q54 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
26. The compound of Claim 25, wherein A6 is -CH2-;
Q41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
Q45 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; and
Q'2 and Q54 are independently hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy, provided, however, that at least one of Q5" and Q54 is hydrogen, fluoro, chloro, lower alkyl or fluoro substituted lower alkyl.
27. The compound of Claim 22, wherein A5 is -CH2-;
M8 is -C(O)NHCH2-, -C(O)NH-CH(CH^)- or -C(O)NH-(CH2),-;
Q41 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, fluoro substituted methyl, methoxy, and fluoro substituted methoxy; Q45 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; and Q52 and Q54 are independently hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl.
28. The compound of Claim 22, selected from the group consisting of
3-(l-Benzyl-3.5-dimethyl-lH-pyrazol-4-ylmcthyl)-lH-pyrrolo[2,3-b]p>τidine>
2-[3,5-Dimethyl-4-(l H-p>τroIo[2,3-b]pyridin-3-ylmethyl)-p\τazol-l -yl]-l-phenyl-ethanone,
3,5-Dimethyl-4-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 4-methoxy- benzylamide,
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-y]methyl)-pyrazole-l-carboxylic acid 2-chloro- benzylamide,
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazoIe-l -carboxylic acid 2-fluoro- benzylamide,
3-[3,5-DimethyI-l -(5-trifluoromethyl-ftιran-2-ylmethyl)-lH-pyrazol-4-yImethyl]-lH-pyrrolo[2,3- b]pyridine,
3-[3,5-Dimethyl-l -(5-methyl-isoxazol-3-y]methyl)-lH-pyrazol-4-yImethyl]-l H-pyrrolo[2,3- bjpyridine,
3, 5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 4-chloro- benzylamide,
3,5-Dimethy]-4-(lH-pyrrolo[2,3-blpyridin-3-yImethyl)-pyrazoIc-l -carboxylic acid [2-(4-methoxy- phenyl)-ethyl]-amide,
3, 5-Dimethyl-4-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 3-methoxy- benzylamide,
3-{3,5-Dimethyl-l -[4-methyI-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-l II-pyrazoI-4- ylmethyI} -l H-pyrrolo[2,3-b]pyridine,
3-[3,5-Dimethyl-l-(4-methyl-2-phenyl-thiazoI-5-ylmethyl)-lH-pyrazol-4-ylmethyl]-l H- pyrrolo[2,3-b]p>τidine,
3,5-DimethyI-4-(lH-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-pyrazoIe-l -carboxylic acid 2-methoxy- benzylamide,
3, 5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyra/ole-l -carboxylic acid [2-(2,4- dichloro-phenyl)-ethyl] -amide,
3,5-Dimethyl-4-(lH-pyrrolo[2,3-b]pyridin-3-yImethyl)-pyrazole-l -carboxylic acid [2-(4-fluoro- phenyl)-cthyl]-amide,
3, 5-Dimethyl-4-(lH-pyrroIo[2,3-b]pyridin-3-yImethyl)-pyrazole-l -carboxylic acid [^-^-fluorophenyl) -ethyl] -amide.
3,5-Dimelhyl-4-(lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyrazole-l -carboxylic acid ((S)-l -phenyl- ethyl)-amide,
3,5-DimethyI-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-pyrazole-l -carboxylic acid 3-fluoro- benzylamide,
3,5-Dimethyl-4-(lH-pyrroIo[2,3-b]pyridin-3-ylmethyl)-pyrazole-l -carboxylic acid 4-fluoro- ben/ylamidc,
3,5-Dimcthyl-4-( lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyra/ole-l -carboxylic acid 4-mcthyl- benzylamide,
3,5-Dimcthyl-4-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-p>τazole-l -carboxylic acid 2-methyl- benzylamide,
4-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-pyrazole-l -carboxylic acid [2-(4- fluoro-phenyl)-ethyl]-amide,
4-(5-Chlorϋ-lH-pyiτolo[2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-p>τazole-l -carboxylic acid 4- fluoro-benzylamidc.
4-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-3,5-dimethyl-pyrazolc-l -carboxylic acid 4- chloro-benzylamide,
4-(5-Chloro-lH-pyrrolof2,3-b]pyridin-3-ylmethyl)-3,5-dimethyl-p}τazole-l -carboxylic acid [(S)-
1 -(4-iluoro-phcnyl)-ethyl]-amide: and all salts, prodrugs, tautomers, and isomers thereof.
29. The compound of Claim 1 having the chemical structure of Formula Ilf,
Figure imgf000389_0001
all salts, prodrugs, tautomers, and isomers thereof, wherein:
Q'5 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted hetcroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR23, -OR2', -SR23, -C(O)R21, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR2'. -C(O)NR23R33. -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23. -S(O)^NR23R23, -NHC(O)R23, -NR"C(O)R2\ -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R13, -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR21C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR23C(S)NR21R2'. -NHS(O)2NHR23, -NR23S(O)2NH2. -NR23S(O)7NHR23. -NHS(O)2NR21R23. and -NR23S(O)2NR23R23.
30. The compound of Claim 1 having the chemical structure of Formula Hg,
Q72
Figure imgf000390_0001
all salts, prodrugs, tautomers, and isomers thereof, wherein:
Q65 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NIIC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR23, -0R2\ -SR23, -C(O)R23, -C(S)R", -S(O)R23, -S(O)2R23, -C(O)NHR25, -C(O)NR23R23, -C(S)NHR2', -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R23, -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR", -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR23C(S)NR23R23, -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)7NR23R23, and -NR23S(O)2NR23R23.
31. The compound of Claim 30, wherein
Q61 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR23, -NR23R23, -OR23 and -S(O)2R23; and
Q65 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heleroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR" , -NR23R23, -OR23 and -S(O)2R23.
32. The compound of Claim 31, wherein M10 is -NR26(CRl9R20)s- or -NR211C(O)(CR19R20X-; and As is -CR19R20- or -C(O)-.
33. The compound of Claim 30, wherein As is -CH2- or -C(O)-; Q61 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41. -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q61, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR4:, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
Q6' is hydrogen, -CN, -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R4', -NR111C(O)R4', -NR39S(O)2R41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41 ;
M10 is a bond, -NR39-, -S-, -0-, -NR39CH2-, -NR39CH2CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-, -C(O)NR39-, -S(O)2NR39-, -CH2NR39-, -CH(R40)NR39-, -NR39C(O)-, or -NR39S(O)2-;
Q74 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44; and
Q ' is hydrogen, lower alkyl, or fluoro substituted lower alkyl.
34. The compound of Claim 33, wherein A8 is -CH2-;
Q61 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
Q65 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; and
Q74 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
35. The compound of Claim 30, wherein M10 is -NIICII2-;
As is -CH2-; Q6' is phenyl optionally substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, methyl, trifluoromethyl. methoxy, difluoromethoxy, or trifluoromethoxy: Qfo is hydrogen, fluoro, -CK, or 1 -methyl-pyrazol-4-yl; Q - is lower alkyl or fluoro substituted lower alkyl; and Q 4 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl.
36. The compound of Claim 30, selected from the group consisting of [l -Ethyl-5-(lH-p\τrolo[2,3-b]pyridin-3-ylmethyl)-l H-pyrazol-3-yl]-(4-fluoro-benzyl)-amine, (4-Fluoro-benzyl)-[l-methyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-lH-pyrazol-3-yl]-aminc, t5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l -methyl-lH-pyrazol-3-yl]-(4-fluoro-benzyl)- amine,
(4-Fluoro-benzyl)-{l -methyl-5-[5-(l -methyl-lH-pyrazol-4-yl)-l H-pyrrolo[2,3-b]pyridin-3- ylmethyl]-lH-pyrazol-3-yl} -amine,
(5-Chloro-lH-pyrrolϋ[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]- methanone,
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l -ethyl-lH-pyrazol-3-yl]-(4-fluoiO-benzyl)- amine,
3-[5-(4-Fluoro-beπzylamino)-2-methyl-2II-pyrazol-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5- carbonitrile,
(3-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-l -methyl-lH-pyrazol-3-yl]- amine,
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-l-methyl-lH-pyrazol-3-yl]-(2,5-difluoro- benzyl)-amine,
[5-(5-Chloro- l H-ρyrrolo[2,3-b]pyridin-3-ylmethyl)-l -methyl-lH-pyrazol-3-yl]-(2-fluoro-bcnzyl)- amine; and all salts, prodrugs, tautomers, and isomers thereof.
37. The compound of Claim 1 having the chemical structure of Formula Hh,
Figure imgf000392_0001
all salts, prodrugs, tautomers, and isomers thereof, wherein: Q ' is selected from the group consisting of hydrogen, halogen, optionally substituted lower alky], optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH?> -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2. -C(S)NH2, -S(O)2NH2, -NR24R2\ -NHR21, -OR21,
Figure imgf000393_0001
-C(O)R21, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR23R21, -C(S)NHR23, -C(S)NR23R23, -S(O)2MIR23, -S(O)2NR23R23, -NHC(O)R23, -NR21C(O)R2', -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R2', -NHC(O)NHR2', -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR21R2', -NR25C(O)NR21R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R21. -NR21C(S)NR23R2', -NHS(O)2NHR23, -NR23S(O)2NII2, -NR23S(O)2NHR23, -NHS(O)2NR21R23, and -NR23S(O)2NR23R23.
38. The compound of Claim 1 having the chemical structure of Formula Hi,
Figure imgf000393_0002
all salts, prodrugs, tautomers, and isomers thereof, wherein:
Q85 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NII2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR23, -OR21, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR21R21, -C(S)NHR23, -C(S)NR21R23, -S(O)2NHR23, -S(O)2NR21R23, -NHC(O)R21, -NR21C(O)R23, -NHC(S)R21, -NR21C(S)R21, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR21, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R21, -NHC(S)NHR21, -NR23C(S)NH2, -NR23C(S)NHR21, NHC(S)NR23R21, -NR21C(S)NR21R21. -NHS(O)2NHR23. -NR23S(O)2NH2, -NR23S(O)2NHR21, -NHS(O)2NR21R21, and -NR21S(O)2NR23R21.
39. The compound of Claim 1 having the chemical structure of Formula Hj.
Figure imgf000394_0001
all salts, prodrugs, tautomers, and isomers thereof. wherein:
Q9" is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR23, -OR23, -SR23, -C(O)R23. -C(S)R23, -S(O)R2', -S(O)2R23, -C(O)NHR23, -C(O)NR23R23, -C(S)NHR23, -C(S)NR23R2', -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R21, -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR2'. -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR21C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR21C(S)NHR23, -NHC(S)NR23R2', -NR25C(S)NR23R2', -NHS(O)2NHR2', -NR21S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)7NR23R23, and -NR2'S(O)2NR23R23.
40. The compound of Claim 1 having the chemical structure of Formula Hk,
Figure imgf000394_0002
all salts, prodrugs, tautomers, and isomers thereof, wherein:
Q105 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -Oil, -NH2, -NO,, -CN, -NHC(O)NH2. -NHC(S)NH2, -NHS(O)2NH2, -C(O)NII2, -C(S)NH2, -S(O)2NH2, -NR2V, -NHR23, -OR21, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR21R23, -C(S)NHR23, -C(S)NR23R21, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R23, -NHC(S)R23, -NR21C(S)R23, -NHS(O)2R23. -NR23S(O)2R23, -NHC(O)NHR2', -NR2O(O)NH2, -NR23C(O)NHR23. -NHC(O)NR23R23, -NR23C(O)NR21R25, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR21, -NHC(S)NR23R23, -NR23C(S)NR23R2' -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23. -NHS(O)2NR23R23, and
-NR23S(O)2NR23R23
41. The compound of Claim 1 having the chemical structure of Formula Hm,
Figure imgf000395_0001
all sails, prodrugs, tautomers, and isomers thereof, wherein:
Q1 '5 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR23, -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR23R23, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R23, -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR21S(O)2R23, -NHC(O)NIIR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR23C(S)NR23R23, -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R23, and -NR23S(O)2NR23R23.
42. The compound of Claim 1 having the chemical structure of Formula Hn,
Figure imgf000395_0002
all salts, prodrugs, tautomers, and isomers thereof, wherein:
Q1""3 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NII2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR23, -OR2', -SR' 1, -C(O)R2', -C(S)R", -S(O)R23, -S(O)2R2', -C(O)NHR21, -C(O)NRMR \ -C(S)NHR23. -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R23, -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R2'. -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR23C(S)NR23R23, -NIIS(O)2NIIR23, -NR23S(O)2NII2, -NR23S(O)2NIIR23, -NIIS(O)2NR23R23, and -NR23S(O)2NR23R23.
43. The compound of Claim 1 having the chemical structure of Formula Ho,
Figure imgf000396_0001
all salts, prodrugs, tautomers, and isomers thereof, wherein:
Q135 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NII2, -S(O)2NII2, -NR24R25. -NIIR23, -OR23, -SR23, -C(O)R23, -C(S)R23, -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR23R23, -C(S)NHR23, -C(S)NR23R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R23, -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R23, -NR23S(O)2R23, -NHC(O)NHR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NIIC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR23C(S)NR23R23, -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R23, and -NR23S(O)2NR23R23.
44. The compound of Claim 1 having the chemical structure of Formula Up,
Figure imgf000396_0002
all salts, prodrugs, tautomers, and isomers thereof, wherein; Q145 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkvl, optionally substituted aryl, optionally substituted heteroaryl, -OH, -NH2, -NO2, -CN. -NIIC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -C(O)NH2, -C(S)NH2, -S(O)2NH2, -NR24R25, -NHR"3, -OR". -SR23, -C(O)R23, -C(S)R23. -S(O)R23, -S(O)2R23, -C(O)NHR23, -C(O)NR"3R'\ -C(S)NHR23, -C(S)NR21R23, -S(O)2NHR23, -S(O)2NR23R23, -NHC(O)R23, -NR23C(O)R23, -NHC(S)R23, -NR23C(S)R23, -NHS(O)2R2', -NR25S(O)2R23, -NHC(O)NIIR23, -NR23C(O)NH2, -NR23C(O)NHR23, -NHC(O)NR23R23, -NR23C(O)NR23R23, -NHC(S)NHR23, -NR23C(S)NH2, -NR23C(S)NHR23, -NHC(S)NR23R23, -NR13C(S)NR23R23, -NHS(O)2NHR23, -NR23S(O)2NH2, -NR23S(O)2NHR23, -NHS(O)2NR23R23, and -NR23S(O)2NR23R23.
45. The compound of Claim 44, wherein
Q141 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR2\ -NR23R23, -OR23 and -S(O)2R23; and
Q145 is hydrogen, -OR23, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkvl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkvl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR" , -NR23R23, -OR23 and -S(O)2R23.
46. The compound of Claim 45, wherein M18 is -NR2^(CR19R20X- or -NR26C(O)(CR19R20V; and A16 is -CR19R20- or -C(O)-.
47. The compound of Claim 44, wherein A16 is -CH2- or -C(O)-;
Q141 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of -OR41, -SR41, -S(O)R41, -S(O)2R41, -NHR41, -NR41R41, -NR39C(O)R41, -NR39S(O)2R41, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Q141, or as a substitucnt of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH7, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylammo; Q145 is hydrogen, -CN, -OR41. -SR41, -S(O)R41, -S(O)2R41, -NHR41 , -NR41R41, -NR^9C(O)R41,
-NR39S(O)2R41, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, and -OR41; M, s is a bond, -NR3"-, -S-, -0-, -NR39CH,-, -NR39CII2CH2-, -NR39CH(R40)-, -SCH2-, -OCH2-,
-C(O)NR19-, -S(O)2NR39-, -CH2NR39-. -CH(R40)NR39-. -NR39C(O)-, or -NR19S(O)2-; and Q152 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR44R44, -OR44, or -SR44.
48. The compound of Claim 47, wherein A16 is -CH2-;
Q141 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, and fluoro substituted lower alkoxy;
Q145 is hydrogen, -CN, fluoro, chloro. lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; and
Q152 is hydrogen, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy.
49. The compound of Claim 44, wherein M18 is -NH-CH2-;
A] ft is -CH2-;
Q141 is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with 1 or 2 substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, and heterocycloalkyl; Q14'' is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, or fluoro substituted lower alkoxy; and Q152 is hydrogen, fluoro, chloro, lower alkyl, or fluoro substituted lower alkyl.
50. The compound of Claim 44, selected from the group consisting of [4-Chloro-5-( l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine. [4-Ethyl-5-(lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine, (4-Fluoro-benzyl)-[4-methyl-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine, [4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-thia2ol-2-yl]-pyτidin-3-ylmethyl-ainine, f4-Chloro-5-(lH-p>τrolo[2J3-b]p\τidin-3-ylmethyl)-thiazol-2-y)]-pyridin-2-ylmethyl-amine,
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-4-ylmethyl-amine,
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-thiazol-2-yl]-(6-methyl-pyridin-2-y)methyl)- amine,
[4-Chloro-5-(iπ-pyrrolo[2,3-b]p>τidin-3-ylmcthyl)-thiazol-2-yl]-(l ,5-dimethyl-lH-pyτazol-3- ylmcthyl)-amine,
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(6-trifluororaethyl-pyridin-3- ylmethyl)-amine,
[4-Chloro-5-(llI-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2;5-dimethyl-2H-pyrazol-3- ylmethyl)-amine,
[2-(4-Fluoro-benzy)amino)-thiazol-5-yl]-(lII-pyrrolo[2,3-b]pyridin-3-yl)-methanone,
{2-[(4-Chloro-benzyI)-methyl-amino]-thiazol-5-yl}-(lH-pyrrolof2,3-b]pyridin-3-y])-methanonc,
[4-Chloro-5-(5-chloro-lH-p>τrolo[2,3-b]pyridin-3-ylmethyl)-thiazoI-2-yI]-thiazol-2-ylmethyl- amine,
[4-Chloro-5-(5-chloro-l H-pyrrolof2,3-b]pyridin-3-ylmethy])-thiazol-2-yl]-(6-methoxy-pyridin-3- ylmethyl)-amine,
Benzyl-[4-chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolof2,3-b]pyridin-3-ylmcthyl)-thiazol-2-yl]-(3-methoxy-benzyl)- amine,
(4-Chloro-benzyl)-[4-chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyI)-thiazol-2-yl]- amine,
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)- amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2,4-dimethyl-thiazol-5- ylmcthy))-amine,
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-ethy]-5-methy]-3H- imidazol-4-ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-thiazol-2-yl]-(2-cthyl-2H-pyrazol-3- ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-thiazol-2-yl]-(6-methoxy-pyridin-2- ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrro)of2,3-b]p>τidin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-4- ylmethyl)-amine,
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]p>τidin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-tliiazol-4- y)methy])-ajnine, [4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yI]-(4-methyl-thiazol-5- ylmethyl)-amine,
[4-Chloro-5-(5-chloro-ni-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-chloro-pyridin-2- ylmethyl)-amine,
[4-Chloro-5-(l H-ρyrrolo[2,3-b]pyτidin-3-ylmethyl>thiazol-2-ylJ-(2,4-dimethyl-thia7θl-5- ylmethyl)-amine,
[4-Chloro-5-(l H-pyrrolo[2,3-b]p>τidin-3-yImethyl)-thiazol-2-yl]-(2-ethyl-5-methyl-3H-imidazoI-
4-ylmethyl) -amine,
[4-Chloro-5-(l H-ρyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-y[]-(5-fluoro-pyridin-2-ylmethyl)- amine, r4-Chloro-5-(lH-pyrroloL2,3-bJpyridin-3-yImethyl)-thiazϋl-2-yl]-(5-methoxy-pyridin-3-ylmethyl)- amine,
[4-ChIoro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4,5-dimcthyl-thiophen-2- ylmethyl) -amine,
[4-Chloro-5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazυl-2-yl]-(2,5-dimethyl-thiophen-3- ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-fluoro-pyridin-3- ylmethyl)-aminc,
[4-ChIoro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-pyridin-3-ylmethyl- amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridiπ-3-yImethyl)-thiazol-2-yl]-pyridin-4-ylincthyI- amine,
[4-Chloro-5-(5-chloro-l H-pyrroIo[2,3-bJpyridin-3-ylmethyI)-thiazol-2-yl]-(3-chloro-pyridin-4- ylmethyl)-amine,
^-Chloro-S-CS-chloro-lH-pyrrolϋP^-bJpyridin^-ylmethyO-thiazol^-ylJ-C l -ethyl-lH-pyrazol^- ylmethyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-thia7ol-2-yl]-(5-fluoro-pyridin-2- ylmethyl)-amine,
[4-ChIoro-5-(5-chIoro- l H-pyττolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(5-methoxy-pyridin-3- ylmethyO-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridiπ-3-ylmethyl)-thiazol-2-yl]-(6-trifluoromethyl- pyridin-3-ylmcthyl)-aminc.
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-th.iazol-2-yl]-(2-chloro-6-fIuoro- benzyl)-amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-thiazol-2-yl]-phenethy]-amine.
[4-Chloro-5-(5-chlorυ-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2.4-difluoro-benzyl)- amine,
[4-Ch[oro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-fluoro-benzyl)- amine,
[4-Chloro-5-(5-chloro-l H-ρ>rrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methoκy-pyridin-3- ylmethyl)-amine,
(2-Chloro-benzyl)-[4-chloro-5-(5-chloro-l II-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]- amine,
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-methyl-benzyl)- amine,
[4-Chloro-5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmefhyl)-thiazol-2-yl]-(2-chloro-4-fluoro- benzyl)-amine,
[4-Ch]oro-5-(5-chloro-l H-pyrrolo[2>3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(3-fluoro-pyridin-2- ylmethyl)-amine,
[4-Chloro-5-(5-ehloro-l H-pyrrolo[2,3-b]pyπdin-3-ylmethyl)-thiazol-2-yl]-(6-moφholin-4-yl- pyπdm-2-ylmethyl)-amine,
[4-ChIoTO-S-(S-ChIOrO-I II-pyrrolo[2,3-b]pyridm-3-ylmethyl)-thiazol-2-yl]-(3,5-dichloro-pyridin-4- ylmethyl)-amine,
[4-Chloro-5-(5-ϋhloro-lH-pyπOlo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(2-trifluoromethyl- benzyl )-aminc,
[4-Chloro-5-(5-chloro-l H-pyrrolo[2,3-b]pyridiπ-3-ylmethyl)-thiazol-2-yl]-(6-methyl-pyridin-2- ylmethyl)-amine,
[5-(5-Chloro-l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-thiazol-2-yl]-(4-fluoro-benzyl)-amine, and all salts, prodrags, tautomers. and isomers thereof.
51. A compound having the chemical structure of Formula III,
Figure imgf000401_0001
all salts, prodrugs, tautomers, and isomers thereof, wherein:
L4 is -CH2-, -CH7CH2-, -CH(R40)-, -C(O)- or -C(O)NH-;
RSI is selected from the group consisting of hydrogen, -OR41. -CN, fluoro, chloro, lower alkyl, tluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NHR41, -NR41R41, -OR4: and -S(O)2R41;
Rs2 is selected from the group consisting of hydrogen, CY3 alkyl. fluoro substituted C2^ alkyl, OH, Ci-3 alkoxy, and fluoro substituted C1 -3 alkoxy;
RS3 is heterocycloalkyl, heteroaryl, or
Figure imgf000402_0001
R , in which ' indicates the attachment point of RSJ to L4 of Formula III, wherein heterocycloalkyl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino. -NHR41, -NR41R41, -OR4' and -S(O)2R41;
R92, R93, R94, R95, and R96 are independently selected from the group consisting of hydrogen, halogen, lower alkyl, fluoro substituted lower alkyl, cycloalkylamino, -NIIS(O)2R41, -NHC(O)R41, -NHR41, -NR41R41, -OR41 and -S(O)2R41;
R40 is selected from the group consisting of lower alkyl, and fluoro substituted lower alkyl;
R41 at each occurrence is independently selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl. and heteroaryl as R41 or as substituents of lower alkyl are are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR42, -SR42, -NHR42, -NR42R42, -NR39C(O)R42, -NR39S(O)2R42, -S(O)2R42, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and
R42 at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono- alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy;
Figure imgf000403_0001
Figure imgf000404_0001
52. The compound of Claim Sl, selected from the group consisting of: Pyridin-3-ylmethyl-[5-(lH-pyrrolo[2.3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine, (2-Moφholin-4-yl-ethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine, 2-Chloro-4-fluoro-N-[5-(lII-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide, 2,5-Dimethyl~2H-pyrazole-3-carboxylic acid [5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2- yl]-amide,
S-Methyl-pyrazine-^-carboxylic acid [5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amidc,
3-Chloro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide, 4-Fluoro-N-[5-(lH-pyττolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethyl-benzamide, N-[5-( lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-3-trifluoromethyl-benzamide, 3-Chloro-4-fluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-benzamide, 3,4-Difluoro-N-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide, 3-Methoxy-N-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-benzamide, ((R)- 1 -Phenyl -ethyl)-[5 -(I H-pyrrolo[2,3-b]pyridin-3-ylrnethyl)-pyridin-2-yl] -amine, (3-Moφholin-4-yl-benzyl)- [5-( 1 H-pyrrolo[2,3-b]p>τidin-3 -ylmethyl)-pyridin-2-yl] -amine, [l-(2-Fluoro-phenyl)-ethyl]-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl] -amine, [2-(3-Fluoro-phenyl)-ethyl]-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl] -amine, (3-Chloro-benzyl)-[5-(lIl-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine, [5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifJuoromcthyl-p>τidin-3- ylmethyl)-amine,
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(6-trifluoromethyl-pyridin-3-ylmethyl)- amine,
(3-Chloro-pyridin-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-yl]-aminc, Phcnethyl-[5-( lH-pyrτolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine, (2,4-Difluoro-benzyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine, (2-Fluoro-benzyl)-[5-(l II-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-aminc, (2-Methoxy-pyridin-3-ylmethyl)-[5-(lH-p>rrrolo[2,3-b]pyridin-3-ylmethyl)-p\τidin-2-yl]-amine, (2-Methyl-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yI]-aminc,
(6-Methoxy-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine,
(2-Chloro-4-fluoro-benzyl)-[5-(lII-p>τrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine.
(5-Methoxy-p\τidin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyπdin-3-ylmethyl)-pyridm-2-ylJ-amine,
(3-Fluoro-pyτidin-4-ylmethyl)-[5-(l H-p>τrolo[2,3-b]pyridin-3-ylmethyl)-p>τidin-2-yl]-amine,
(6-Methoxy-pyridin-2-ylmeth)'l)-[5-(lH-pyτrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl] -amine,
(4-Fluoro-2-trifluoromethy[-benzyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyi-idin-2-yl]- amine,
[5-(lH-Pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)-amine,
(3,5-Dichloro-pyridin-4-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyiidin-3-ylmethyl)-pyridin-2-yl]-amine,
(6-Morpholm-4-yl-pyridin-2-ylmethyl)-[5-(l H-pyrrolo[2,3-b]pyridin-3-ylmcthyl)-pyridin-2-ylJ- amine,
(5-Fluoro-pyridin-3-ylmethyl)-[5-(lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-p\τidin-2-yl]-amine,
(3-Chloro-pyridin-4-ylmethyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]- amine,
3-{6-[(3-Chloro-pyridin-4-ylmethyl)-amino]-pyridin-3-ylmethyl}-lH-pyrrolo[2,3-b]p>τidine-5- carbonitrik,
3-[6-(4-Chloro-benzylamino)-pyridin-3-ylmethyl]-l II-pyrrolo[2,3-b]pyridine-5-carbonitrile,
3-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyridine-5- carbonitrile,
[5-(5-ChloiO- lH-pyriolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-fluoro-benzyl)-amine,
3-[6-(2-Fluoro-benzylamino)-pyridin-3-y[methyl]-lII-pyrrolo[2,3-b]pyridine-5-carbonitrile,
(2-Fluoro-benzyl)-[5-(5 -methyl- lH-pyrrolo[2,3-b]pyridin-3-ylmethy[)-pyridin-2-yl]-amine,
3-{6-[(6-Trifluoromethyl-pyridin-3-ylmethyl)-amino]-pyridin-3-ylmethyl}-l H-pyrrolo[2,3- b]pyridine-5-carbonitrile,
3-[6-(2-Trifluoromethyl-benzylamino)-pyridin-3-ylmcthyl]-l H-pyrroIo[2,3-b]pyridinc-5- carbonitrile,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)- amine.
[5-(5-Methyl-lH-pyrrolo[2,3-bJpyridin-3-ylmcthyl)-pyridin-2-yl]-(2-trifluoromethyl-benzyl)- amine,
3-[6-(2,6-Difluoro-benzylamino)-pyridin-3-ylmethyl]-lH-p>τrolo[2,3-b]pyridine-5-carbonitrile.
[5-(5-Chloro- l H-pyiτolo[2,3-b]pyiidin-3-ylmethyl)-pyridin-2-yl]-(2,6-difluoro-benzyl)-amine,
(2-Chloro-benzyl)-[5-(5-methyl-l H-pyrrolo[2,3-bJpyridin-3-ylmethyl)-pyridin-2-yl]-amme,
(2-Chloro-benzyl)-[5-(5-chloro-lH-pyrrolo[2,3-b]pyridin-3-ylmethyl)-pyridin-2-yl]-amine,
3-[6-(2-Chloro-benzylamino)-pyridm-3-ylmethyl]-l H-pyrrolo[2,3-b]pyridine-5-carbonitrile, (6-Methox\-pyπdin-3-ylmethyl)-[5-(5-meth}.l-lH-pyπOlo[2,3-b]p)τidm-3-ylmethyl)-p>τidin-2- yl]-amine,
[5-(5-Chloro-lH-pyrrolo[2,3-b]pyridm-3-ylmethyl)-pyπdin-2-yl]-(6-methoxy-pyridin-3- ylmethyl) - amine,
3-{6-[(6-Methox}-pyridin-3-ylmethyl)-amino]-pyridιn-3-ylmelhyl}-lH-pyrτϋlo[2,3-b]pyπdine-5- carbomtπle,
[5-(5-Chloro- l H-pyπ"olo[2,3-b]pyridm-3-ylmethyl)-pyridin-2-yl]-(2-methox:y-pyπdm-3- ylmethy])-amme,
3-[6-(2-TπΩuoromethoxy-benz>laminϋ)-pyπdm-3->lmethyl]-lH-pyrrolo[2,3-b]pyπdinc-5- carbomtπle,
3-[6-(2-Ethoxy-benzylamino)-pyridin-3-ylmethyl]-lH-pyrrolo[2,3-b]pyndine-5-carbonitrile, and all salts, prodrugs, tautomers, or isomers thereof
53. A composition comprising a pharmaceutically acceptable carrier; and a compound according to any one of Claims 1-52
54. A method for treating a subject suffering from or at risk of a c-kit and/or c-fms mediated disease or condition, comprising administering to the subject an effective amount of a compound of any one of Claims 1-52
55. The method of Claim 54, wherein the compound is approved for administration to a human
56. The method of Claim 54, wherein the disease or condition is selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors, glioblastoma, astrocytoma, neuroblastoma, carcinomas of the female genital tract, sarcomas of neuroectodermal origin colorectal carcinoma, carcinoma in situ, Schwann cell neoplasia associated with neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chrome myelogenous leukemia, multiple myeloma, mastocytosis, melanoma breast cancer, ovarian cancer, prostate cancer, canine mast cell tumors, metastasis of cancer to bone or other tissues, chronic myeloproliferative diseases such as myelofibrosis, renal hypertrophy, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, osteoarthritis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosa, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease, emphysema, Kawasaki's Disease, hemophagocytic syndrome, multicentric reticulohistiocytosis, atherosclerosis, Type I diabetes, Type II diabetes, insulin resistance, hyperglycemia, obesity, hpolvsis, hypcrcosmophiha. osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, osteomyelitis, pen-prosthetic 01 wear-debπs- mediated osteolysis, endometriosis, glomerulonephritis, interstitial nephritis. Lupus nephritis tubular necrosis, diabetic nephropathy, stroke, Alzheimer's, disease, Parkinson's disease, inflammatory pain, chronic pam. and bone pam
57. A kit comprising a composition according to Claim 53
58. The kit of Claim 57, wherein the composition is approved for a medical indication selected from the group consisting of mast cell tumors, small cell lung cancer, testicular cancer, gastrointestinal stromal tumors, glioblastoma, astrocytoma, neuroblastoma carcinomas of the female genital tract, sarcomas of neuroectodermal origin, colorectal carcinoma, carcinoma m situ, Schwann cell neoplasia associated with neurofibromatosis, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, multiple myeloma, mastocytosis, melanoma, breast cancer, ovarian cancer, prostate cancer, canine mast cell tumors, metastasis of cancer to bone or other tissues, chronic myeloproliferative diseases such as myelofibrosis, renal hypertiophy, asthma, rheumatoid arthritis, allergic rhinitis, multiple sclerosis, osteoarthritis, inflammatory bowel syndrome, transplant rejection, systemic lupus erythematosa, ulcerative colitis, Crohn's disease, chronic obstructive pulmonary disease, emphysema, Kawasaki's Disease, hemophagocytic syndrome, multicentric reticulohistiocytosis, atherosclerosis, Type I diabetes, Type H diabetes, insulin resistance, hyperglycemia, obesity, hpolysis, hypereosmophiha, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, osteomyelitis, peπ- prosthetic or wear-debπs-mediated osteolysis, endometriosis, glomerulonephritis, mteistitial nephritis. Lupus nephritis, tubular necrosis, diabetic nephropathy, stroke, Alzheimer's disease, Parkinson's disease, inflammatory pam, chronic pain, and bone pam
59. A method for treating a subject suffeπng from or at risk of a c-fms mediated disease or condition selected from the group consisting of osteoarthritis, mflammatoiy bowel syndrome, ulcerative colitis, Crohn's disease, Kawasaki's Disease, hemophagocytic syndrome, multicentπc reticulohistiocytosis, Type I diabetes, Type II diabetes, obesity, Paget's disease, osteomyelitis, pen-prosthetic or wear-debπs-mediated osteolysis, endometriosis, diabetic nephropathy, multiple sclerosis, stroke Alzheimer's disease and Parkinson's disease, inflammatory pam, chronic pam, bone pam, prostate cancer, melanoma, glioblastoma multiforme, metastasis of tumors to tissues other than bone, and other chronic myeloproliferative diseases such as myelofibrosis, comprising administering to the subject an effective amount of a compound of any of Formulae I, Ia, Ib or Ig
60. The method of Claim 59, wherein the c-fms mediated disease or condition is selected from the group consisting of inflammatory bowel syndrome, ulcerative colitis. Crohn's disease, Type I diabetes, Type II diabetes, Paget 's disease, diabetic nephropathy, multiple sclerosis, stroke. Alzheimer's disease and Parkinson's disease, inflammatory pain, chronic pain, bone pain, prostate cancer, and metastasis of tumors to tissues other than bone.
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