WO2016135163A1 - Alkynyl alcohols and methods of use - Google Patents

Alkynyl alcohols and methods of use Download PDF

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Publication number
WO2016135163A1
WO2016135163A1 PCT/EP2016/053805 EP2016053805W WO2016135163A1 WO 2016135163 A1 WO2016135163 A1 WO 2016135163A1 EP 2016053805 W EP2016053805 W EP 2016053805W WO 2016135163 A1 WO2016135163 A1 WO 2016135163A1
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alkyl
methyl
compound
hydroxy
ethynyl
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PCT/EP2016/053805
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French (fr)
Inventor
Nicole Blaquiere
Georgette Castanedo
Jianwen A. FENG
James John CRAWFORD
Wendy Lee
Xingyu LIN
Baihua Hu
Guosheng Wu
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F. Hoffmann-La Roche Ag
Genentech, Inc.
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Application filed by F. Hoffmann-La Roche Ag, Genentech, Inc. filed Critical F. Hoffmann-La Roche Ag
Priority to EP16705959.1A priority Critical patent/EP3262035A1/en
Priority to JP2017544739A priority patent/JP2018510140A/en
Priority to CN201680011885.2A priority patent/CN107406427A/en
Publication of WO2016135163A1 publication Critical patent/WO2016135163A1/en

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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to inhibitors of NF-kB -inducing kinase (NIK) useful for treating cancer and inflammatory conditions, among others.
  • NIK NF-kB -inducing kinase
  • NF-kB inducing kinase is also known as MAPK kinase kinase 14 (MAP3K14) and is a serine/threonine kinase and a member of the MAPK family. It was originally identified in a two- hybrid screen as a binding partner of TNF receptor (TNFR) associated factor 2 (TRAF2) [See, Malinin, NL, et al., Nature, 1997, 385:540-4].
  • TNFR TNF receptor
  • TNF2 TNF receptor associated factor 2
  • Overexpression of NIK leads to the activation of NF-kB and dominant negative forms of NIK lacking kinase activity were able to inhibit NF-kB activation in response to TNF and IL-1 treatment.
  • NIK has been identified as an important component of the NF-kB signaling pathway.
  • Scientific research has shown that in blocking the NF-kB signaling pathway in cancer cells can cause such cells to stop proliferating, to die, or to become more sensitive to the action of other anti-cancer therapies.
  • NF-kB controls the expression of many genes involved in inflammation and that NF- kB signaling is found to be chronically active in many inflammatory conditions, such as lupus (including systemic lupus erythematosus), rheumatoid arthritis, inflammatory bowel disease, arthritis, sepsis, gastritis and asthma, among others.
  • organic compounds capable of inhibiting NIK and thereby inhibiting, weakening or lessening the undesired or over-activation of the NF-kB signaling pathway can have a therapeutic benefit for the treatment diseases and disorders for which such undesired or over- activation of NF-kB signaling is observed.
  • alkynyl alcohol compounds that are inhibitors of NIK kinase, compositions containing these compounds and methods for treating diseases mediated by NIK kinase such as cancer and inflammatory diseases.
  • ring A is a monocycle or a fused bicycle
  • Q is N or C, wherein when Q is N, then the bond between Ai and Q is not a double bond and the bond between Q and A 4 is not a double bond;
  • Ai is NR 1 , N, S, CR 1 or CHR 1 ;
  • a 2 is NR 2 , N, O, S, CR 2 or CHR 2 ;
  • a 3 is N or C
  • a 4 is N;
  • each R 1 is independently selected from the group consisting of H, halogen, NR a R b , NHC(0)NR a R b , NHS(0) 2 CH 3 , Ci-C 3 alkyl, C 3 -C 7 cycloalkyl, Ci-C 3 alkoxy and 3-11 membered heterocyclyl, wherein the alkyl of R 1 is optionally substituted by F, OH, CN, SH, Ci-C 3 alkoxy or 3-11 membered heterocyclyl; the cycloalkyl of R 1 is optionally substituted by F, OH, CN, SH, CH 3 or CF 3 ; the alkoxy of R 1 is optionally substituted by F, OH, CN or SH; and the heterocyclyl of R 1 is optionally substituted by F, OH, CN, SH, CF 3 or Ci-C 3 alkyl,
  • each R 2 is independently selected from the group consisting of H, NR a R b Ci-C 6 alkyl, C 3 -C 7 cycloalkyl, Ci-C 6 alkoxy, phenyl and 3-11 membered heterocyclyl, wherein R is optionally substituted by R c ; or 1 2
  • R and R" are taken together with the atoms to which they are attached to form a cyclic group selected from the group consisting of C 3 -C7 cycloalkyl, phenyl and 3- 11 membered heterocyclyl, wherein the cyclic group is optionally substituted by R d ;
  • R 4 is selected from the group consisting of H, Ci-C 6 alkyl, CH 2 F and CH 2 OH;
  • R 4 and R 5 together form a C 3 -C 11 cycloalkyl optionally substituted by R e or a 3- 11 membered heterocyclyl optionally substituted by R e ;
  • one of A5-A8 is N and the remaining are CR 6 or all are CR 6 ;
  • R 6 is selected from the group consisting of H, F, CI, NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, OCH 3 , OCHF 2 , OCH 2 F, OCF 3 , SH, SCH 3 , SCHF 2 , SCH 2 F, CN, CH 3 , CHF 2 , CH 2 F, CH 2 OH, CF 3 , N0 2 and N 3 ;
  • R a is selected from the group consisting of H and Ci-C 6 alkyl optionally substituted by C 1 -C 3 alkoxy, F, OH, CN, SH, CH 3 or CF 3 ;
  • R b is selected from the group consisting of H, Ci-C 6 alkyl, Ci-C 6 alkoxy, C 3 -C6 cycloalkyl, C(0)R , phenyl and 3-11 membered heterocyclyl wherein R b may be optionally substituted by C 1 -C 3 alkoxy, F, OH, CN, SH, CH 3 or CF 3 ;
  • R c and R d are each independently selected from the group consisting of halogen, -(X ⁇ o-i- CN, -(XVi-NO,, -(X')o-i-OH, -(X -NH,, -(X -NCHXR 13 ), -(X i- N(R lb )(R la ), -(X 1 )o-i-CF 3 , Ci_C 6 alkyl, Ci_C 6 haloalkyl, Ci_C 6 heteroalkyl, Ci_C 6 alkoxy, Ci_C 6 alkylthio, oxo, -(x i-Q.Ce alkyl, -(x i-Cs-Qo cycloalkyl, -O-C3-C10 cycloalkyl,
  • R e is selected from the group consisting of halogen, OH, Ci-C 6 alkyl and oxo; and R is selected from the group consisting of Ci-C 6 alkyl and C3-C6 cycloalkyl wherein R may be optionally substituted by C1-C3 alkoxy, F, OH, CN, SH, CH 3 or CF 3 ;
  • the compound is other than a compound selected from the group consisting of
  • Q is C, and the compound is of the formula (II):
  • ring B is a substituted phenyl and Q is C; and the compound is of formula (III):
  • ring A, Ai, A 2 , A3, A 4 , R 4 and R 5 are as defined for formula (II), n is 0, 1 or 2, and each R 6 is independently selected from the group consisting of F, CI, OCH 3 , CH 3 and CF 3 .
  • A9 is O, NR 11 or CR n R 12 , wherein R 11 and R 12 are each independently selected from the group consisting of H, halogen, OH and C 1 -C 3 alkyl;
  • the invention provides for pharmaceutical compositions comprising a compound of formula (I), (II) or (III), and a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention provides for a compounds of formula (I), (II) or (III), or pharmaceutical compositions thereof for use in therapy.
  • the invention provides the use of a compound or pharmaceutical composition for the preparation of a medicament for the treatment of an inflammatory condition.
  • the inventions provides for compounds of formula (I), (II) or (III), and pharmaceutical compositions thereof for the treatment of diseases and disorders, including, cancer, inflammatory conditions, and autoimmune diseases, among others.
  • the invention provides for a method (or use) of compounds of formulae (I), (II) and (III), or pharmaceutical compositions thereof in the treatment of diseases and disorders, such as, for example, cancer, inflammatory conditions, or autoimmune diseases, among others.
  • the invention provides for compounds of formulae (I), (II) and (III), for the preparation of a medicament for the treatment of cancer, inflammatory conditions, or
  • the invention provides for compound intermediates useful in synthesis of compounds of formulae (I), (II) and (III).
  • the invention provides, inter alia, compounds of formulae (I), (II) and (III), and variations thereof, pharmaceutical compositions comprising compounds of formulae (I), (II) and (III), and methods of using such compounds and compositions in treating diseases and disorders related to undesired or overactivation of the NF-kB signaling pathway, such as, for example, certain cancers and inflammatory conditions.
  • compounds of formulae (I), (II) and (III) and variations thereof, pharmaceutical compositions comprising compounds of formulae (I), (II) and (III), and methods of using such compounds and compositions in treating diseases and disorders related to undesired or overactivation of the NF-kB signaling pathway, such as, for example, certain cancers and inflammatory conditions.
  • alkyl refers to a saturated linear or branched-chain monovalent hydrocarbon radical, wherein the alkyl radical may be optionally substituted independently with one or more substituents described herein.
  • the alkyl radical is one to eighteen carbon atoms (Ci-Cig).
  • the alkyl radical is Co-C 6 , C0-C5, C0-C3, C1-C12, C1-C10 , Ci-Cg, C 6 , C1-C5, C1-C4, or C1-C3.
  • Co alkyl refers to a bond.
  • alkyl groups include methyl (Me, -CH 3 ), ethyl (Et, -CH 2 CH 3 ), 1 -propyl (n-Pr, n-propyl, -CH 2 CH 2 CH 3 ), 2-propyl (i-Pr, i- propyl, -CH(CH 3 ) 2 ), 1 -butyl (n-Bu, n-butyl, -CH 2 CH 2 CH 2 CH 3 ), 2-methyl-l -propyl (i-Bu, i-butyl, -CH 2 CH(CH 3 ) 2 ), 2-butyl (s-Bu, s-butyl, -CH(CH 3 )CH 2 CH 3 ), 2-methyl-2-propyl (t-Bu, t-butyl, - C(CH 3 ) 3 ), 1-pentyl (n-pentyl, -CH 2 CH 2 CH 2 CH 2 CH 3 ), 2-pentyl (-CH(CH 3
  • substituents for "optionally substituted alkyls" include one to six instances of F, CI, Br, I, OH, SH, CN, NH 2 , N0 2 , N 3 , COOH, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, S0 2 , phenyl, piperidinyl, piperizinyl,or pyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereof may be optionally substituted.
  • alkylene by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH 2 CH 2 CH 2 CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 12 carbon atoms, such as 1-8, 1-6 or 1-3 carbon atoms.
  • alkenylene and alkynylene refer to the unsaturated forms of “alkylene” having double or triple bonds, respectively, and typically have from 2 to 12 carbon atoms, such as 2-8, 2-6 or 2-3 carbon atoms.
  • Alkylene", “alkenylene” and “alkynylene” groups may be optionally substituted.
  • heteroalkyl refers to a straight or branched chain monovalent hydrocarbon radical, consisting of the stated number of carbon atoms, or, if none are stated, up to 18 carbon atoms, and from one to five heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized.
  • the heteroatom is selected from O, N and S, wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized.
  • the heteroatom(s) can be placed at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule (e.g., -0-CH 2 -CH 3 ).
  • heteroalkyl groups can be optionally substituted.
  • substituents for "optionally substituted heteroalkyls" include one to four instances of F, CI, Br, I, OH, SH, CN, NH 2 , N0 2 , N 3 , COOH, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, S0 2 , phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereof
  • heteroalkylene means a divalent radical derived from heteroalkyl, as exemplified by -CH 2 CH 2 SCH 2 CH 2 , -CH 2 SCH 2 CH 2 NHCH 3 and -OCH 2 CH 3 .
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy,
  • alkylenedioxy, alkyleneamino, alkylenediamino, and the like may be optionally substituted.
  • Cycloalkyl refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group wherein the cycloalkyl group may be optionally substituted with one or more substituents described herein.
  • the cycloalkyl group is 3 to 12 carbon atoms (C 3 -Ci 2 ).
  • cycloalkyl is C 3 -C 6 , C 3 -Cs, C 3 -Cio or C 5 -C10.
  • the cycloalkyl group, as a monocycle is C 3 -Cs, C 3 -C 6 or C 5 -C6.
  • the cycloalkyl group, as a bicycle is C 7 -Ci 2 .
  • the cycloalkyl group, as a spiro system is C 5 -Ci 2 .
  • Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l- enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-l- enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl.
  • Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems.
  • Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[4.1.0]heptane, bicycle[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[4.1.0]heptane and bicyclo[3.2.2]nonane.
  • spiro cycloalkyl examples include, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro [2.5] octane and spiro[4.5]decane.
  • substituents for "optionally substituted cycloalkyls" include one to four instances of F, CI, Br, I, OH, SH, CN, NH 2 , N0 2 , N 3 , COOH, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, S0 2 , phenyl, piperidinyl, piperizinyl, and
  • pyrimidinyl wherein the alkyl, aryl and heterocyclic portions thereof may be optionally substituted.
  • cycloalkylene means a divalent radical derived from a cycloalkyl group.
  • a cycloalkylene group may be optionally substituted.
  • Heterocyclic group “heterocyclic”, “heterocycle”, “heterocyclyl”, or “heterocyclo” are used interchangeably and refer to any monocyclic, bicyclic, or spiro, saturated or unsaturated, aromatic (heteroaryl) or non-aromatic (e.g., heterocycloalkyl), ring system, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule.
  • heterocyclyl includes 3-11 ring atoms ("members", that is, a 3-11 membered heterocycle) and includes monocycles, bicycles, and spiro ring systems, wherein the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen.
  • heterocyclyl includes 1 to 4 heteroatoms.
  • heterocyclyl includes 3- to 7-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen.
  • heterocyclyl includes 4- to 6- membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen.
  • heterocyclyl includes 3-membered monocycles.
  • heterocyclyl includes 4-membered monocycles. In another example, heterocyclyl includes 5-6-membered monocycles. In one example, the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, S0 2 ), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR 4 ] + Cr, [NR 4 ] + OH ⁇ ). In another example, heterocyclyl includes 3- to 9-membered spiro cycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen.
  • Example heterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1 ,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-lH-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinohnyl, tetrahydroisoquinohnyl, morphohnyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl,
  • tetrahydroindazolyl 1,1-dioxohexahydrothiopyranyl.
  • 5 -membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including l,3,4-thiadiazol-5-yl and 1,2,4- thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as l,3,4-oxadiazol-5-yl, and l,2,4-oxadiazol-5-yl.
  • Example 5-membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as l,3,4-triazol-5-yl; 1,2,3- triazol-5-yl, l,2,4-triazol-5-yl, and tetrazolyl, such as lH-tetrazol-5-yl.
  • Example benzo-fused 5- membered heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl.
  • Example 6-membered heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as l,3,4-triazin-2-yl and l,3,5-triazin-4-yl;
  • pyridazinyl in particular pyridazin-3-yl, and pyrazinyl.
  • the pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the l,3,4-triazin-2-yl groups, are other example heterocycle groups. Heterocycles may be optionally substituted.
  • substituents for "optionally substituted heterocycles" include one to six instances of F, CI, Br, I, OH, SH, CN, NH 2 , N0 2 , N 3 , COOH, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, S0 2 , phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereof may be optionally substituted.
  • heterocyclylene means a divalent radical derived from a heterocyclyl group.
  • a heterocyclylene group may be optionally substituted.
  • Heteroaryl refers to any mono-, bi-, or tricyclic ring system where at least one ring is a 5- or 6- membered aromatic ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in an example embodiment, at least one heteroatom is nitrogen. See, for example, Lang's Handbook of Chemistry (Dean, J. A., ed.) 13 th ed. Table 7-2 [1985]. Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to an aryl ring, wherein the aryl ring or the heteroaryl ring is joined to the remainder of the molecule.
  • heteroaryl includes 4-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. In another embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen.
  • Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[l,5- b]pyridazinyl, imidazol[l,2-a]pyrimidinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl.
  • Heteroaryl groups can be optionally substituted.
  • substituents for "optionally substituted heteroaryls" include one to six instances of F, CI, Br, I, OH, SH, CN, NH 2 , N0 2 , N 3 , COOH, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, S0 2 , phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereof may be optionally substituted.
  • a heterocyclyl group is attached at a carbon atom of the heterocyclyl group.
  • carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quino
  • the heterocyclyl group is N-attached.
  • the nitrogen bonded heterocyclyl or heteroaryl group include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2- imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of an isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or ⁇ -carboline.
  • alkoxy refers to those alkyl groups attached to the remainder of the molecule via an oxygen atom. Non-limiting examples include methoxy, ethoxy and propoxy. Alkoxy groups may be optionally substituted, such as by halogen.
  • alkylthio refers to those alkyl groups attached to the remainder of the molecule via a sulfur atom. Non-limiting examples include -SCH 3 , -SCH 2 CH 3 and -SCH 2 CH 2 CH 3 . Alkylthio groups may be optionally substituted, such as by halogen.
  • halo or halogen
  • haloalkyl is meant to include both an “alkyl” and a “haloalkyl” substituent. Additionally, the term “haloalkyl,” is meant to include monohaloalkyl and polyhaloalkyl.
  • aryl means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon ring radical, which can be a single ring or multiple rings (up to three rings) which are fused together and having the stated number of aryl ring atoms.
  • An aryl group can be optionally substituted.
  • a "phenylene” group refers to a divalent radical derived from a phenyl group.
  • a phenylene group may be optionally substituted.
  • Optionally substituted unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4, or 5 or more) of the substituents listed for that group in which said substituents may be the same or different. That is, an optionally substituted substituent is independent at each occurrence. In an embodiment an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents. In another embodiment an optionally substituted group has 4 substituents.
  • Optional substituents for alkyl and cycloalkyl can be a variety of groups including, but not limited to, halogen, oxo, CN, N0 2 , N 3 , OR', perfluoro-Ci_4 alkoxy, unsubstituted cycloalkyl, unsubstituted aryl (e.g., phenyl), unsubstituted heterocyclyl, NR'R", SR', SiR'R"R"', OC(0)R', C(0)R, C0 2 R, CONR'R", OC(0)NRR", NR"C(0)R', NR"'C(0)NR'R", NR"C(0) 2 R', S(0) 2 R ⁇ S(0) 2 NR'R", NR'S(0) 2 R", NR"'S(0) 2 NR'R", amidino, guanidine, (CH 2 )i_ 4 OR', (CH 2 ) !
  • R', R" and R' each independently refer to groups including, for example, hydrogen; unsubstituted Ci- 6 alkyl; unsubstituted heteroalkyl; unsubstituted aryl; aryl substituted with 1-3 halogens, unsubstituted Ci_C 6 alkyl, Ci_ C 6 alkoxy or Ci_C 6 thioalkoxy groups, unsubstituted aryl-Ci-C 4 alkyl groups, and unsubstituted heteroaryl.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring wherein a ring atom is optionally substituted with N, O or S.
  • NR'R is meant to include 1 -pyrrolidinyl and 4- morpholinyl.
  • substituents for aryl and heterocyclyl groups are varied.
  • substituents for aryl and heterocyclyl groups are selected from the group including, but not limited to, halogen, OR', OC(0)R', NR'R", SR', R', CN, N0 2 , C0 2 R, CONR'R", C(0)R', OC(0)NR'R", NR"C(0)R, NR"C(0) 2 R', NR'C(0)NR"R”', S(0)R', S(0) 2 R', S(0) 2 NR'R", NR'S(0) 2 R", N 3 , perfluoro-Ci-C 4 alkoxy, perfluoro-Ci-C 4 alkoxy, (CH 2 )i_ 4 OR', (CH 2 ) 1 .
  • Suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of from 1-4 carbon atoms.
  • heteroatom is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
  • heteroatom refers to O, N or S.
  • heteroatom refers to O or N.
  • chiral refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.
  • stereoisomers refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
  • Diastereomer refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as electrophoresis and chromatography.
  • Enantiomers refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
  • the compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention.
  • optically active compounds i.e., they have the ability to rotate the plane of plane-polarized light.
  • the prefixes D and L, or R and S are used to denote the absolute configuration of the molecule about its chiral center(s).
  • the prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory.
  • a compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another.
  • a specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture.
  • a 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or
  • racemic mixture and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
  • tautomer or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • Valence tautomers include interconversions by reorganization of some of the bonding electrons.
  • stereochemistry In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. Unless otherwise specified, if solid wedges or dashed lines are used, relative stereochemistry is intended. If a discrepancy exists between a structure and its name, the structure governs.
  • solvate refers to an association or complex of one or more solvent molecules and a compound of the invention.
  • solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.
  • hydrate refers to the complex where the solvent molecule is water.
  • protecting group refers to a substituent that is commonly employed to block or protect a particular functional group on a compound.
  • an “amino- protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound.
  • Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc).
  • a "hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl.
  • a “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality.
  • Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2- (p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like.
  • protecting groups and their use see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4 th edition, Wiley- Interscience, New York, 2006.
  • mammal includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.
  • a “subject,” “individual,” or “patient” is a vertebrate.
  • the vertebrate is a mammal.
  • a subject, individual or patient may be in need of a compound of the present invention.
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • salts derived from pharmaceutically- acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like.
  • Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • suitable inert solvent examples include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
  • the neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds which are in a prodrug form.
  • prodrug refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
  • Prodrugs of the invention include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of a compound of the present invention.
  • the amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3- methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.
  • prodrugs are also encompassed.
  • a free carboxyl group of a compound of the invention can be derivatized as an amide or alkyl ester.
  • compounds of this invention comprising free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19: 115.
  • Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups.
  • Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed.
  • Prodrugs of this type are described in J. Med. Chem., (1996), 39: 10.
  • More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (Ci-C 6 )alkanoyloxymethyl, l-((Ci- C 6 )alkanoyloxy)ethyl, l-methyl-l-((Ci-C 6 )alkanoyloxy)ethyl, (Ci-C 6 )alkoxycarbonyloxymethyl, N-(Ci-C6)alkoxycarbonylaminomethyl, succinoyl, (Ci-C 6 )alkanoyl, alpha-amino(Ci_4)alkanoyl, arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each alpha- aminoacyl group is independently selected from the naturally occurring L-amino acids,
  • prodrug derivatives see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of
  • a "metabolite” refers to a product produced through metabolism in the body of a specified compound or salt thereof. Such products can result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.
  • Metabolite products typically are identified by preparing a radiolabelled (e.g., 14 C or 3 H) isotope of a compound of the invention, administering it in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples.
  • a detectable dose e.g., greater than about 0.5 mg/kg
  • metabolites In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art.
  • the metabolite products so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are intended to be within the scope of the present invention.
  • the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replace by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses.
  • Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as H ("D"), 3 H, n C, 13 C, 14 C, 13 N, 15 N, 15 0, 17 0, 18 0, 3 2 P, 33 P, 35 S, 18 F, 36 C1, 123 I and 125 I.
  • Certain isotopically labeled compounds of the present invention e.g., those labeled with 3 H or 14 C
  • Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability.
  • Positron emitting isotopes such as 15 0, 13 N, n C, and
  • Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • an isotopically substituted moiety is the following:
  • compound(s) of this invention and “compound(s) of the present invention” and the like, unless otherwise indicated, include compounds of formulae (I), (II) and (III) and stereoisomers (including atropisomers), geometric isomers, tautomers, solvates, metabolites, isotopes, salts (e.g., pharmaceutically acceptable salts), and prodrugs thereof. In some embodiments, solvates, metabolites, isotopes or prodrugs are excluded, or any combination thereof.
  • Treatment refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis.
  • compounds of the invention are used to delay development of a disease or disorder or to slow the progression of a disease or disorder.
  • Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation) or those in which the condition or disorder is to be prevented.
  • prophylaxis is excluded from the definition of "treatment.”
  • therapeutically effective amount means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein.
  • efficacy can, for example, be measured by assessing the time to disease progression (TTP) or determining the response rate (RR).
  • TTP time to disease progression
  • RR response rate
  • the therapeutically effective amount is an amount sufficient to decrease or alleviate an allergic disorder, the symptoms of an allergic disorder.
  • autoimmune or inflammatory condition e.g., psoriasis or inflammatory bowel disease
  • symptoms of an acute inflammatory reaction e.g. asthma.
  • a autoimmune or inflammatory condition e.g., psoriasis or inflammatory bowel disease
  • an acute inflammatory reaction e.g. asthma
  • therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly decrease the activity or number of B-cells.
  • inhibiting includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of activity (e.g., NIK activity) compared to normal.
  • NIK activity e.g., NIK activity
  • bioavailability refers to the systemic availability (i.e., blood/plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term that indicates measurement of both the time (rate) and total amount (extent) of drug that reaches the general circulation from an administered dosage form.
  • Inflammatory condition refers to any disease, disorder, or syndrome in which an excessive or unregulated inflammatory response leads to excessive inflammatory symptoms, host tissue damage, or loss of tissue function.
  • Inflammation refers to a localized, protective response elicited by injury or destruction of tissues, which serves to destroy, dilute, or wall off (sequester) both the injurious agent and the injured tissue. Inflammation is notably associated with influx of leukocytes or neutrophil chemotaxis. Inflammation can result from infection with pathogenic organisms and viruses and from noninfectious means such as trauma or reperfusion following myocardial infarction or stroke, immune response to foreign antigen, and autoimmune responses.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth or proliferation.
  • a “tumor” comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
  • Autoimmune disease refers to any group of disorders in which tissue injury is associated with humoral or cell-mediated responses to the body's own constituents.
  • any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention.
  • any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any compound or composition of the invention.
  • ring A is a monocycle or a fused bicycle
  • Q is N or C, wherein when Q is N, then the bond between Ai and Q is not a double bond and the bond between Q and A 4 is not a double bond;
  • Ai is NR 1 , N, S, CR 1 or CHR 1 ;
  • a 2 is NR 2 , N, O, S, CR 2 or CHR 2 ;
  • a 3 is N or C
  • a 4 is N;
  • each R 1 is independently selected from the group consisting of H, halogen, NR a R b , NHC(0)NR a R b , NHS(0) 2 CH 3 , C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 alkoxy and 3-11 membered heterocyclyl, wherein the alkyl of R 1 is optionally substituted by F, OH, CN, SH, C 1 -C 3 alkoxy or 3-11 membered heterocyclyl; the cycloalkyl of R 1 is optionally substituted by F, OH, CN, SH, CH 3 or CF 3 ; the alkoxy of R 1 is optionally substituted by F, OH, CN or SH; and the heterocyclyl of R 1 is optionally substituted by F, OH, CN, SH, CF 3 or C 1 -C 3 alkyl,
  • each R 2 is independently selected from the group consisting of H, NR a R b , Ci-C 6 alkyl, C 3 -C 7 cycloalkyl, Ci-C 6 alkoxy, phenyl and 3-11 membered heterocyclyl, wherein R is optionally substituted by R c ; or
  • R" are taken together with the atoms to which they are attached to form a cyclic group selected from the group consisting of C 3 -C7 cycloalkyl, phenyl and 3-11 membered heterocyclyl, wherein the cyclic group is optionally substituted by R d ;
  • R 4 is selected from the group consisting of H, Ci-C 6 alkyl, CH 2 F and CH 2 OH;
  • R 4 and R 5 together form a C 3 -C 11 cycloalkyl optionally substituted by R e or a 3-11 membered heterocyclyl optionally substituted by R e ;
  • one of A5-A8 is N and the remaining are CR 6 or all are CR 6 ;
  • R 6 is selected from the group consisting of H, F, CI, NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, OCH 3 , OCHF 2 , OCH 2 F, OCF 3 , SH, SCH 3 , SCHF 2 , SCH 2 F, CN, CH 3 , CHF 2 , CH 2 F, CH 2 OH, CF 3 , N0 2 and N 3 ;
  • R a is selected from the group consisting of H and Ci-C 6 alkyl optionally substituted by C1-C3 alkoxy, F, OH, CN, SH, CH 3 or CF 3 ;
  • R b is selected from the group consisting of H, Ci-C 6 alkyl, Ci-C 6 alkoxy, C 3 -C 6 cycloalkyl, C(0)R , phenyl and 3-11 membered heterocyclyl wherein R b may be optionally substituted by Ci-C 3 alkoxy, F, OH, CN, SH, CH 3 or CF 3 ;
  • R c and R d are each independently selected from the group consisting of halogen, -(X ⁇ o-i- CN, -(X 1 )o-i-N0 2 , -(x i-SFj, -(X')o-i-OH, -(X 1 ) 0 -i-NH 2 , -(X -NCHXR 13 ), -(x i- N(R lb )(R la ), -(X 1 )o-i-CF 3 , Ci_C 6 alkyl, Ci_C 6 haloalkyl, Ci_C 6 heteroalkyl, Ci_C 6 alkoxy, Ci_C 6 alkylthio, oxo, -(x i-Ci-Ce alkyl, -(x i-Cs-Qo cycloalkyl, -O-C 3 _Ci 0 cycloalkyl, membered heterocyclyl, -(x
  • R e is selected from the group consisting of halogen, OH, Ci-C 6 alkyl and oxo; and R is selected from the group consisting of Ci-C 6 alkyl and C 3 -C 6 cycloalkyl wherein R may be optionally substituted by Ci-C 3 alkoxy, F, OH, CN, SH, CH 3 or CF 3 .
  • the compound of formula (I) is other than Compound Nos. 1-199 in PCT/EP2014/067872, filed August 22, 2014, or any intermediate disclosed therein. In some embodiments, the compound of formula (I) is other than a compound selected from the group consisting of Compound Nos. lx-199x in Table lx.
  • the compound is of formula (I) where in Q is C. In some embodiments, the compound is of formula (I) where in Q is C, provided that the compound is other than a compound selected from the group consisting of Compound Nos. lx-146x and 148x-199x. In some embodiments, a compound of formula (I) is further defined as a compound of formula (II):
  • ring A is a monocycle or a fused bicycle
  • Ai is NR 1 , N, S, CR 1 or CHR 1 ;
  • a 2 is NR 2 , N, O, S, CR 2 or CHR 2 ;
  • a 3 is N or C
  • a 4 is N; and one, two or three of A1-A4 are N, wherein:
  • each R 1 is independently selected from the group consisting of H, halogen, NR a R b , NHC(0)NR a R b , NHS(0) 2 CH 3 , C1-C3 alkyl, C 3 -C 7 cycloalkyl, Ci-C 3 alkoxy and 3- 11 membered heterocyclyl, wherein the alkyl of R 1 is optionally substituted by F, OH, CN, SH, Ci-C 3 alkoxy or 3-11 membered heterocyclyl; the cycloalkyl of R 1 is optionally substituted by F, OH, CN, SH, CH 3 or CF 3 ; the alkoxy of R 1 is optionally substituted by F, OH, CN or SH; and the heterocyclyl of R 1 is optionally substituted by F, OH, CN, SH, CF 3 or Ci-C 3 alkyl,
  • each R 2 is independently selected from the group consisting of H, NR a R b Ci-C 6 alkyl, C 3 -C 7 cycloalkyl, Ci-C 6 alkoxy, phenyl and 3-11 membered heterocyclyl, wherein R is optionally substituted by R c ; or
  • R and R" are taken together with the atoms to which they are attached to form a cyclic group selected from the group consisting of C 3 -C 7 cycloalkyl, phenyl and 3- 11 membered heterocyclyl, wherein the cyclic group is optionally substituted by R d ;
  • R 4 is selected from the group consisting of H, Ci-C 6 alkyl, CH 2 F and CH 2 OH;
  • R 4 and R 5 together form a C 3 -Cn cycloalkyl optionally substituted by R e or a 3- 11 membered heterocyclyl optionally substituted by R e ;
  • one of A5-A8 is N and the remaining are CR 6 or all are CR 6 ;
  • R 6 is selected from the group consisting of H, F, CI, NH 2 , NHCH 3 , N(CH 3 ) 2 , OH, OCH 3 , OCHF 2 , OCH 2 F, OCF 3 , SH, SCH 3 , SCHF 2 , SCH 2 F, CN, CH 3 , CHF 2 , CH 2 F, CH 2 OH, CF 3 , N0 2 and N 3 ;
  • R a is selected from the group consisting of H and Ci-C 6 alkyl optionally substituted by Ci-C 3 alkoxy, F, OH, CN, SH, CH 3 or CF 3 ;
  • R b is selected from the group consisting of H, Ci-C 6 alkyl, Ci-C 6 alkoxy, C 3 -C 6 cycloalkyl, C(0)R , phenyl and 3-11 membered heterocyclyl wherein R b may be optionally substituted by Ci-C 3 alkoxy, F, OH, CN, SH, CH 3 or CF 3 ;
  • R c and R d are each independently selected from the group consisting of halogen, -(X ⁇ o-i- CN, -(x i-NO,, -(x i-SFj, -(X')o-i-OH, -(x i-NH,, -(x i-NCHXR 13 ), -(x i- N(R lb )(R la ), -(X 1 )o-i-CF 3 , Ci_C 6 alkyl, Ci_C 6 haloalkyl, Ci_C 6 heteroalkyl, Ci_C 6 alkoxy, Ci_C 6 alkylthio, oxo, -(x i-Ci-Ce alkyl, -(x i-Cs-Qo cycloalkyl, -O-C 3 _Ci 0 cycloalkyl, -( ⁇ ⁇ -3-11 membered heterocyclyl, aryl, -C(
  • R e is selected from the group consisting of halogen, OH, Ci-C 6 alkyl and oxo; and R is selected from the group consisting of Ci-C 6 alkyl and C3-C6 cycloalkyl wherein R may be optionally substituted by C1-C3 alkoxy, F, OH, CN, SH, CH 3 or CF 3 .
  • the compound is of formula (II), provided that the compound is other than a compound selected from the group consisting of Compound Nos. lx-146x and 148x-199x.
  • ring A is a monocycle.
  • Ai is N or CHR 1 . In some embodiments, Ai is N.
  • Ai is N
  • a 2 is S and A 3 is C.
  • a 2 is N, O or CHR .
  • a 2 is N. In some embodiments, Ai is S, A 2 is N and A 3 is C. In some embodiments, A 2 is O, Ai is CR 1 , A 2 is O and A 3 is C.
  • Ai is CHR 1 and A 2 is CHR 2 , and ring A is a non-aromatic heterocyle. In some embodiments, Ai is CHR 1 and A 2 is CHR 2 , and ring A is a non-aromatic monocyclic heterocyle. In some embodiments, Ai is CHR 1 and A 2 is CHR 2 , and ring A is a fused bicyclic non-aromatic heterocyle.
  • Ai is CHR 1 ;
  • a 2 is CHR 2 ; and
  • R 1 and R2 are taken together with the atoms to which they are attached to form a C 3 -C 7 cycloalkyl optionally substituted by R d or a 3-11 membered heterocyclyl optionally substituted by R d .
  • R 1 and R 2 together form the following cyclic group, wherein the asterisks indicate the points of ring fusion to ring A, and each cyclic group is optionally substituted by R d :
  • R 1 and 2 are taken together with the atoms to which they are attached to form a moiety of the structure: t , which is optionally substituted by R d , wherein the asterisks indicate the points of ring fusion to ring A.
  • Ai is CR 1 wherein R 1 is selected from the group consisting of NHC(0)NR a R b ; NHS(0) 2 CH 3 ; C 1 -C3 alkyl substituted by Ci-C 3 alkoxy or 3-11 membered heterocyclyl; and 3-11 membered heterocyclyl substituted by Ci-C 3 alkyl.
  • Ai is CR 1 wherein R 1 is NHC(0)NR a R b .
  • R a and R b are independently selected from the group consisting of H and Ci-C 6 alkyl.
  • Ai is CR 1 wherein R 1 is NHS(0) 2 CH 3 . In some embodiments, Ai is CR 1 wherein R 1 is 3-11 membered heterocyclyl substituted by Ci-C 3 alkyl. In some embodiments, Ai is CR 1 wherein R 1 is Ci-C 3 alkyl substituted by Ci-C 3 alkoxy or 3-11 membered heterocyclyl. In som sisting of:
  • Ai is NR 1 , S or CR 1 ; and A 2 is NR 2 , S or CR 2 .
  • A is a monocycle
  • Ai is NR . In some embodiments, Ai is 2
  • a 2 is CR and A 3 is C.
  • R 1 is H or Ci-C 3 alkyl.
  • Ai is CR 1 . In some embodiments, is 1 2 1
  • Ai CR , A 2 is CR and A 3 is N. In some embodiments, Ai is CR and A 6 is CR°. In some of these embodiments, A 2 is CR where R is H or -OCH 3 .
  • Ai is CR 1
  • a 2 is S and A 3 is C.
  • R 1 is other than -NH 2 or -CH 3 .
  • R 1 is H, F or CI.
  • R 1 is NR a R b .
  • R a is H or Ci-C 6 alkyl.
  • R b is H; Ci-C 6 alkyl optionally substituted by Ci-C 3 alkoxy, F, OH, CN, SH, CH 3 or CF 3 ; or 3-11 membered heterocyclyl optionally substituted by Ci-C 3 alkoxy, F, OH, CN, SH, CH 3 or CF 3 .
  • R b is C(0)R .
  • R is C 3 -C 6 cycloalkyl optionally substituted by F.
  • R 1 is Ci-C 3 alkyl optionally substituted by F, OH, CN, SH, Ci-C 3 alkoxy or 3-11 membered heterocyclyl; C 3 -C 7 cycloalkyl optionally substituted by F, OH, CN, SH, CH 3 or CF 3 ; or Ci-C 3 alkoxy.
  • R 1 is 3-11 membered heterocyclyl optionally substituted by F, OH, CN, SH, CF 3 or Ci-C 3 alkyl.
  • R 1 is a 5-6 membered heteroaryl optionally substituted by F, OH, CN, SH, CF 3 or Ci-C 3 alkyl.
  • R 1 is selected from the group consisting of:
  • Ai is S. In some embodiments, Ai is S, A 2 is CR and A 3 is C. In some embodiments, R is H. In some embodiments,
  • Ai is NR 1 or CR1 ; and A 2 is NR 2 or CR 2.
  • Ai is NR 1 or CR1 ;
  • a 2 is NR 2 or CR 2 ; and
  • R 1 and R2 are taken together with the atoms to which they are attached to form a C 3 -C 7 cycloalkyl optionally substituted by R d , or a 3-11 membered heterocyclyl optionally substituted by R d .
  • R 1 and R 2 are taken together with the atoms to which they are attached to form a moiety selected from the roup consisting of: wherein the asterisks indicate the points of ring fusion to ring A.
  • a 7 is CR 6 where R 6 is H. In some embodiments, As is CR 6 where R 6 is H or F. In some embodiments, A5 is CR 6 where R 6 is H. In some embodiments, A 6 is CR 6 where R 6 is selected from the group consisting of H, F, OCH 3 and CH 3 . In some embodiments, A 5 , A 6 , A 7 and A 8 are each independently CR 6 where R 6 is, independently at each occurrence, selected from the group consisting of H, F, OCH 3 and CH 3 and n is 0.
  • a compound of formula (I) is further defined as a compound of formula (HI):
  • ring A, Ai, A 2 , A3, A 4 , R and R are as defined for formula (II) or any variation detailed herein, n is 0, 1 or 2, and each R 6 is independently selected from the group consisting of F, CI, OCH 3 , CH 3 and CF 3 .
  • the compound is of formula (III), provided that the compound is other than a compound selected from the group consisting of Compound Nos. lx- 3x, 12x-14x, 16x, 18x-50x, 53x, 57x, 67x-70x, 73x-77x, 84x-140x, 143x-164x and 167x-199x in Table lx.
  • R 4 and R 5 are taken together with carbon to which they are attached to form a Cs-Cio cycloalkyl optionally substituted by R e . In some embodiments, R 4 and R 5 are taken together with carbon to which they are attached to form a 4-9 membered heterocyclyl optionally substituted by R e .
  • a 9 is O, NR 11 or CR n R 12 , wherein R 11 and R 12 are each independently selected from the group consisting of H, halogen, OH and C 1 -C 3 alkyl;
  • R 9 and R 10 are each independently selected from H and R e , or R 9 and R 10 are taken together with the atoms to which they are attached to form a C5-C6 cycloalkyl optionally substituted by R e or a 5-6 membered heterocyclyl optionally substituted by R e .
  • R R together form 0; R and R are each H; and A 9 is NR 11 where R 11 is C 1 -C 3 alkyl.
  • the moiety is selected from the group consisting of:
  • the moiety is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • ring A is a monocycle
  • Ai is NR 1
  • each A 5 , A 6 , A 7 and A 8 is independently CR 6
  • the -C(R 4 )(R 5 )OH moiety is 3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl.
  • ring A is a monocycle
  • Ai is CR 1 wherein R 1 is other than -NH 2 or -CH 3
  • a 2 is S
  • A3 is C
  • each A5, A 6 , A 7 and As is independently CR 6
  • the -C(R 4 )(R 5 )OH moiety is 3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl.
  • ring 1 2 is a monocycle
  • Ai is CR 1 wherein R 1 is other than -NH 2 or -CH 3
  • a 2 is S
  • A3 is C
  • each A5, A 6 , A 7 and As is independently CR 6
  • A is a monocycle, Ai is CR , A 2 is CR , A3 is N,
  • a 6 is CR 6 , and the -C(R 4 )(R 5 )OH moiety is 3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl.
  • Ai is NR , S or CR ; and A 2 is NR , S or CR .
  • a 2 i S or CR provided that the compound is other than a compound selected from the group consisting of Compound Nos. 55x, 78x-83x, 89x, 195x and 197x.
  • the compound of is formula (I), (II) or (III), wherein the -C(R 4 )(R 5 )OH moiety is 3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl. In some embodiments, the compound of is formula (I), (II) or (III), wherein the -C(R 4 )(R 5 )OH moiety is 3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl; provided that the compound is other than a compound selected from the group consisting of Compound Nos.
  • one of A 1 -A4 is N. In some embodiments, A 4 is N. In some embodiments, two of A 1 -A4 is N. For example, in some embodiments, Ai and A 4 are each N. In other embodiments, A3 and A 4 are each N. In any such embodiment, ring B may be phenyl or phenyl independently substituted by one or two R 6 . In some embodiments, A 1 is CR 1 , A 2 is CR 2 , A 3 is N and A 4 is N.
  • R 1 is selected from the group consisting of H, F and CI. In some embodiments, R is selected from the group consisting of H, NH 2 , CH 3 and cyclopropyl. In other embodiments, R 2 is a 1
  • R and R2 together form the following cyclic group, wherein the asterisks indicate the points of ring fusion to ring A, and each c scrap group is optionally substituted by R d :
  • R 1 and R 2 together form the following cyclic group, wherein the asterisks indicate the points of ring fusion to ring A, and each cyclic group is optionally substituted by R d :
  • R d is selected from the group consisting of OH, CN, F, C 1 -C3 alkoxy, -O-Q-C3 alkyl-phenyl, NR a R b , 4-6 membered heterocyclyl, C(0)R , C(0) 2 R and Ci-C 6 alkyl optionally substituted by OH, CN, or 4-6 membered heterocyclyl.
  • ring B is phenyl
  • R c and R d are each independently selected from the group consisting of halogen, -(XV-CN, -(X 1 )o-i-N0 2 , -(x i-SFj, -(X')o-i-OH, -(x i-NH,, i-N(H)(R la ), -(X 1 )o-i-N(R lb )(R la ), -(X 1 ) 0 -i-CF 3 , Ci_C 6 alkyl, Ci_C 6 haloalkyl, Ci_C 6 heteroalkyl, Ci_C 6 alkoxy, Ci_C 6 alkylthio, oxo, -(x i-Ci-Ce alkyl, cycloalkyl,
  • heterocyclyl e.g., a 4-7 membered heterocycloalkyl or a 5-6 membered heteroaryl
  • heterocycloalkyl or a 5-6 membered heteroaryl comprising 0-3 additional heteroatoms selected from N, O and S;
  • Y 1 is O, NR lc or S wherein R lc is H or Ci_C 6 alkyl; wherein any portion of an R c or R d substituent, including R la , R lb and R lc , at each occurrence is each independently further substituted by from 0 to 4 R substituents selected from the group consisting of halogen, CN, N0 2 , OH, NH 2 , -N(Ci_C 6 alkyl) 2 , -NH(Ci_C 6 alkyl), oxo, Ci_C 6 alkyl, Ci_C 6 haloalkyl, Ci_C 6 hydroxyalkyl, Ci_C 6 heteroalkyl, Ci_C 6 alkoxy, Ci_C 6 alkylthio, C3-C7 cycloalkyl, or 3-11 membered hetero
  • a heterocyclyl group contains one to three nitrogen atoms, one oxygen atom, or one sulfur atom, or any combination thereof.
  • a compound of the present invention is defined as any one or more of the following:
  • a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, diluent or excipient.
  • a compound or pharmaceutical composition described herein can be used in therapy, such as the treatment of an inflammatory condition (e.g., lupus, such as systemic lupus erythematosus, extrarenal lupus, or lupus nephritis, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and transplant rejection).
  • an inflammatory condition e.g., lupus, such as systemic lupus erythematosus, extrarenal lupus, or lupus nephritis
  • COPD rhinitis
  • multiple sclerosis IBD
  • arthritis arthritis
  • rheumatoid arthritis dermatitis
  • endometriosis and transplant rejection e.g.,
  • erythematosus erythematosus, extra-renal lupus, or lupus nephritis, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and transplant rejection).
  • a method for the treatment of an inflammatory condition in a patient comprising administering an effective amount of a compound or pharmaceutical composition as described herein to the patient.
  • the inflammatory condition can be selected from the group consisting of lupus, such as systemic lupus erythematosus, extra-renal lupus, or lupus nephritis, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and transplant rejection.
  • [M] is a boronic acid, a boronic ester, or a trifluoroborate salt, in the presence of (a)(i) a palladium(O) catalyst or (a)(ii) a copper catalyst and (b) a base under Suzuki reaction conditions to yield a compound of formula (I).
  • Non- limiting examples of palladium catalysts include Pd(PPh 3 ) 4 , Pd(OAc) 2 and Pd(PPh 3 ) 2 Cl 2 .
  • a non- limiting example of a copper catalyst is copper(II) acetate.
  • bases include sodium carbonate, potassium carbonate and cesium carbonate, or mixtures thereof. In some embodiments, copper(II) acetate and pyridine as the base are employed under Chan-Lam coupling conditions, as is known in the art.
  • the carbon-nitrogen bond in an indazole or an aza-indazole can be formed using Chan-Lam coupling conditions.
  • a variety of organic solvents may be employed, including toluene, THF, dioxane, 1 ,2-dichloroethane, DMF, DMSO and acetonitrile.
  • Reaction temperatures vary depending on conditions but typically range from room temperature to 150°C.
  • the invention provides a compound of Table 1 A and Table IB:
  • the invention provides a compound in the Examples.
  • the compound is selected from Compounds 1-69, and salts thereof. In some embodiments, the compound is selected from Compounds 4, 5, 12, 16, 20, 26, 37, 43, 49, 52, 55, 65 and 67 and salts thereof.
  • the starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), or Beilstein's Handbuch der organishcen chemie, 4, Aufl. Ed. Springer- Verlag, Berlin including supplements also included via the Beilstein online database.
  • Aldrich Chemicals Mowaukee, WI
  • Beilstein's Handbuch der organishcen chemie 4, Aufl. Ed. Springer- Verlag, Berlin including supplements also included via the Beilstein online database.
  • Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column or supercritical fluid chromatography.
  • a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., J. Chromatogr., 113(3):283-302 (1975)).
  • Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • suitable method including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.
  • Diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, -methyl- -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid.
  • enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, -methyl- -phenylethylamine (amphetamine), and the like
  • acidic functionality such as carboxylic acid and sulfonic acid.
  • the diastereomeric salts may be induced to separate by fractional
  • the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994, p. 322).
  • Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer.
  • a method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob, J. Org. Chem.
  • Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.
  • the absolute stereochemistry of chiral centers and enantiomers can be determined by x-ray crystallography.
  • Positional isomers for example E and Z forms, of compounds of formulae (I), (II) and (III) and intermediates for their synthesis, may be observed by characterization methods such as NMR and analytical HPLC. For certain compounds where the energy barrier for interconversion is sufficiently high, the E and Z isomers may be separated, for example by preparatory HPLC.
  • the compounds with which the invention is concerned are NIK kinase inhibitors, and are useful in the treatment of several diseases, for example, cancer or inflammatory conditions.
  • compositions and medicaments comprising a compound of formula (I), (II), (III) or any variations thereof detailed herein and at least one pharmaceutically acceptable carrier, diluent or excipient.
  • the compositions of the invention can be used for inhibiting NF-kB signaling activity in mammals (e.g., human patients), by for example, inhibiting NIK activity.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the invention provides for pharmaceutical compositions (or medicaments) comprising a compound of formula (I), (II), (III) or any variations thereof detailed herein and a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention provides for preparing compositions (or medicaments) comprising compounds of the invention.
  • the invention provides for administering compounds of formula (I), (II), (III) or any variations thereof detailed herein and compositions comprising compounds of formula (I), (II), (III) or any variations thereof detailed herein to a mammal (e.g., a human patient) in need thereof.
  • compositions are formulated, dosed, and administered in a fashion consistent with good medical practice.
  • Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.
  • the effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit NIK activity as required to prevent or treat the undesired disease or disorder, such as for example, neurodegeneration, amyloidosis, formation of neurofibrillary tangles, or undesired cell growth (e.g., cancer cell growth). For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.
  • the therapeutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about e.g., 0.1 to 20 mg/kg of patient body weight per day, such as 0.3 to 15 mg/kg/day.
  • the daily does is, in certain embodiments, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
  • the compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration.
  • Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
  • compositions comprising compounds of formula (I), (II), (III) or any variations thereof detailed herein are normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • a typical formulation is prepared by mixing a compound of the present invention and a diluent, carrier or excipient. Suitable diluents, carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy.
  • the formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • buffers stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing
  • Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • the particular carrier, diluent or excipient used will depend upon the means and purpose for which a compound of the present invention is being applied.
  • Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal.
  • safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water.
  • Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof.
  • the formulations can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
  • Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, aspara
  • a active pharmaceutical ingredient of the invention can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions.
  • colloidal drug delivery systems for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules
  • sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula (I), (II), (III) or any variations thereof detailed herein, which matrices are in the form of shaped articles, e.g., films, or microcapsules.
  • sustained-release matrices include polyesters, hydrogels (for example, poly(2- hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Patent No.
  • injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate
  • poly-D-(-)-3-hydroxybutyric acid injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate
  • the formulations include those suitable for the administration routes detailed herein.
  • the formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005) 21 st Edition, Lippincott Williams & Wilkins, Philadelphia, PA. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, diluents or excipients or finely divided solid carriers, diluents or excipients, or both, and then, if necessary, shaping the product.
  • a typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient.
  • the formulations can be prepared using conventional dissolution and mixing procedures.
  • the bulk drug substance i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above.
  • a compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
  • compounds of formulae (I), (II) and (III) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers.
  • the pH of the formulation depends mainly on the particular use and the concentration of compound, but typically ranges anywhere from about 3 to about 8.
  • a compound of formula (I), (II), (III) or any variations thereof detailed herein is formulated in an acetate buffer, at pH 5.
  • the compounds of formulae (I), (II) and (III) are sterile.
  • the compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
  • Formulations of a compound of the invention suitable for oral administration can be prepared as discrete units such as pills, capsules, cachets or tablets each containing a
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
  • Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs can be prepared for oral use.
  • Formulations of a compound of the invention intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
  • Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable.
  • excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.
  • An example of a suitable oral administration form is a tablet containing about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg and 500 mg of the compound of the invention, or any range derivable therein, compounded with about 5-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate.
  • the powdered ingredients are first mixed together and then mixed with a solution of the PVP.
  • the resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using
  • an example of an aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired.
  • a suitable buffer solution e.g. a phosphate buffer
  • a tonicifier e.g. a salt such sodium chloride
  • the solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.
  • the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w.
  • the active ingredient can be employed with either a paraffinic or a water-miscible ointment base.
  • the active ingredients can be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base can include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof.
  • the topical formulations can desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
  • the oily phase of the emulsions of this invention can be constituted from known ingredients in a known manner. While the phase can comprise merely an emulsifier, it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat.
  • Emulsifiers and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.
  • Aqueous suspensions of a compound of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate).
  • a suspending agent such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl
  • the aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
  • preservatives such as ethyl or n-propyl p-hydroxybenzoate
  • coloring agents such as a coloring agent
  • flavoring agents such as sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • Formulations of a compound of the invention can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension.
  • a sterile injectable preparation such as a sterile injectable aqueous or oleaginous suspension.
  • This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder.
  • the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils can conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid can likewise be used in the preparation of injectables.
  • a time-release formulation intended for oral administration to humans can contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which can vary from about 5 to about 95% of the total compositions (weight:weight).
  • the pharmaceutical composition can be prepared to provide easily measurable amounts for administration.
  • an aqueous solution intended for intravenous infusion can contain from about 3 to 500 ⁇ g of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
  • Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient.
  • the active ingredient is preferably present in such formulations in a concentration of about 0.5 to 20% w/w, for example about 0.5 to 10% w/w, for example about 1.5% w/w.
  • Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Formulations for rectal administration can be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
  • Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs.
  • Suitable formulations include aqueous or oily solutions of the active ingredient.
  • Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents such as compounds heretofore used in the treatment of disorders as described below.
  • Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • the formulations can be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use.
  • sterile liquid carrier for example water
  • Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described.
  • Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
  • the compounds of formulae (I), (II) and (III) inhibit the activity of NIK. Accordingly, in another aspect of the invention the compounds of the invention can be used for the treatment of diseases and disorders in a mammal, for example a human patient, in which the inhibition of NIK in the patient would be therapeutically effective.
  • the compounds of the invention are useful for the treatment of diseases or disorders in a mammal (e.g., a human patient) associated with overactive or undesired NF-kB signaling through, for example, the overactivation of NIK.
  • the compounds of the invention are used to inhibit the activity of NIK, for example in an in vitro assay setting, by contacting said compound of formula (I), (II), (III) or any variations thereof detailed herein with NIK.
  • compounds of formulae (I), (II) and (III) can be used as a control compound in an in vitro assay setting.
  • the compounds of the invention are used to inhibit the undesired signaling of NF-kB, e.g. in an cell proliferation assay, by introducing into a cell a compound of formula (I), (II), (III) or any variations thereof detailed herein.
  • the present invention provides the treatment of diseases or disorders in a mammal (e.g., human patient) associated with overactive or undesired NF-kB signaling (e.g., cancer, inflammatory diseases, among others) said method comprising administering to a mammal (e.g., a human patient) in need thereof a therapeutically effective amount of a compound of the invention.
  • Diseases and disorders treatable according to the methods of this invention include, cancer, inflammatory conditions, autoimmune disease and proliferation induced after medical procedures (e.g., arthritis, graft rejection, inflammatory bowel disease, cell proliferation induced after surgery angioplasty, among others).
  • a mammal e.g., a human patient
  • a pharmaceutically acceptable carrier, adjuvant, or vehicle wherein said compound of the invention is present in an amount to inhibit NF-kB signaling through, for example, but not limited to, inhibition of NIK.
  • a compound of the invention can be used in the treatment of cell proliferative disorders.
  • cancers that may be treated by the compounds of formulae (I), (II) and (III) are selected from the group consisting of Lung (bronchogenic carcinoma (non-small cell lung); Gastrointestinal - rectal, colorectal and colon; Genitourinary tract - kidney (papillary renal cell carcinoma); and skin - head and neck squamous cell carcinoma.
  • compounds of formulae (I), (II) and (III) can be use for the treatment of a cancer selected from the group consisting of head and neck squamous cell carcinomas, histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, papillary renal cell carcinoma, liver cancer, gastric cancers, colon cancer, leukemias, lymphomas, multiple myeloma, glioblastomas and breast carcinoma.
  • a cancer selected from the group consisting of head and neck squamous cell carcinomas, histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, papillary renal cell carcinoma, liver cancer, gastric cancers, colon cancer, leukemias, lymphomas, multiple myeloma, glioblastomas and breast carcinoma.
  • compounds of formulae (I), (II) and (III) can be used for the treatment of a cancer selected from the group consisting of histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, liver cancer, gastric cancer, colon cancer, leukemias, lymphomas, multiple myeloma, glioblastomas and breast carcinoma.
  • a cancer selected from the group consisting of histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, liver cancer, gastric cancer, colon cancer, leukemias, lymphomas, multiple myeloma, glioblastomas and breast carcinoma.
  • compounds of formulae (I), (II) and (III) can be used for the treatment of cancer selected from the group consisting of lymphomas, leukemias and multiple myeloma.
  • the invention provides for the preparation of a medicament comprising a compound of formula (I), (II), (III) or any variations thereof detailed herein for the treatment of lymphoma, leukemia or multiple myeloma.
  • the invention provides for the treatment of lymphoma, leukemia or multiple myeloma, which method comprises administering an effective amount of a compound of formula (I), (II), (III) or any variations thereof detailed herein.
  • compounds of the invention are useful for the treatment of inflammatory diseases and conditions including, but not limited to, lupus (including systemic lupus erythematosus, extra-renal lupus and lupus nephritis), asthma, COPD, rhinitis, multiple sclerosis, IBD, arthritis, gastritis, rheumatoid arthritis, dermatitis, endometriosis, transplant rejection, cardiac infarction, Alzheimer's diseases, diabetes Type II, inflammatory bowel disease, sepsis, and artherosclerosis.
  • the invention provides for the use of a compound of formula (I), (II), (III) or any variations thereof detailed herein for the treatment of an inflammatory condition.
  • the invention provideds for the use of a compound of formula (I), (II), (III) or any variations thereof detailed herein for the preparation of a medicament for the treatment of an inflammatory condition.
  • the invention provides for a compound of formula (I), (II), (III) or any variations thereof detailed herein for the treatment of an inflammatory condition.
  • the invention provides for a method for the treatment of an inflammatory condition, which method comprises administering an effective amount of a compound of formula (I), (II), (III) or any variations thereof detailed herein to a patient in need thereof.
  • the invention provides for the the treatment of an inflammatory condition selected from the group consisting of lupus (including systemic lupus erythematosus, extra-renal lupus and lupus nephritis), COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatisis, endometriosis and transplant rejection, which method comprises administering an effective amount of a compound of formula (I), (II), (III) or any variations thereof detailed herein.
  • an inflammatory condition selected from the group consisting of lupus (including systemic lupus erythematosus, extra-renal lupus and lupus nephritis), COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatisis, endometriosis and transplant rejection, which method comprises administering an effective amount of a compound of formula (I), (II
  • the compounds of formulae (I), (II) and (III) may be employed alone or in combination with other therapeutic agents for treatment.
  • compounds of this invention may be employed alone or in combination with chemotherapeutic agents.
  • compounds of this invention may be employed alone or in combination with anti-inflammatory agents.
  • the compounds of the present invention can be used in combination with one or more additional drugs, for example an anti-inflammatory compound or anti-cancer compounds, that work by a different mechanism of action.
  • the second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of this invention such that they do not adversely affect each other. Such molecules are suitably present in combination in amounts that are effective for the purpose intended.
  • the compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.
  • a compound of formula (I), (II), (III) or any variations thereof detailed herein is combined in a pharmaceutical combination formulation, or dosing regimen as combination therapy, with a second therapeutic compound that has anti-inflammatory or anticancer properties or that is useful for treating an inflammation, immune-response disorder, or hyperproliferative disorder (e.g., cancer).
  • the second therapeutic agent may be a NSAID (Nonsteroidal Anti-Inflammatory Drug) or other anti-inflammatory agent.
  • the second therapeutic agent may be a chemotherapeutic agent.
  • a pharmaceutical composition of this invention comprises a compound of formula (I), (II), (III) or any variations thereof detailed herein in combination with a therapeutic agent such as an NSAID.
  • Aromatic or non-aromatic heterocyclic acid (leq) and HATU (1.2eq) were weighed out and transferred to a vial to which DMF and DIPEA (3-5 eq) were subsequently added.
  • the amine (HNRR) was added to the reaction mixture as a free base or HC1 salt after a short period and the reaction was stirred at room temperature or at 50°C for 2-18 hours. Reaction conversion was monitored by LCMS. Upon completion, the reaction was cooled and the crude product was triterated via addition of water and collected by filtration or extracted with sat ammonium chloride and DCM. Trituration or purification by chromatography gave the amide.
  • reaction mixture was allowed to cool to room temperature and was either filtered thru celite and submitted directly to reverse phase HPLC purification or extracted with dichloromethane and a solution of saturated ammonium chloride before drying, evaporating and submitting to reverse phase purification or using in the subsequent step without purification.
  • Step 1 A solution of diisopropylamine (1.7 eq.) in THF (4.6 mL/mmol) was cooled to - 78 °C, then a solution of n-butyl lithium in hexanes (1.6 M, 1.5 eq.) was added dropwise. After stirring for 5 minutes, this mixture was added via cannula to a -78 °C solution of ethyl diazoacetate (1.6 eq.) and cycloalkylketone (1.0 eq.) in THF (4.6 mL/mmol). The mixture was stirred for 1 hour at -78 °C, then quenched by the addition of sat. NH 4 Cl(aq). The mixture was diluted with water and extracted with EtOAc (2 times). The combined organic extracts were dried (MgS0 4 ) and concentrated in vacuo. Purification by CombiFlash (heptane: EtO Ac) provided the desired product.
  • Step 2 To a solution of product from the previous step (1.0 eq.) in pyridine (4.6 mL/mmol) was added POCI 3 (4.35 eq.) and the mixture was allowed to stir at room temperature overnight. After in vacuo concentration, the mixture was poured onto ice, then extracted with EtOAc (3 times). The combined organic extracts were dried (MgS0 4 ) and concentrated in vacuo. This residue was diluted with octane (2.1 mL/mmol) and heated to 110 °C for two hours. After in vacuo concentration, purification by CombiFlash (heptane:EtOAc) provided the desired product.
  • octane 2.1 mL/mmol
  • Step 3 A solution of product from the previous step (1.0 eq.) in THF (20 mL/mmol) was cooled to 0 °C, then sodium hydride (60%, 3.0 eq.) was added. After stirring for 1 hour, SEMC1 (1.2 eq.) was added and the mixture was allowed to warm to room temperature overnight. After excess hydride was quenched by the addition of water at 0 °C, the mixture was extracted with EtOAc (3 times), the organic extracts dried (MgS0 4 ) and concentrated in vacuo. Purification by CombiFlash (heptane: EtOAc) provided the desired ester containing product.
  • This ester was diluted with THF (5.4 mL/mmol), acetonitrile (5.4 mL/mmol) and water (5.4 mL/mmol) and lithium hydroxide monohydrate (7.0 eq.) was added and the mixture was stirred overnight.
  • the mixture was diluted with water, acidified to pH 3 with 1 N HCl(aq) and extracted with Et 2 0 (once) and 10% MeOH/CH 2 Cl 2 (3 times).
  • the combined organic extracts were dried (MgS0 4 ) and concentrated in vacuo to provide the desired carboxylic acid of sufficient purity to be used directly.
  • Step 1 A solution of cycloalkyl ketone (1.0 eq.) in EtOH (0.5 mL/mmol) was cooled to 0 °C, then sodium ethoxide (21% wt solution in EtOH, 1.1 eq.) was added. To this mixture was added diethyl oxylate (1.0 eq.) and the mixture was allowed to warm to room temperature overnight. In vacuo concentration provided the desired product of sufficient purity to be used directly (yield assumed to be quantitative).
  • Step 2 A solution of product from the previous step (1.0 eq.) in glacial acetic acid (0.5 mL/mmol) was cooled to 0 °C, then hydrazine hydrate (1.1 eq.) was added. After warming to room temperature, the mixture was stirred for 1 hour, then diluted with sat. NaHC0 3 (aq) and extracted with 10% MeOH/CH 2 Cl 2 . The organic extracts were dried (MgS0 4 ) and concentrated in vacuo. Purification by CombiFlash (heptane: EtO Ac) provided the desired tetrahydroindazole- 3-carboxylate.
  • Step 3 Performed in an analogous manner to Step 3 General Procedure X.
  • stereoisomers are separated to give single enantiomers or diastereomers as single, unknown stereoisomers, and are arbitrarily drawn as single isomers. Where appropriate, information is given on separation method and elution time and order.
  • Step 1 Synthesis of ethyl 2-amin -5-chlorothiazole-4-carboxylate
  • Step 3 Synthesis of (ii)-ethyl 5-chloro-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxylate
  • Step 4 Synthesis of (ii)-5-chloro-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
  • Step 5 Synthesis of (ii)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(l- methyl-lH-pyrazol-4-yl)thiazole-4-carboxamide
  • Step 1 Synthesis of l-(3-methoxyphenyl)-4-[(l-methyl-lH-pyrazol-5-yl)amino]-lH-pyrazole-3- carboxylic acid
  • Step 2 Synthesis of l-(3-methoxyphenyl)-4-[(l-methyl-lH-pyrazol-5-yl)amino]-lH-pyrazole-3- carboxamide
  • Step 3 Synthesis of 1 -(3 -hydroxyphenyl)-4-[(l -methyl- lH-pyrazol-5 -yl)amino]-l H-pyrazole-3- carboxamide
  • Step 5 Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(l- methyl-lH-pyrazol-5-ylamino)-lH-pyrazole-3-carboxamide
  • Step 1 Synthesis of methyl 4-(l ,3-dimethyl-lH-pyrazol-4-yl)-lH-pyrazole-3-carboxylate
  • Step 2 Synthesis of methyl l-(3-bromophenyl)-4-(l,3-dimethyl-lH-pyrazol-4-yl)-lH-pyrazole- 3-carboxylate
  • Step 3 Synthesis of methyl 4-(l,3-dimethyl-lH-pyrazol-4-yl)-l-(3-[2-[(3ii)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate
  • Step 4 Synthesis of 4-( 1,3 -dimethyl- lH-pyrazol-4-yl)-l -(3- [2- [(3R)-3 -hydroxy- l-methyl-2- oxo rrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxamide
  • Step 2 Synthesis of l-(3-bromophenyl)-4-[(methylcarbamoyl)amino]-lH-pyrazole-3- carboxamide
  • Step 3 Synthesis of l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4- [(methylcarbamoyl)amino]-lH-pyrazole-3-carboxarnide
  • Step 1 Synthesis of ethyl l'-ethyl- '-bi(lH-pyrazole)-3-carboxylate
  • Step 2 Synthesis of ethyl l-(3-bromophenyl)-l'-ethyl-4,4'-bi(lH-pyrazole)-3-carboxylate
  • Step 3 Synthesis of (ii)-ethyl 1 '-ethyl- l-(3-((3-hydroxy- l-methyl-2-ox opyrrolidin-3- l)ethynyl)phenyl)-4,4'-bi(lH-pyrazole)-3-carboxylate
  • Step 4 Synthesis of (ii)-l'-ethyl-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-4,4'-bi(lH-pyrazole)-3-carboxamide
  • Step 1 Synthesis of ethyl l-(3-bromophenyl)-4-(N-ethylacetamido)-lH-pyrazole-3-carboxylate
  • Step 2 Synthesis of l-(3-bromophenyl)-4-(N-ethylacetamido)-lH-pyrazole-3-carboxamide
  • Step 3 Synthesis of l-(3-bromophenyl)-4-(ethylamino)-lH-pyrazole-3-carboxarnide
  • Step 4 Synthesis of 4-(ethylamino)-l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-lH-pyrazole-3-carboxamide
  • Step 1 Synthesis of ethyl 2-amino-5-iodothiazole-4-carboxylate
  • Step 3 Synthesis of ethyl 2-chloro-5-(trifluoromethyl)thiazole-4-carboxylate
  • Step 4 Synthesis of (ii)-ethyl 2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)- -(trifluoromethyl)thiazole-4-carboxylate
  • Step 5 Synthesis of (ii)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5- (trifluoromethyl)thiazole-4-carboxamide
  • Step 2 Synthesis of ethyl l-(3-bromophenyl)-4-(trifluoromethyl)-lH-pyrazole-3-carboxylate
  • Step 3 Synthesis of ethyl l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-4-(trifluoromethyl)-lH-pyrazole-3-carboxylate
  • Step 4 Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- (trifluoromethyl)-lH-pyrazole-3-carboxamide
  • Step 1 Synthesis of methyl 4-( 1 ,5 -dimethyl- lH-pyrazol-4-yl)-lH-pyrazole-3 -carboxylate
  • Step 2 Synthesis of methyl l-(3-bromophenyl)-4-(l,5-dimethyl-lH-pyrazol-4-yl)-lH-pyrazole-
  • Step 3 Synthesis of methyl 4-( 1 ,5 -dimethyl- lH-pyrazol-4-yl)-l -(3- [2- [(3R)-3 -hydroxy- 1- methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate
  • Step 4 Synthesis of 4-( 1 ,5 -dimethyl- lH-pyrazol-4-yl)-l -(3- [2- [(3R)-3 -hydroxy- l-methyl-2- oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxarnide
  • Step 1 Synthesis of ethyl 2-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-5 - [( 1 -methyl- 1 H-pyrazol- -yl)amino] - 1 ,3 -thiazole-4-carboxylate
  • Step 2 Synthesis of 2-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5- [(l-methyl-lH-pyrazol-4-yl)amino]-l,3-thiazole-4-carboxylic acid
  • Step 3 Synthesis of (ii)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(l- methyl-lH-pyrazol-4-ylamino)thiazole-4-carboxamide
  • Step 1 Synthesis of (3ii)-3-[2-[3-(3-bromo-l ,2,4-thiadiazol-5-yl)-4-fluorophenyl]ethynyl]-3- hydroxy- 1 -methylpyrrolidin-2-one
  • Step 2 Synthesis of 5-(2-fluoro-5-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-l ,2,4-thiadiazole-3-carbonitrile
  • Step 3 Synthesis of (ii)-5-(2-fluoro-5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-l ,2,4-thiadiazole-3-carboxamide
  • Step 2 Synthesis of l-(3-methoxyphenyl)-4-[(l-methyl-lH-pyrazol-4-yl)amino]-lH-pyrazole-3- carboxylic acid
  • Step 3 Synthesis of l-(3-methoxyphenyl)-4-[(l-methyl-lH-pyrazol-4-yl)amino]-lH-pyrazole-3- carboxamide
  • Step 4 Synthesis of 1 -(3 -hydroxyphenyl)-4-[(l -methyl- lH-pyrazol-4-yl)amino]-lH-pyrazole-3- carboxamide
  • Step 5 Synthesis of 3-[3-carbamoyl-4-[(l-methyl-lH-pyrazol-4-yl)amino]-lH-pyrazol-l- yl]phenyl trifluoromethanesulfonate
  • Step 6 Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(l- methyl- 1 H-pyrazol-4-ylamino)- 1 H-pyrazole-3-carboxamide
  • Step 4 Synthesis of 3-[3-carbamoyl-4-(pyridin-2-yl)-lH-pyrazol-l -yl]phenyl
  • Step 5 Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- (pyridin-2-yl)-lH-pyrazole-3-carboxamide
  • Step 1 Synthesis of ethyl 2-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-5-[(oxetan-3-yl)amino]-l,3-thiazole-4-carboxylate
  • Step 2 Synthesis of 2-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5- [(oxetan-3-yl)amino]-l,3-thiazole-4-carboxylic acid
  • Step 3 Synthesis of (ii)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-
  • Step 1 Synthesis of (ii)-ethyl 5-ethyl-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxylate
  • Step 1 Synthesis of tert-butyl 3-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate
  • Step 2 Synthesis of tert-butyl 3-[(3-bromophenyl)carbonyl]morpholine-4-carboxylate
  • n-Butyllithium (8 mL, 2M in THF, 1.10 equiv) was added dropwise into a solution of 1 ,3-dibromobenzene (3.44 g, 14.58 mmol, 1.00 equiv) in tetrahydrofuran (200 mL) under nitrogen. The resulting solution was stirred for 2 h at -78°C and then tert-butyl 3- [methoxy(methyl)carbamoyl]morpholine-4-carboxylate (4.00 g, 14.58 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) was added dropwise at -78°C.
  • Step 4 Synthesis of 3-(3-bromophenyl)-l-iodo-4H,6H,7H-imidazo[4,3-c][l ,4]oxazine
  • Step 5 Synthesis of methyl 3-(3-bromophenyl)-4H,6H,7H-imidazo[4,3-c][l ,4]oxazine-l- carboxylate
  • Step 6 Synthesis of methyl 3-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- l]ethynyl]phenyl)-4H,6H,7H-imidazo[4,3-c][l,4]oxazine-l-carboxylate
  • Step 7 Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-6,8- dih dro-5H-imidazo[5 , 1 -c] [1 ,4]oxazine-3-carboxamide
  • Step 2 Synthesis of ethyl 4-cyclopropaneamido-l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate
  • Step 3 Synthesis of (ii)-4-(cyclopropanecarboxamido)-l-(3-((3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
  • Step 3 Synthesis of (ii)-4-acetamido-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
  • Step 1 Synthesis of ethyl l-(3-bromophenyl)-4-nitro-lH-pyrazole-3-carboxylate
  • Step 2 Synthesis of ethyl 4-amino-l-(3-bromophenyl)-lH-pyrazole-3-carboxylate
  • Step 3 Synthesis of ethyl 4-amino-l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate
  • Step 4 Synthesis of 4-amino-l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-lH-pyrazole-3-carboxamide
  • Step 1 Synthesis of ethyl l-(3-bromophenyl)-4-[(2-fluorocyclopropane)amido]-lH-pyrazole-3- carboxylate
  • Step 2 Synthesis of ethyl 4-[(trans-2-fluorocyclopropane)amido]-l-(3-[2-[(3R)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)- -pyrazole-3-carboxylate
  • Step 3 Synthesis of 4-((l ⁇ ,2ii)-2-fluorocyclopropanecarboxarnido)-l-(3-(((ii)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide and 4-(( ⁇ ?,25)-2- fluorocyclopropanecarboxamido)-l-(3-(((ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide

Abstract

The invention relates to compounds of formula (I), wherein Q, A1-A8, R4 and R5 are as described herein. Compounds of formula (I) and pharmaceutical compositions thereof are useful in the treatment of diseases and disorders in which undesired or over-activation of NF-kB signaling is observed.

Description

ALKYNYL ALCOHOLS AND METHODS OF USE
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit under 35 U.S.C. § 119(a) of International Application No. PCT/CN2015/077176, filed on February 25, 2015, which is incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to inhibitors of NF-kB -inducing kinase (NIK) useful for treating cancer and inflammatory conditions, among others.
BACKGROUND OF THE INVENTION
NF-kB inducing kinase (NIK) is also known as MAPK kinase kinase 14 (MAP3K14) and is a serine/threonine kinase and a member of the MAPK family. It was originally identified in a two- hybrid screen as a binding partner of TNF receptor (TNFR) associated factor 2 (TRAF2) [See, Malinin, NL, et al., Nature, 1997, 385:540-4]. Overexpression of NIK leads to the activation of NF-kB and dominant negative forms of NIK lacking kinase activity were able to inhibit NF-kB activation in response to TNF and IL-1 treatment. Thus, NIK has been identified as an important component of the NF-kB signaling pathway. Scientific research has shown that in blocking the NF-kB signaling pathway in cancer cells can cause such cells to stop proliferating, to die, or to become more sensitive to the action of other anti-cancer therapies. Additionally, research has shown that NF-kB controls the expression of many genes involved in inflammation and that NF- kB signaling is found to be chronically active in many inflammatory conditions, such as lupus (including systemic lupus erythematosus), rheumatoid arthritis, inflammatory bowel disease, arthritis, sepsis, gastritis and asthma, among others. Accordingly, organic compounds capable of inhibiting NIK and thereby inhibiting, weakening or lessening the undesired or over-activation of the NF-kB signaling pathway can have a therapeutic benefit for the treatment diseases and disorders for which such undesired or over- activation of NF-kB signaling is observed. BRIEF SUMMARY OF THE INVENTION
Disclosed are alkynyl alcohol compounds that are inhibitors of NIK kinase, compositions containing these compounds and methods for treating diseases mediated by NIK kinase such as cancer and inflammatory diseases.
In one aspect, provided is a com ound of formula (I):
Figure imgf000003_0001
or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein:
ring A is a monocycle or a fused bicycle;
Q is N or C, wherein when Q is N, then the bond between Ai and Q is not a double bond and the bond between Q and A4 is not a double bond;
Ai is NR1, N, S, CR1 or CHR1;
A2 is NR2, N, O, S, CR2 or CHR2;
A3 is N or C;
A4 is N; and
one, two or three of Ai-A4 are N, wherein:
each R1 is independently selected from the group consisting of H, halogen, NRaRb, NHC(0)NRaRb, NHS(0)2CH3, Ci-C3 alkyl, C3-C7 cycloalkyl, Ci-C3 alkoxy and 3-11 membered heterocyclyl, wherein the alkyl of R1 is optionally substituted by F, OH, CN, SH, Ci-C3 alkoxy or 3-11 membered heterocyclyl; the cycloalkyl of R1 is optionally substituted by F, OH, CN, SH, CH3 or CF3; the alkoxy of R1 is optionally substituted by F, OH, CN or SH; and the heterocyclyl of R1 is optionally substituted by F, OH, CN, SH, CF3 or Ci-C3 alkyl,
each R2 is independently selected from the group consisting of H, NRaRb Ci-C6 alkyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, phenyl and 3-11 membered heterocyclyl, wherein R is optionally substituted by Rc; or 1 2
R and R" are taken together with the atoms to which they are attached to form a cyclic group selected from the group consisting of C3-C7 cycloalkyl, phenyl and 3- 11 membered heterocyclyl, wherein the cyclic group is optionally substituted by Rd;
R4 is selected from the group consisting of H, Ci-C6 alkyl, CH2F and CH2OH;
R5 is 3-1 1 membered heterocyclyl optionally substituted by Re or -C(=0)N(Ci-C6 alkyl)2; or
R4 and R5 together form a C3-C11 cycloalkyl optionally substituted by Re or a 3- 11 membered heterocyclyl optionally substituted by Re;
one of A5-A8 is N and the remaining are CR6 or all are CR6;
R6, independently at each occurrence, is selected from the group consisting of H, F, CI, NH2, NHCH3, N(CH3)2, OH, OCH3, OCHF2, OCH2F, OCF3, SH, SCH3, SCHF2, SCH2F, CN, CH3, CHF2, CH2F, CH2OH, CF3, N02 and N3;
Ra is selected from the group consisting of H and Ci-C6 alkyl optionally substituted by C1-C3 alkoxy, F, OH, CN, SH, CH3 or CF3;
Rb is selected from the group consisting of H, Ci-C6 alkyl, Ci-C6 alkoxy, C3-C6 cycloalkyl, C(0)R , phenyl and 3-11 membered heterocyclyl wherein Rb may be optionally substituted by C1-C3 alkoxy, F, OH, CN, SH, CH3 or CF3;
Rc and Rd are each independently selected from the group consisting of halogen, -(X^o-i- CN, -(XVi-NO,,
Figure imgf000004_0001
-(X')o-i-OH, -(X -NH,, -(X -NCHXR13), -(X i- N(Rlb)(Rla), -(X1)o-i-CF3, Ci_C6 alkyl, Ci_C6 haloalkyl, Ci_C6 heteroalkyl, Ci_C6 alkoxy, Ci_C6 alkylthio, oxo, -(x i-Q.Ce alkyl, -(x i-Cs-Qo cycloalkyl, -O-C3-C10 cycloalkyl,
Figure imgf000004_0002
membered heterocyclyl, -(x i-Ce-Qo aryl, -C(=O)(X1)i-C3-Ci0 cycloalkyl, -C(=0)(X1)i-3-ll membered heterocyclyl, -(X1)0-i-C(=Y1)N(H)(Rla), -(X1)0-i-C(=Y1)NH2, -(XVi-
Figure imgf000004_0003
-(X1)0-i-N(H)C(=Y1)(Rla),
Figure imgf000004_0004
C(=NORlb)Rla, -(X1)o-i-NHC(=Y1)N(H)(Rla), -(X1)0.1-NHC(=Y1)NH2, -(x i- NHC(=Y1)N(Rlb)(Rla), -(X1)o-i-N(Rla)C(=Y1)N(H)(Rla), -(X1)0_i-N(Rla)C(=Y1)N(Rla)(Rlb),
Figure imgf000004_0005
-(X1)o-i-OC(=Y1)Rla, -(X1)0-i-OC(=Y1)H, -(X1)0-i-OC(=Y1)ORla, -(X1)o-i-OP(=Y1)(ORla)(ORlb), -(X1)-SC(=Y1)ORla and -(X1)-SC(=Y1)N(Rla)(Rlb) wherein X1 is selected from the group consisting of Ci_C6 alkylene, Ci_C6 heteroalkylene, C2_C6 alkenylene, C2_ C6 alkynylene, Ci_C6 alkyleneoxy, C3-C7 cycloalkylene, 3-11 membered heterocyclylene and phenylene; Rla and Rlb are each independently selected from the group consisting of Ci_C6 alkyl, Ci_C6 haloalkyl, Ci_C6 heteroalkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkylene)Ci_C6 alkyl, 3-11 membered heterocyclyl, (3-11 membered heterocyclylene)Ci-C6 alkyl, C6 aryl, and (C6-Cio arylene)Ci-C6 alkyl, or Rla and Rlb when attached to the same nitrogen atom are optionally combined to form a 3-11 membered heterocyclyl comprising 0-3 additional heteroatoms selected from N, O and S; Y1 is O, NRlc or S wherein Rlc is H or Ci_C6 alkyl; wherein any portion of an Rc or Rd substituent, including Rla, Rlb and Rlc, at each occurrence is each independently further substituted by from 0 to 4 R substituents selected from the group consisting of halogen, CN, N02, SF5, OH, NH2, -N(Ci_C6 alkyl)2, -NH(Ci_C6 alkyl), oxo, Ci_C6 alkyl, -(C2-C6 alkynylene)- (3-11 membered heterocyclyl, wherein the heterocyclyl is optionally substituted by Re), Ci_C6 hydroxyalkyl, Ci_C6 heteroalkyl, Ci_C6 alkoxy, Ci_C6 alkylthio, C3-C7 cycloalkyl, 3-11 membered heterocyclyl, -C(=0)N(H)(Ci_C6 alkyl), -C(=0)N(Ci_C6 alkyl)2, -C(=0)NH2, -C(=0)OCi_C6 alkyl, -C(=0)OH, -N(H)C(=0)(Ci_C6 alkyl), -N(Ci_C6 alkyl)C(=0)(Ci_C6 alkyl),
-N(H)C(=0)OCi_C6 alkyl, -N(Ci_C6 alkyl)C(=0)OCi_C6 (halo)alkyl, -S(0)i_2Ci_C6
alkyl, -N(H)S(0)i_2Ci_C6 alkyl, -N(Ci_C6 alkyl)S(0)i_2Ci_C6 alkyl, -S(O)0-1N(H)(C1-C6 alkyl), - S(0)o-iN(Ci_C6 alkyl)2, -S(O)0-1NH2, -C(=0)Ci_C6 alkyl, -C(=0)C3-C7 cycloalkyl, -C(=NOH)Ci_ C6 alkyl, -C(=NOCi_C6 alkyl)Ci_C6 alkyl, -NHC(=0)N(H)(Ci_C6 alkyl), -NHC(=0)N(Ci_C6 alkyl)2, -NHC(=0)NH2, -N(Ci_C6 alkyl)C(=0)N(H)(Ci_C6 alkyl), -N(Ci_C6 alkyl)C(=0)NH2, - OC(=0)Ci_C6 alkyl, -OC(=0)OCi_C6 alkyl, -OP(=0)(OCi_C6 alkyl)2, -SC(=0)OCi_C6 alkyl and - SC(=0)N(Ci_C6 alkyl)2, wherein any alkyl portion of R is optionally substituted with halogen;
Re is selected from the group consisting of halogen, OH, Ci-C6 alkyl and oxo; and R is selected from the group consisting of Ci-C6 alkyl and C3-C6 cycloalkyl wherein R may be optionally substituted by C1-C3 alkoxy, F, OH, CN, SH, CH3 or CF3;
provided that the compound is other than a compound selected from the group consisting of
Compound Nos. lx-199x in Table lx..
In some embodiments, Q is C, and the compound is of the formula (II):
Figure imgf000006_0001
wherein ring A, Ai, A2, A3, A4, A5, A6, A7, As, R4 and R5 are as defined for formula (I).
In some embodiments, ring B is a substituted phenyl and Q is C; and the compound is of formula (III):
Figure imgf000006_0002
wherein ring A, Ai, A2, A3, A4, R4 and R5 are as defined for formula (II), n is 0, 1 or 2, and each R6 is independently selected from the group consisting of F, CI, OCH3, CH3 and CF3.
In some embodiments of the compound of formula (I), (II) or (III), wherein the following moiety:
Figure imgf000006_0003
wherein:
A9 is O, NR11 or CRnR12, wherein R11 and R12 are each independently selected from the group consisting of H, halogen, OH and C1-C3 alkyl;
7 8 7 8
R' and R° are each independently selected from halogen, OH, Ci-C6 alkyl, or R and R together form =0, and R9 and R10 are each independently selected from H and Re, or R9 and R10 are taken together with the atoms to which they are attached to form a C5-C6 cycloalkyl optionally substituted by Re or a 5-6 membered heterocyclyl optionally substituted by Re.
In another aspect, the invention provides for pharmaceutical compositions comprising a compound of formula (I), (II) or (III), and a pharmaceutically acceptable carrier, diluent or excipient.
In another aspect, the invention provides for a compounds of formula (I), (II) or (III), or pharmaceutical compositions thereof for use in therapy. In another embodiment, the invention provides the use of a compound or pharmaceutical composition for the preparation of a medicament for the treatment of an inflammatory condition.
In another aspect, the inventions provides for compounds of formula (I), (II) or (III), and pharmaceutical compositions thereof for the treatment of diseases and disorders, including, cancer, inflammatory conditions, and autoimmune diseases, among others.
In another aspect, the invention provides for a method (or use) of compounds of formulae (I), (II) and (III), or pharmaceutical compositions thereof in the treatment of diseases and disorders, such as, for example, cancer, inflammatory conditions, or autoimmune diseases, among others.
In another aspect, the invention provides for compounds of formulae (I), (II) and (III), for the preparation of a medicament for the treatment of cancer, inflammatory conditions, or
autoimmune diseases, among others.
In another aspect, the invention provides for compound intermediates useful in synthesis of compounds of formulae (I), (II) and (III).
DETAILED DESCRIPTION OF THE INVENTION
The invention provides, inter alia, compounds of formulae (I), (II) and (III), and variations thereof, pharmaceutical compositions comprising compounds of formulae (I), (II) and (III), and methods of using such compounds and compositions in treating diseases and disorders related to undesired or overactivation of the NF-kB signaling pathway, such as, for example, certain cancers and inflammatory conditions. Definition
The term "alkyl" refers to a saturated linear or branched-chain monovalent hydrocarbon radical, wherein the alkyl radical may be optionally substituted independently with one or more substituents described herein. In one example, the alkyl radical is one to eighteen carbon atoms (Ci-Cig). In other examples, the alkyl radical is Co-C6, C0-C5, C0-C3, C1-C12, C1-C10, Ci-Cg,
Figure imgf000008_0001
C6, C1-C5, C1-C4, or C1-C3. Co alkyl refers to a bond. Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i- propyl, -CH(CH3)2), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l -propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, - C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3- pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (- CH(CH3)CH(CH3)2), 3-methyl-l -butyl (-CH2CH2CH(CH3)2), 2-methyl-l -butyl (- CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (- CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (- C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (- CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (- CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (- CH(CH3)C(CH3)3, 1-heptyl and 1-octyl. In some embodiments, substituents for "optionally substituted alkyls" include one to six instances of F, CI, Br, I, OH, SH, CN, NH2, N02, N3, COOH, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, S02, phenyl, piperidinyl, piperizinyl,or pyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereof may be optionally substituted.
The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkane, as exemplified by -CH2CH2CH2CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 12 carbon atoms, such as 1-8, 1-6 or 1-3 carbon atoms. "Alkenylene" and "alkynylene" refer to the unsaturated forms of "alkylene" having double or triple bonds, respectively, and typically have from 2 to 12 carbon atoms, such as 2-8, 2-6 or 2-3 carbon atoms. "Alkylene", "alkenylene" and "alkynylene" groups may be optionally substituted.
The term "heteroalkyl" refers to a straight or branched chain monovalent hydrocarbon radical, consisting of the stated number of carbon atoms, or, if none are stated, up to 18 carbon atoms, and from one to five heteroatoms selected from the group consisting of O, N, Si and S, and wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. In some embodiments, the heteroatom is selected from O, N and S, wherein the nitrogen and sulfur atoms can optionally be oxidized and the nitrogen heteroatom can optionally be quaternized. The heteroatom(s) can be placed at any interior position of the heteroalkyl group, including the position at which the alkyl group is attached to the remainder of the molecule (e.g., -0-CH2-CH3). Examples include -CH2-CH2-0-CH3, -CH2-CH2-0-CF3, -CH2- CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S(0)-CH3, -CH2-CH2-S(0)2-CH3, - Si(CH3)3, -CH2-CH=N-OCH3, and -OCF3. Up to two heteroatoms can be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-0-Si(CH3)3. Heteroalkyl groups can be optionally substituted. In some embodiments, substituents for "optionally substituted heteroalkyls" include one to four instances of F, CI, Br, I, OH, SH, CN, NH2, N02, N3, COOH, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, S02, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereof may be optionally substituted.
The term "heteroalkylene" means a divalent radical derived from heteroalkyl, as exemplified by -CH2CH2SCH2CH2, -CH2SCH2CH2NHCH3 and -OCH2CH3. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy,
alkylenedioxy, alkyleneamino, alkylenediamino, and the like). A heteroalkylene group may be optionally substituted.
"Cycloalkyl" refers to a non-aromatic, saturated or partially unsaturated hydrocarbon ring group wherein the cycloalkyl group may be optionally substituted with one or more substituents described herein. In one example, the cycloalkyl group is 3 to 12 carbon atoms (C3-Ci2). In other examples, cycloalkyl is C3-C6, C3-Cs, C3-Cio or C5-C10. In other examples, the cycloalkyl group, as a monocycle, is C3-Cs, C3-C6 or C5-C6. In another example, the cycloalkyl group, as a bicycle, is C7-Ci2. In another example, the cycloalkyl group, as a spiro system, is C5-Ci2.
Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-l- enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, perdeuteriocyclohexyl, 1-cyclohex-l- enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl and cyclododecyl. Exemplary arrangements of bicyclic cycloalkyls having 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring systems. Exemplary bridged bicyclic cycloalkyls include, but are not limited to, bicyclo[4.1.0]heptane, bicycle[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[4.1.0]heptane and bicyclo[3.2.2]nonane. Examples of spiro cycloalkyl include, spiro[2.2]pentane, spiro[2.3]hexane, spiro[2.4]heptane, spiro [2.5] octane and spiro[4.5]decane. In some embodiments, substituents for "optionally substituted cycloalkyls" include one to four instances of F, CI, Br, I, OH, SH, CN, NH2, N02, N3, COOH, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, S02, phenyl, piperidinyl, piperizinyl, and
pyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereof may be optionally substituted.
The term "cycloalkylene" means a divalent radical derived from a cycloalkyl group. A cycloalkylene group may be optionally substituted.
"Heterocyclic group", "heterocyclic", "heterocycle", "heterocyclyl", or "heterocyclo" are used interchangeably and refer to any monocyclic, bicyclic, or spiro, saturated or unsaturated, aromatic (heteroaryl) or non-aromatic (e.g., heterocycloalkyl), ring system, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. If any ring atom of a cyclic system is a heteroatom, that system is a heterocycle, regardless of the point of attachment of the cyclic system to the rest of the molecule. In one example, heterocyclyl includes 3-11 ring atoms ("members", that is, a 3-11 membered heterocycle) and includes monocycles, bicycles, and spiro ring systems, wherein the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. In one example, heterocyclyl includes 1 to 4 heteroatoms. In another example, heterocyclyl includes 3- to 7-membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 4- to 6- membered monocycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 3-membered monocycles. In another example, heterocyclyl includes 4-membered monocycles. In another example, heterocyclyl includes 5-6-membered monocycles. In one example, the heterocyclyl group includes 0 to 3 double bonds. Any nitrogen or sulfur heteroatom may optionally be oxidized (e.g., NO, SO, S02), and any nitrogen heteroatom may optionally be quaternized (e.g., [NR4]+Cr, [NR4]+OH~). In another example, heterocyclyl includes 3- to 9-membered spiro cycles having one or more heteroatoms selected from nitrogen, sulfur or oxygen. Example heterocycles are oxiranyl, aziridinyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, 1 ,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-lH-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinohnyl, tetrahydroisoquinohnyl, morphohnyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl,
hexahydrothiopyranyl, hexahydropyrimidinyl, oxazinanyl, thiazinanyl, thioxanyl,
homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, oxazepinyl, oxazepanyl, diazepanyl, 1,4-diazepanyl, diazepinyl, thiazepinyl, thiazepanyl, tetrahydrothiopyranyl, oxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,1-dioxoisothiazolidinonyl, oxazolidinonyl, imidazolidinonyl, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydrobenzoimidazolyl, 4,5,6,7- tetrahydrobenzo[d]imidazolyl, 1 ,6-dihydroimidazol[4,5-d]pyrrolo[2,3-b]pyridinyl, thiazinyl, oxazinyl, thiadiazinyl, oxadiazinyl, dithiazinyl, dioxazinyl, oxathiazinyl, thiatriazinyl, oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3- dioxolanyl, pyrazolinyl, pyrazohdinyl, dithianyl, dithiolanyl, pyrimidinonyl, pyrimidindionyl, pyrimidin-2,4-dionyl, piperazinonyl, piperazindionyl, pyrazolidinylimidazolinyl, 3- azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3- azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2- azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.2]octanyl, 8- azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl,
azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, l-azaspiro[4.5]decan-2-only,
azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl,
tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl. Examples of 5 -membered heterocycles containing a sulfur or oxygen atom and one to three nitrogen atoms are thiazolyl, including thiazol-2-yl and thiazol-2-yl N-oxide, thiadiazolyl, including l,3,4-thiadiazol-5-yl and 1,2,4- thiadiazol-5-yl, oxazolyl, for example oxazol-2-yl, and oxadiazolyl, such as l,3,4-oxadiazol-5-yl, and l,2,4-oxadiazol-5-yl. Example 5-membered ring heterocycles containing 2 to 4 nitrogen atoms include imidazolyl, such as imidazol-2-yl; triazolyl, such as l,3,4-triazol-5-yl; 1,2,3- triazol-5-yl, l,2,4-triazol-5-yl, and tetrazolyl, such as lH-tetrazol-5-yl. Example benzo-fused 5- membered heterocycles are benzoxazol-2-yl, benzthiazol-2-yl and benzimidazol-2-yl. Example 6-membered heterocycles contain one to three nitrogen atoms and optionally a sulfur or oxygen atom, for example pyridyl, such as pyrid-2-yl, pyrid-3-yl, and pyrid-4-yl; pyrimidyl, such as pyrimid-2-yl and pyrimid-4-yl; triazinyl, such as l,3,4-triazin-2-yl and l,3,5-triazin-4-yl;
pyridazinyl, in particular pyridazin-3-yl, and pyrazinyl. The pyridine N-oxides and pyridazine N-oxides and the pyridyl, pyrimid-2-yl, pyrimid-4-yl, pyridazinyl and the l,3,4-triazin-2-yl groups, are other example heterocycle groups. Heterocycles may be optionally substituted. For example, substituents for "optionally substituted heterocycles" include one to six instances of F, CI, Br, I, OH, SH, CN, NH2, N02, N3, COOH, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, S02, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereof may be optionally substituted.
The term "heterocyclylene" means a divalent radical derived from a heterocyclyl group. A heterocyclylene group may be optionally substituted.
"Heteroaryl" refers to any mono-, bi-, or tricyclic ring system where at least one ring is a 5- or 6- membered aromatic ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen, and sulfur, and in an example embodiment, at least one heteroatom is nitrogen. See, for example, Lang's Handbook of Chemistry (Dean, J. A., ed.) 13th ed. Table 7-2 [1985]. Included in the definition are any bicyclic groups where any of the above heteroaryl rings are fused to an aryl ring, wherein the aryl ring or the heteroaryl ring is joined to the remainder of the molecule. In one embodiment, heteroaryl includes 4-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. In another embodiment, heteroaryl includes 5-6 membered monocyclic aromatic groups where one or more ring atoms is nitrogen, sulfur or oxygen. Example heteroaryl groups include thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, tetrazinyl, tetrazolo[l,5- b]pyridazinyl, imidazol[l,2-a]pyrimidinyl and purinyl, as well as benzo-fused derivatives, for example benzoxazolyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, benzoimidazolyl and indolyl. Heteroaryl groups can be optionally substituted. In some embodiments, substituents for "optionally substituted heteroaryls" include one to six instances of F, CI, Br, I, OH, SH, CN, NH2, N02, N3, COOH, methyl, ethyl, propyl, iso-propyl, butyl, isobutyl, cyclopropyl, methoxy, ethoxy, propoxy, oxo, trifluoromethyl, difluoromethyl, sulfonylamino, methanesulfonylamino, SO, S02, phenyl, piperidinyl, piperizinyl, and pyrimidinyl, wherein the alkyl, aryl and heterocyclic portions thereof may be optionally substituted.
In particular embodiments, a heterocyclyl group is attached at a carbon atom of the heterocyclyl group. By way of example, carbon bonded heterocyclyl groups include bonding arrangements at position 2, 3, 4, 5, or 6 of a pyridine ring, position 3, 4, 5, or 6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine ring, position 2, 3, 5, or 6 of a pyrazine ring, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole ring, position 2, 4, or 5 of an oxazole, imidazole or thiazole ring, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring.
In certain embodiments, the heterocyclyl group is N-attached. By way of example, the nitrogen bonded heterocyclyl or heteroaryl group include bonding arrangements at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2- imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, lH-indazole, position 2 of an isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline.
The term "alkoxy" refers to those alkyl groups attached to the remainder of the molecule via an oxygen atom. Non-limiting examples include methoxy, ethoxy and propoxy. Alkoxy groups may be optionally substituted, such as by halogen.
The term "alkylthio" refers to those alkyl groups attached to the remainder of the molecule via a sulfur atom. Non-limiting examples include -SCH3, -SCH2CH3 and -SCH2CH2CH3. Alkylthio groups may be optionally substituted, such as by halogen.
The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. The term "haloalkyl" is meant to include both an "alkyl" and a "haloalkyl" substituent. Additionally, the term "haloalkyl," is meant to include monohaloalkyl and polyhaloalkyl.
The term "oxo" refers to =0 or (=0)2.
The term "aryl" means, unless otherwise stated, a polyunsaturated, typically aromatic, hydrocarbon ring radical, which can be a single ring or multiple rings (up to three rings) which are fused together and having the stated number of aryl ring atoms. An aryl group can be optionally substituted.
A "phenylene" group refers to a divalent radical derived from a phenyl group. A phenylene group may be optionally substituted.
"Optionally substituted" unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 0, 1, 2, 3, 4, or 5 or more) of the substituents listed for that group in which said substituents may be the same or different. That is, an optionally substituted substituent is independent at each occurrence. In an embodiment an optionally substituted group has 1 substituent. In another embodiment an optionally substituted group has 2 substituents. In another embodiment an optionally substituted group has 3 substituents. In another embodiment an optionally substituted group has 4 substituents.
Optional substituents for alkyl and cycloalkyl can be a variety of groups including, but not limited to, halogen, oxo, CN, N02, N3, OR', perfluoro-Ci_4 alkoxy, unsubstituted cycloalkyl, unsubstituted aryl (e.g., phenyl), unsubstituted heterocyclyl, NR'R", SR', SiR'R"R"', OC(0)R', C(0)R, C02R, CONR'R", OC(0)NRR", NR"C(0)R', NR"'C(0)NR'R", NR"C(0)2R', S(0)2R\ S(0)2NR'R", NR'S(0)2R", NR"'S(0)2NR'R", amidino, guanidine, (CH2)i_4OR', (CH2) !.4NR'R", (CH2) i_4SR', (CH2) i_4SiR'R"R"', (CH2)1.4OC(0)R, (CH2)1.4C(0)R, (CH2)1.4C02R', and (CH2) i_4CONR'R", or combinations thereof, in a number ranging from zero to (2m'+l), where m' is the total number of carbon atoms in such radical. R', R" and R'" each independently refer to groups including, for example, hydrogen; unsubstituted Ci-6 alkyl; unsubstituted heteroalkyl; unsubstituted aryl; aryl substituted with 1-3 halogens, unsubstituted Ci_C6 alkyl, Ci_ C6 alkoxy or Ci_C6 thioalkoxy groups, unsubstituted aryl-Ci-C4 alkyl groups, and unsubstituted heteroaryl. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 3-, 4-, 5-, 6-, or 7-membered ring wherein a ring atom is optionally substituted with N, O or S. For example, NR'R" is meant to include 1 -pyrrolidinyl and 4- morpholinyl.
Similarly, optional substituents for the aryl and heterocyclyl groups are varied. In some embodiments, substituents for aryl and heterocyclyl groups are selected from the group including, but not limited to, halogen, OR', OC(0)R', NR'R", SR', R', CN, N02, C02R, CONR'R", C(0)R', OC(0)NR'R", NR"C(0)R, NR"C(0)2R', NR'C(0)NR"R"', S(0)R', S(0)2R', S(0)2NR'R", NR'S(0)2R", N3, perfluoro-Ci-C4 alkoxy, perfluoro-Ci-C4 alkoxy, (CH2)i_ 4OR', (CH2)1.4NR'R", (CH2)1.4SR', (CH2)1.4SiR'R"R", (CH2)1 OC(0)R', (CH2)1 C(0)R, (CH2)!_ 4C02R', (CH2)i_4CONR'R", or combinations thereof, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R" and R'" are
independently selected from hydrogen, Ci-C6 alkyl, C3-C6 cycloalkyl, C2-C6 alkenyl, C2_C6 alkynyl, unsubstituted aryl, and unsubstituted heteroaryl. Other suitable substituents include each of the above aryl substituents attached to a ring atom by an alkylene tether of from 1-4 carbon atoms.
As used herein, the term "heteroatom" is meant to include oxygen (O), nitrogen (N), sulfur (S) and silicon (Si). In some embodiments, heteroatom refers to O, N or S. In some embodiments, heteroatom refers to O or N.
As used herein, the term "chiral" refers to molecules which have the property of non- superimposability of the mirror image partner, while the term "achiral" refers to molecules which are superimposable on their mirror image partner.
As used herein, the term "stereoisomers" refers to compounds which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.
"Diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers can separate under high resolution analytical procedures such as electrophoresis and chromatography.
"Enantiomers" refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.
Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. The compounds of the invention can contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of the invention, including but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer can also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can occur where there has been no stereoselection or
stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.
As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.
In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined. Unless otherwise specified, if solid wedges or dashed lines are used, relative stereochemistry is intended. If a discrepancy exists between a structure and its name, the structure governs.
As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to the complex where the solvent molecule is water.
As used herein, the term "protecting group" refers to a substituent that is commonly employed to block or protect a particular functional group on a compound. For example, an "amino- protecting group" is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Suitable amino-protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a "hydroxy-protecting group" refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A "carboxy-protecting group" refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include phenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl, 2- (p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis 4th edition, Wiley- Interscience, New York, 2006.
As used herein, the term "mammal" includes, but is not limited to, humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows, pigs, and sheep.
A "subject," "individual," or "patient" is a vertebrate. In certain embodiments, the vertebrate is a mammal. A subject, individual or patient may be in need of a compound of the present invention.
As used herein, the term "pharmaceutically acceptable salts" is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds of the present invention contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of salts derived from pharmaceutically- acceptable inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Salts derived from pharmaceutically-acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, Ν,Ν'-dibenzylethylenediamine, diethylamine, 2- diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N- ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. When compounds of the present invention contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric,
monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al.,
"Pharmaceutical Salts", J. Pharm. Sci., 1977, 66, 1-19). Certain specific compounds of the present invention contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
In addition to salt forms, the present invention provides compounds which are in a prodrug form. As used herein the term "prodrug" refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Additionally, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent.
Prodrugs of the invention include compounds wherein an amino acid residue, or a polypeptide chain of two or more (e.g., two, three or four) amino acid residues, is covalently joined through an amide or ester bond to a free amino, hydroxy or carboxylic acid group of a compound of the present invention. The amino acid residues include but are not limited to the 20 naturally occurring amino acids commonly designated by three letter symbols and also includes phosphoserine, phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine, gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylic acid, statine, l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, 3- methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid, citrulline, homocysteine, homoserine, methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.
Additional types of prodrugs are also encompassed. For instance, a free carboxyl group of a compound of the invention can be derivatized as an amide or alkyl ester. As another example, compounds of this invention comprising free hydroxy groups can be derivatized as prodrugs by converting the hydroxy group into a group such as, but not limited to, a phosphate ester, hemisuccinate, dimethylaminoacetate, or phosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. et al., (1996) Improved oral drug delivery: solubility limitations overcome by the use of prodrugs Advanced Drug Delivery Reviews, 19: 115. Carbamate prodrugs of hydroxy and amino groups are also included, as are carbonate prodrugs, sulfonate esters and sulfate esters of hydroxy groups. Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group can be an alkyl ester optionally substituted with groups including, but not limited to, ether, amine and carboxylic acid functionalities, or where the acyl group is an amino acid ester as described above, are also encompassed. Prodrugs of this type are described in J. Med. Chem., (1996), 39: 10. More specific examples include replacement of the hydrogen atom of the alcohol group with a group such as (Ci-C6)alkanoyloxymethyl, l-((Ci- C6)alkanoyloxy)ethyl, l-methyl-l-((Ci-C6)alkanoyloxy)ethyl, (Ci-C6)alkoxycarbonyloxymethyl, N-(Ci-C6)alkoxycarbonylaminomethyl, succinoyl, (Ci-C6)alkanoyl, alpha-amino(Ci_4)alkanoyl, arylacyl and alpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where each alpha- aminoacyl group is independently selected from the naturally occurring L-amino acids,
P(0)(OH)2, -P(0)(0(Ci_6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate).
For additional examples of prodrug derivatives, see, for example, a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of
Prodrugs," by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77: 285 (1988); and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each of which is specifically incorporated herein by reference. Additionally, the present invention provides for metabolites of compounds of the invention. As used herein, a "metabolite" refers to a product produced through metabolism in the body of a specified compound or salt thereof. Such products can result for example from the oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, and the like, of the administered compound.
Metabolite products typically are identified by preparing a radiolabelled (e.g., 14C or 3H) isotope of a compound of the invention, administering it in a detectable dose (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the metabolite). The metabolite structures are determined in conventional fashion, e.g., by MS, LC/MS or NMR analysis. In general, analysis of metabolites is done in the same way as conventional drug metabolism studies well known to those skilled in the art. The metabolite products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention.
Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. Compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are intended to be within the scope of the present invention.
The compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replace by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as H ("D"), 3H, nC, 13C, 14C, 13N, 15N, 150, 170, 180, 3 2P, 33P, 35S, 18F, 36C1, 123I and 125I. Certain isotopically labeled compounds of the present invention (e.g., those labeled with 3H or 14C) are useful in compound or substrate tissue distribution assays. Tritiated (3H) and carbon-14 (14C) isotopes are useful for their ease of preparation and detectability. Further substitution with heavier isotopes such as deuterium (i.e., H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as 150, 13N, nC, and
18 F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and Examples herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. One non- limiting example of an isotopically substituted moiety is the following:
Figure imgf000021_0001
The terms "compound(s) of this invention," and "compound(s) of the present invention" and the like, unless otherwise indicated, include compounds of formulae (I), (II) and (III) and stereoisomers (including atropisomers), geometric isomers, tautomers, solvates, metabolites, isotopes, salts (e.g., pharmaceutically acceptable salts), and prodrugs thereof. In some embodiments, solvates, metabolites, isotopes or prodrugs are excluded, or any combination thereof.
"Treatment" (and variations such as "treat" or "treating") refers to clinical intervention in an attempt to alter the natural course of the individual or cell being treated, and can be performed either for prophylaxis or during the course of clinical pathology. Desirable effects of treatment include preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized (i.e., not worsening) state of disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and remission or improved prognosis. In some embodiments, compounds of the invention are used to delay development of a disease or disorder or to slow the progression of a disease or disorder. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder, (for example, through a genetic mutation) or those in which the condition or disorder is to be prevented. In some embodiments, prophylaxis is excluded from the definition of "treatment."
The phrase "therapeutically effective amount" or "effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) attenuates, ameliorates, or eliminates one or more symptoms of the particular disease, condition, or disorder, or (iii) prevents or delays the onset of one or more symptoms of the particular disease, condition, or disorder described herein. For cancer therapy, efficacy can, for example, be measured by assessing the time to disease progression (TTP) or determining the response rate (RR). In the case of immunological disease, the therapeutically effective amount is an amount sufficient to decrease or alleviate an allergic disorder, the symptoms of an
autoimmune or inflammatory condition (e.g., psoriasis or inflammatory bowel disease), or the symptoms of an acute inflammatory reaction (e.g. asthma). In some embodiments, a
therapeutically effective amount is an amount of a chemical entity described herein sufficient to significantly decrease the activity or number of B-cells.
The terms "inhibiting" and "reducing," or any variation of these terms, includes any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease of about, at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, or any range derivable therein, reduction of activity (e.g., NIK activity) compared to normal.
The term "bioavailability" refers to the systemic availability (i.e., blood/plasma levels) of a given amount of drug administered to a patient. Bioavailability is an absolute term that indicates measurement of both the time (rate) and total amount (extent) of drug that reaches the general circulation from an administered dosage form.
"Inflammatory condition" as used herein refers to any disease, disorder, or syndrome in which an excessive or unregulated inflammatory response leads to excessive inflammatory symptoms, host tissue damage, or loss of tissue function.
"Inflammation" as used herein refers to a localized, protective response elicited by injury or destruction of tissues, which serves to destroy, dilute, or wall off (sequester) both the injurious agent and the injured tissue. Inflammation is notably associated with influx of leukocytes or neutrophil chemotaxis. Inflammation can result from infection with pathogenic organisms and viruses and from noninfectious means such as trauma or reperfusion following myocardial infarction or stroke, immune response to foreign antigen, and autoimmune responses.
The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth or proliferation. A "tumor" comprises one or more cancerous cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies.
"Autoimmune disease" as used herein refers to any group of disorders in which tissue injury is associated with humoral or cell-mediated responses to the body's own constituents.
It is specifically contemplated that any limitation discussed with respect to one embodiment of the invention may apply to any other embodiment of the invention. Furthermore, any compound or composition of the invention may be used in any method of the invention, and any method of the invention may be used to produce or to utilize any compound or composition of the invention.
The use of the term "or" is used to mean "and/or" unless explicitly indicated to refer to alternatives only or the alternative are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and "and/or."
Throughout this application, the term "about" is used to indicate that a value includes the standard deviation of error for the device or method being employed to determine the value. As used herein, "a" or "an" means one or more, unless clearly indicated otherwise. As used herein, "another" means at least a second or more.
Headings used herein are intended only for organizational purposes.
Inhibitors of NIK
One aspect of the invention rovides compounds of formula (I):
Figure imgf000023_0001
(I) or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein:
ring A is a monocycle or a fused bicycle;
Q is N or C, wherein when Q is N, then the bond between Ai and Q is not a double bond and the bond between Q and A4 is not a double bond;
Ai is NR1, N, S, CR1 or CHR1;
A2 is NR2, N, O, S, CR2 or CHR2;
A3 is N or C;
A4 is N; and
one, two or three of Ai-A4 are N, wherein:
each R1 is independently selected from the group consisting of H, halogen, NRaRb, NHC(0)NRaRb, NHS(0)2CH3, C1-C3 alkyl, C3-C7 cycloalkyl, C1-C3 alkoxy and 3-11 membered heterocyclyl, wherein the alkyl of R1 is optionally substituted by F, OH, CN, SH, C1-C3 alkoxy or 3-11 membered heterocyclyl; the cycloalkyl of R1 is optionally substituted by F, OH, CN, SH, CH3 or CF3; the alkoxy of R1 is optionally substituted by F, OH, CN or SH; and the heterocyclyl of R1 is optionally substituted by F, OH, CN, SH, CF3 or C1-C3 alkyl,
each R2 is independently selected from the group consisting of H, NRaRb, Ci-C6 alkyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, phenyl and 3-11 membered heterocyclyl, wherein R is optionally substituted by Rc; or
R 1 2
and R" are taken together with the atoms to which they are attached to form a cyclic group selected from the group consisting of C3-C7 cycloalkyl, phenyl and 3-11 membered heterocyclyl, wherein the cyclic group is optionally substituted by Rd;
R4 is selected from the group consisting of H, Ci-C6 alkyl, CH2F and CH2OH;
R5 is 3-11 membered heterocyclyl optionally substituted by Re or -C(=0)N(Ci-C6 alkyl)2; or
R4 and R5 together form a C3-C11 cycloalkyl optionally substituted by Re or a 3-11 membered heterocyclyl optionally substituted by Re;
one of A5-A8 is N and the remaining are CR6 or all are CR6;
R6, independently at each occurrence, is selected from the group consisting of H, F, CI, NH2, NHCH3, N(CH3)2, OH, OCH3, OCHF2, OCH2F, OCF3, SH, SCH3, SCHF2, SCH2F, CN, CH3, CHF2, CH2F, CH2OH, CF3, N02 and N3; Ra is selected from the group consisting of H and Ci-C6 alkyl optionally substituted by C1-C3 alkoxy, F, OH, CN, SH, CH3 or CF3;
Rb is selected from the group consisting of H, Ci-C6 alkyl, Ci-C6 alkoxy, C3-C6 cycloalkyl, C(0)R , phenyl and 3-11 membered heterocyclyl wherein Rb may be optionally substituted by Ci-C3 alkoxy, F, OH, CN, SH, CH3 or CF3;
Rc and Rd are each independently selected from the group consisting of halogen, -(X^o-i- CN, -(X1)o-i-N02, -(x i-SFj, -(X')o-i-OH, -(X1)0-i-NH2, -(X -NCHXR13), -(x i- N(Rlb)(Rla), -(X1)o-i-CF3, Ci_C6 alkyl, Ci_C6 haloalkyl, Ci_C6 heteroalkyl, Ci_C6 alkoxy, Ci_C6 alkylthio, oxo, -(x i-Ci-Ce alkyl, -(x i-Cs-Qo cycloalkyl, -O-C3_Ci0 cycloalkyl,
Figure imgf000025_0001
membered heterocyclyl, -(x i-Ce-Qo aryl, -C(=O)(X1)i-C3_Ci0 cycloalkyl, -C(=0)(X1)i-3-l l membered heterocyclyl, -(X1)0_i-C(=Y1)N(H)(Rla), -(X1)0_i-C(=Y1)NH2, -(Xl)0A-
Figure imgf000025_0002
Figure imgf000025_0003
-(X1)0,-N(H)S(O)1.2Rla,
Figure imgf000025_0004
NHC(=Y1)N(Rlb)(Rla), -(X1)o-i-N(Rla)C(=Y1)N(H)(Rla), -(X1)0-i-N(Rla)C(=Y1)N(Rla)(Rlb), -(X'k-NCR1")^1)^, -(X1)o-i-OC(=Y1)Rla, -(X1)o-i-OC(=Y1)H, -(X1)0-i-OC(=Y1)ORla, -(X1)o-i-OP(=Y1)(ORla)(ORlb), -(X1)-SC(=Y1)ORla and -(X1)-SC(=Y1)N(Rla)(Rlb) wherein X1 is selected from the group consisting of Ci_C6 alkylene, Ci_C6 heteroalkylene, C2_C6 alkenylene, C2_ C6 alkynylene, Ci_C6 alkyleneoxy, C3_C7 cycloalkylene, 3-11 membered heterocyclylene and phenylene; Rla and Rlb are each independently selected from the group consisting of Ci_C6 alkyl, Ci_C6 haloalkyl, Ci_C6 heteroalkyl, C3_C7 cycloalkyl, (C3_C7 cycloalkylene)Ci_C6 alkyl, 3- 11 membered heterocyclyl, (3- 11 membered heterocyclylene)Ci-C6 alkyl, C6 aryl, and (C6-Cio arylene)Ci-C6 alkyl, or Rla and Rlb when attached to the same nitrogen atom are optionally combined to form a 3-11 membered heterocyclyl comprising 0-3 additional heteroatoms selected from N, O and S; Y1 is O, NRlc or S wherein Rlc is H or Ci_C6 alkyl; wherein any portion of an Rc or Rd substituent, including Rla, Rlb and Rlc, at each occurrence is each independently further substituted by from 0 to 4 R substituents selected from the group consisting of halogen, CN, N02, SF5, OH, NH2, -N(Ci_C6 alkyl)2, -NH(Ci_C6 alkyl), oxo, Ci_C6 alkyl, -(C2-C6 alkynylene)- (3-11 membered heterocyclyl, wherein the heterocyclyl is optionally substituted by Re), Ci_C6 hydroxyalkyl, Ci_C6 heteroalkyl, Ci_C6 alkoxy, Ci_C6 alkylthio, C3-C7 cycloalkyl, 3-11 membered heterocyclyl, -C(=0)N(H)(Ci_C6 alkyl), -C(=0)N(Ci_C6 alkyl)2, -C(=0)NH2, -C(=0)OCi_C6 alkyl, -C(=0)OH, -N(H)C(=0)(Ci_C6 alkyl), -N(Ci_C6 alkyl)C(=0)(Ci_C6 alkyl),
-N(H)C(=0)OCi_C6 alkyl, -N(Ci_C6 alkyl)C(=0)OCi_C6 (halo)alkyl, -S(0)i_2Ci_C6
alkyl, -N(H)S(0)i_2Ci_C6 alkyl, -N(Ci_C6 alkyl)S(0)i_2Ci_C6 alkyl, -S(O)0-1N(H)(C1-C6 alkyl), - S(0)o-iN(Ci_C6 alkyl)2, -S(O)0-1NH2, -C(=0)Ci_C6 alkyl, -C(=0)C3-C7 cycloalkyl, -C(=NOH)Ci_ C6 alkyl, -C(=NOC1-C6 alkyl)Ci_C6 alkyl, -NHC(=0)N(H)(Ci_C6 alkyl), -NHC(=0)N(C1-C6 alkyl)2, -NHC(=0)NH2, -N(Ci_C6 alkyl)C(=0)N(H)(Ci_C6 alkyl), -N(Ci_C6 alkyl)C(=0)NH2, - OC(=0)Ci_C6 alkyl, -OC(=0)OCi_C6 alkyl, -OP(=0)(OCi_C6 alkyl)2, -SC(=0)OCi_C6 alkyl and - SC(=0)N(Ci_C6 alkyl)2, wherein any alkyl portion of R is optionally substituted with halogen;
Re is selected from the group consisting of halogen, OH, Ci-C6 alkyl and oxo; and R is selected from the group consisting of Ci-C6 alkyl and C3-C6 cycloalkyl wherein R may be optionally substituted by Ci-C3 alkoxy, F, OH, CN, SH, CH3 or CF3.
In some embodiments, the compound of formula (I) is other than Compound Nos. 1-199 in PCT/EP2014/067872, filed August 22, 2014, or any intermediate disclosed therein. In some embodiments, the compound of formula (I) is other than a compound selected from the group consisting of Compound Nos. lx-199x in Table lx.
Table lx
Figure imgf000026_0001
yl]ethynyl]-2-pyridyl]-6,6-dimethyl-5,7-dihydro-4H-indazole-3-carboxamide
8x (5R)-5-benzyloxy-l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]-2-pyridyl]-6,6-dimethyl-5,7-dihydro-4H-indazole-3-carboxamide
9x (5R)-5-hydroxy-l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]-2-pyridyl]-6,6-dimethyl-5,7-dihydro-4H-indazole-3-carboxamide lOx 4-fluoro-l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-2- pyridyl]indazole-3-carboxamide
l lx (5S)-5-hydroxy-l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]-2-pyridyl]-6,6-dimethyl-5,7-dihydro-4H-indazole-3-carboxamide
12x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5,6- dihydro-4H-pyrano[2,3-c]pyrazole-3-carboxamide
13x 5-fluoro- 1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3 - yl]ethynyl]phenyl]indazole-3-carboxamide
14x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- methoxy-indazole-3-carboxamide
15x (4R)-4-(cyclopropanecarbonylamino)- 1 - [4- [2- [(3R)-3-hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]-2-pyridyl]-4,5,6,7-tetrahydroindazole-3-carboxamide
16x tert-butyl 3 -carbamoyl- 1 - [3- [2- [(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
17x (4S)-4-(cyclopropanecarbonylamino)-l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo- pyrrolidin-3-yl]ethynyl]-2-pyridyl]-4,5,6,7-tetrahydroindazole-3-carboxamide
18x 1 - [3-fluoro-5- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3 - yl]ethynyl]phenyl]pyrazolo[3,4-b]pyridine-3-carboxamide
19x 5-acetyl-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-carboxamide
20x 5-(cyclopropanecarbonyl)- 1 - [3 - [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3 - yl]ethynyl]phenyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-carboxamide
21x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]- 4,5,6,7-tetrahydropyrazolo[4,3-c]pyridine-3-carboxamide
22x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- methoxy-indazole-3-carboxamide
23x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-7- methoxy-indazole-3-carboxamide
24x 4,4-difluoro- 1 - [3 - [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]-6,7-dihydro-5H-indazole-3-carboxamide
25x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- methyl-pyrazolo[3,4-d]thiazole-3-carboxamide x l-[3-[(3R)-3-hydroxy-3-(5-methyl-l,3,4-oxadiazol-2-yl)but-l- ynyl]phenyl]indazole-3-carboxamide
x 6-fluoro- 1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-3 - piperidyl]ethynyl]phenyl]indazole-3-carboxamide
x l-[3-[(3R)-3-hydroxy-3-pyrimidin-2-yl-but-l-ynyl]phenyl]indazole-3- carboxamide
x l-[3-[(3R)-3-hydroxy-3-(5-methyl-l,2,4-oxadiazol-3-yl)but-l- ynyl]phenyl]indazole-3-carboxamide
x 1 - [3- [2- [(3S)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3 - yl]ethynyl]phenyl]indazole-3-carboxamide
x 1 - [4-fluoro-3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3 - yl]ethynyl]phenyl]pyrazolo[3,4-b]pyridine-3-carboxamide
x (4R)-4-(cyclopropanecarbonylamino)- 1 - [3- [2- [(3R)-3-hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-4,5,6,7-tetrahydroindazole-3-carboxamidex l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- (oxetan-3-yl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-carboxamidex (4R)-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]- 4-pyrazol-l-yl-4,5,6,7-tetrahydroindazole-3-carboxamide
x 5-(hydroxymethyl)-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]indazole-3-carboxamide
x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5- (trifluoromethyl)phenyl]pyrazolo[3,4-b]pyridine-3-carboxamide
x (4S)-4-(cyclopropanecarbonylamino)-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-4,5,6,7-tetrahydroindazole-3-carboxamidex (4S)-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-4- pyrazol-l-yl-4,5,6,7-tetrahydroindazole-3-carboxamide
x 4-chloro- 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]indazole-3-carboxamide
x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5-(2- hydroxy-2-methyl-propyl)-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3- carboxamide
x 5-(cyanomethyl)-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]indazole-3-carboxamide
x 5-cyano-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]indazole-3-carboxamide
x 5- [( 1 R)- 1 -hydroxyethyl] - 1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]indazole-3-carboxamide
x l-[3-chloro-5-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[3,4-b]pyridine-3-carboxamidex 5-[(lS)-l -hydroxyethyl] - 1 - [3 - [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]indazole-3-carboxamide
x 6-cyano-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]indazole-3-carboxamide
x (5aS )-5 ,5 -difluoro- 1 - [3 - [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]-5a-methyl-4a,6-dihydro-4H-cyclopropa[f]indazole-3- carboxamide
x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- (pyrrolidin-l-ylmethyl)indazole-3-carboxamide
x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-4- (methylamino)pyrazolo[4,3-c]pyridine-3-carboxamide
x (5aR)-5 ,5-difluoro- 1 - [3 - [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3 - yl]ethynyl]phenyl]-5a-methyl-4a,6-dihydro-4H-cyclopropa[f]indazole-3- carboxamide
x l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-2-pyridyl]- 4,5,6,7-tetrahydroindazole-3-carboxamide
x l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-2- pyridyl]indazole-3-carboxamide
x 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[3,4-b]pyridine-3-carboxamide
x 5-fluoro-l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-2- pyridyl]indazole-3-carboxamide
x l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-2- pyridyl]pyrazole-3-carboxamide
x l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-2-pyridyl]-5,6- dihydro-4H-cyclopenta[c]pyrazole-3-carboxamide
x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]- 4,5,6,7-tetrahydroindazole-3-carboxamide
x (R)-l-(4-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)pyridin-2-yl)- 4,5,6,7-tetrahydro-lH-5,7-methanoindazole-3-carboxamide
x (R)-l-(4-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)pyridin-2-yl)- 4,5,6,7-tetrahydro-lH-4,6-methanoindazole-3-carboxamide
x 1 - [4- [(3R)-3 -hydroxy-3 -(5-methylisoxazol-3-yl)but- 1 -ynyl] -2-pyridyl] -4,5 ,6,7- tetrahydroindazole-3-carboxamide
x (6R)-6-hydroxy- 1 - [4- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]-2-pyridyl]-4,5,6,7-tetrahydroindazole-3-carboxamide
x (6S)-6-hydroxy-l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]-2-pyridyl]-4,5,6,7-tetrahydroindazole-3-carboxamide
63x 6-fluoro-l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-2- pyridyl]indazole-3-carboxamide
64x l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-2-pyridyl]-5,5- dimethyl-6,7-dihydro-4H-indazole-3-carboxamide
65x l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-2-pyridyl]-5- methoxy-indazole-3-carboxamide
66x 5-bromo-l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-2- pyridyl]indazole-3-carboxamide
67x l-[3-[(3R)-3-hydroxy-3-(5-methyl-l,3,4-oxadiazol-2-yl)but-l- ynyl]phenyl]pyrazolo[3,4-b]pyridine-3-carboxamide
68x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6,6- dioxo-5,7-dihydro-4H-thiopyrano[3,4-c]pyrazole-3-carboxamide
69x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5,7- dihydro-4H-pyrano[3,4-c]pyrazole-3-carboxamide
70x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6,7- dihydro-4H-pyrano[4,3-c]pyrazole-3-carboxamide
71x 6-fluoro- 1 - [4- [2- [(3R)-3 -hydroxy-2-oxo-pyrrolidin-3 -yl]ethynyl] -2- pyridyl]indazole-3-carboxamide
72x 6-fluoro-l-[4-[2-[(7R)-7-hydroxy-5,6-dihydrocyclopenta[b]pyridin-7- yl]ethynyl]-2-pyridyl]indazole-3-carboxamide
73x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5-methoxy- phenyl]pyrazolo[3,4-b]pyridine-3-carboxamide
74x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- methoxy-pyrazolo[3,4-b]pyridine-3-carboxamide
75x 5-fluoro- 1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3 - yl]ethynyl]phenyl]pyrazolo[3,4-b]pyridine-3-carboxamide
76x 6-chloro- 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[4,3-c]pyridine-3-carboxamide
77x 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]irnidazo[l,5-a]pyridine-3-carboxamide
78x 4-chloro- 1 - [4- [2- [(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3-yl]ethynyl] -2- pyridyl]-5-methyl-pyrazole-3-carboxamide
79x l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-2-pyridyl]-5- methyl-pyrazole-3-carboxamide
80x l-[4-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-l-ynyl]-2-pyridyl]-5-methyl- pyrazole-3-carboxamide 81x 5-cyclopropyl-l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]- 2-pyridyl]pyrazole-3-carboxamide
82x 4- chloro- 1 - [4- [(3R)-3 -hydroxy-3 -(5-methylisoxazol-3 -yl)but- 1 -ynyl] -2-pyridyl] -
5- methyl-pyrazole-3-carboxamide
83x 5-amino-l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-2- pyridyl]pyrazole-3-carboxamide
84x 3-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]- 5,6,7, 8-tetrahydroimidazo[l,5-a]pyridine-l-carboxamide
85x 8-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]imidazo[l,5-a]pyrimidine-6-carboxamide
86x 7-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]imidazo[l,5-b]pyridazine-5-carboxamide
87x 7-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-2,3- dihydro- 1 H-imidazo[ 1 ,5 -a]imidazole-5 -carboxamide
88x 3-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]imidazo[l,5-a]pyridine-l -carboxamide
89x 4-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]thiazole-2-carboxamide
90x 7-cyano-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]imidazo[l,5-a]pyridine-3-carboxarnide
91x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-7- (trifluoromethyl)imidazo[l,5-a]pyridine-3-carboxarnide
92x 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]imidazo[l,5-a]pyrazine-3-carboxamide
93x 6-chloro- 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]imidazo[l,5-a]pyridine-3-carboxarnide
94x 7-chloro-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]imidazo[l,5-a]pyridine-3-carboxarnide
95x l,7-bis[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]imidazo[l,5-a]pyridine-3-carboxarnide
96x 7-(cyclobutoxy)- 1 - [3-[2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]imidazo[l,5-a]pyridine-3-carboxamide
97x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-7- methoxy-imidazo [ 1 ,5 -a]pyridine-3 -carboxamide
98x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- methoxy-imidazo [ 1 ,5 -a]pyridine-3 -carboxamide
99x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-7- (morpholinomethyl)imidazo[l ,5-a]pyridine-3-carboxamide
ΙΟΟχ l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- (morpholinomethyl)imidazo[l ,5-a]pyridine-3-carboxamide
lOlx l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5-(l- methylpyrazol-3-yl)indazole-3-carboxamide
102x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5-(l- methylpyrazol-4-yl)indazole-3-carboxamide
103x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5-(l- methylpyrazol-3-yl)pyrazolo[3,4-b]pyridine-3-carboxamide
104x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5-(l- methylpyrazol-4-yl)pyrazolo[3,4-b]pyridine-3-carboxamide
105x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- morpholino-pyrazolo[3,4-b]pyridine-3-carboxamide
106x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5-(4- methylimidazol-l-yl)indazole-3-carboxamide
107x 5-(l-acetylazetidin-3-yl)-l-[3-[2-[(3R)-3-hydroxy- l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[3,4-b]pyridine-3-carboxamide
108x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5-oxo- 4H-pyrazolo[4,3-b]pyridine-3-carboxamide
109x (4R)-l-[3-[2-[(3R)-3-hydroxy-l -methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]- 4-methyl-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxamide
HOx (4S)-l -[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-4- methyl-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxamide
l l lx l-[3-cyano-5-[2-[(3R)-3-hydroxy- l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[3,4-b]pyridine-3-carboxamide
112x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-N5- methyl-indazole-3,5-dicarboxamide
113x 5-[l-(2-hydroxyethyl)pyrazol-4-yl]-l-[3-[2-[(3R)-3-hydroxy-l -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]indazole-3-carboxamide
114x 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[3,4-d]pyrimidine-3-carboxamide
115x l-[3-[2-[(lS)-l -hydroxy-2-oxo-cyclopentyl]ethynyl]phenyl]indazole-3- carboxamide
116x l-[3-[2-[(lR)-l-hydroxy-2-oxo-cyclopentyl]ethynyl]phenyl]indazole-3- carboxamide
Ι Πχ l-[3-[(3R)-3-hydroxy-3-(lH-triazol-4-yl)but-l-ynyl]phenyl]indazole-3- carboxamide 118x l-[3-[(3S)-3-hydroxy-3-(lH-triazol-4-yl)but-l-ynyl]phenyl]indazole-3- carboxamide
119x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5,6- dihydro-4H-cyclopenta[c]pyrazole-3-carboxamide
120x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- pyrimidin-4-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-carboxamide
121x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- pyrimidin-2-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-carboxamide
122x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- thiazol-2-yl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-carboxamide
123x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5-[(R)- methylsulfinyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-carboxamide
124x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5-[(S)- methylsulfinyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-3-carboxamide
125x 1 - [3- [2- [(3S ,4S)-3 ,4-dihydroxy- 1 -methyl-2-oxo-pyrrolidin-3 - yl]ethynyl]phenyl]indazole-3-carboxamide
126x l-[3-[2-[(3S,4R)-3,4-dihydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]indazole-3-carboxamide
127x 1 - [3- [2- [(3R,4R)-3 ,4-dihydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]indazole-3-carboxamide
128x l-[3-[2-[(3R,4S)-3,4-dihydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]indazole-3-carboxamide
129x 4-(ethylamino)- 1 - [3 - [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[4,3-c]pyridine-3-carboxamide
130x 4-(cyclopropylamino)-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[4,3-c]pyridine-3-carboxamide
131x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- methyl-pyrazolo[4,3-c]pyridine-3-carboxamide
132x 1 - [3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[4,3-c]pyridine-3-carboxamide
133x 6-cyano-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[4,3-c]pyridine-3-carboxamide
134x 6-cyano-l-[3-[2-[(7R)-7-hydroxy-5,6-dihydrocyclopenta[b]pyridin-7- yl]ethynyl]phenyl]pyrazolo[4,3-c]pyridine-3-carboxamide
135x 6-cyano-l-[3-[2-[(7S)-7-hydroxy-5,6-dihydrocyclopenta[b]pyridin-7- yl]ethynyl]phenyl]pyrazolo[4,3-c]pyridine-3-carboxamide
136x 6-ethoxy- 1 - [3 - [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[4,3-c]pyridine-3-carboxamide
137x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- pyrrolidin-l-yl-pyrazolo[4,3-c]pyridine-3-carboxamide
138x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- [(3R)-3-hydroxypyrrolidin-l-yl]pyrazolo[4,3-c]pyridine-3-carboxamide
139x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- [(3S)-3-hydroxypyrrolidin-l-yl]pyrazolo[4,3-c]pyridine-3-carboxamide
140x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- methoxy-pyrazolo[4,3-c]pyridine-3-carboxamide
141x 5-[[4-aminobutanoyl(methyl)amino]methyl]-l-[4-[2-[(3R)-3-hydroxy-l-methyl- 2-oxo-pyrrolidin-3-yl]ethynyl]-2-pyridyl]indazole-3-carboxamide
142x 5-[[butanoyl(methyl)amino]methyl]-l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo- pyrrolidin-3-yl]ethynyl]-2-pyridyl]indazole-3-carboxamide
143x l-[3-[2-[(3S)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6-oxo- 4,5-dihydropyrrolo[3,4-c]pyrazole-3-carboxamide
144x 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[3,4-d]thiazole-3-carboxamide
145x 1 - [2-fluoro-5- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3 - yl]ethynyl]phenyl]-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxamide
146x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-4,6- dihydrofuro[3,4-c]pyrazole-3-carboxamide
147x 3-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]indazole- 1 -carboxamide
148x 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[3,4-c]pyridine-3-carboxamide
149x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- methyl-pyrazolo[3,4-c]pyridine-3-carboxamide
150x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- methoxy-pyrazolo[3,4-c]pyridine-3-carboxamide
151x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]- 4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine-3-carboxamide
152x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-5-methyl- phenyl]pyrazolo[3,4-b]pyridine-3-carboxamide
153x 6-chloro- 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[3,4-b]pyridine-3-carboxamide
154x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- methoxy-pyrazolo[3,4-b]pyridine-3-carboxamide 155x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- morpholino-pyrazolo[3,4-b]pyridine-3-carboxamide
156x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6-(l- methylpyrazol-4-yl)pyrazolo[3,4-b]pyridine-3-carboxamide
157x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- methyl-pyrazolo[3,4-d]pyrimidine-3-carboxamide
158x 6-cyclopropyl- 1 - [3 - [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[3,4-d]pyrimidine-3-carboxamide
159x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- (trifluoromethyl)pyrazolo[3,4-d]pyrimidine-3-carboxamide
160x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- methoxy-pyrazolo[3,4-d]pyrimidine-3-carboxamide
161x 5- [2-(azetidin- 1 -yl)ethoxy] - 1 - [3 - [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin- 3-yl]ethynyl]phenyl]indazole-3-carboxamide
162x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5-(2- morpholinoethoxy)indazole-3-carboxamide
163x l-[3-[4-(dimethylamino)-3-hydroxy-4-oxo-but-l-ynyl]phenyl]indazole-3- carboxamide
164x 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[4,3-b]pyridine-3-carboxamide
165x ethyl 3-carbamoyl-l-[4-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]-2-pyridyl]-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carboxylate
166x l-[2-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-4-pyridyl]- 4,5,6,7-tetrahydroindazole-3-carboxamide
167x l-[4-cyano-3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]-4,5,6,7-tetrahydroindazole-3-carboxamide
168x (6S)-6-hydroxy-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxamide
169x (6R)-6-hydroxy- 1 - [3 - [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxamide
170x l-[3-[(3R)-3-hydroxy-3-thiazol-2-yl-but-l-ynyl]phenyl]indazole-3-carboxamide
171x l-[3-[2-[(3R)-3-hydroxy-2-oxo-tetrahydrofuran-3-yl]ethynyl]phenyl]indazole-3- carboxamide
172x l-[3-[2-[(3S)-3-hydroxy-2-oxo-tetrahydrofuran-3-yl]ethynyl]phenyl]indazole-3- carboxamide
173x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- methoxy-pyrazolo[3,4-c]pyridazine-3-carboxamide 174x 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[3,4-c]pyridazine-3-carboxamide
175x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6- methyl-pyrazolo[3,4-b]pyridine-3-carboxamide
176x 7-fluoro- 1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3 - yl]ethynyl]phenyl]indazole-3-carboxamide
177x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]- 5,6,7, 8-tetrahydroimidazo[l,5-a]pyridine-3-carboxamide
178x 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]imidazo[l,5-a]pyridine-3,7-dicarboxamide
179x 3-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]imidazo[l ,5-a]pyridine-l ,6-dicarboxamide
180x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5-oxo- 6,7-dihydro-4H-pyrazolo[4,3-b]pyridine-3-carboxamide
181x l-[3-[(3R)-3-hydroxy-3-(5-methyl-l,3,4-oxadiazol-2-yl)but-l-ynyl]phenyl]-7- methoxy-imidazo [ 1 ,5 -a]pyridine-3 -carboxamide
182x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5-(lH- imidazol-2-yl)indazole-3-carboxamide
183x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5-(3- methoxyazetidin-l-yl)pyrazolo[3,4-b]pyridine-3-carboxamide
184x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]- N5,N5-dimethyl-indazole-3,5-dicarboxamide
185x 6-chloro- 1 - [3- [(3R)-3 -hydroxy-3 -(5-methyl- 1 ,3 ,4-oxadiazol-2-yl)but- 1 - ynyl]phenyl]imidazo[l,5-a]pyridine-3-carboxamide
186x 6-chloro-l-[2-fluoro-5-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]imidazo[l,5-a]pyridine-3-carboxamide
187x 7-chloro- 1 - [3- [(3R)-3 -hydroxy-3 -(5-methyl- 1 ,3 ,4-oxadiazol-2-yl)but- 1 - ynyl]phenyl]imidazo[l,5-a]pyridine-3-carboxamide
188x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- methyl-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxamide
189x 6-fluoro- 1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3 - yl]ethynyl]phenyl]indazole-3-carboxamide
190x 1 -[3- [2-[(3R)-3-hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazolo[3,4-d]pyridazine-3-carboxamide
191x 1 - [2-fluoro-5- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3 - yl]ethynyl]phenyl]-4,6-dihydrofuro[3,4-c]pyrazole-3-carboxamide
192x 3-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-6,7- dihydro-5H-pyrrolo[l,2-c]imidazole-l-carboxamide
193x (5S)-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- methyl-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxamide
194x (5R)-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]- 5-methyl-5,6-dihydro-4H-cyclopenta[c]pyrazole-3-carboxamide
195x 5-amino-2- [3 - [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]thiazole-4-carboxamide
196x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]-5- (methylamino)pyrazolo[3,4-d]thiazole-3-carboxamide
197x 2-[2-fluoro-5-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]-5-methyl-thiazole-4-carboxamide
198x l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]- 4,5,6,7-tetrahydropyrazolo[3,4-b]pyridine-3-carboxamide
199x 5,5-difluoro-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]-4,6-dihydrocyclopenta[c]pyrazole-3-carboxamide
In some embodiments, the compound is of formula (I) where in Q is C. In some embodiments, the compound is of formula (I) where in Q is C, provided that the compound is other than a compound selected from the group consisting of Compound Nos. lx-146x and 148x-199x. In some embodiments, a compound of formula (I) is further defined as a compound of formula (II):
Figure imgf000037_0001
or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein:
ring A is a monocycle or a fused bicycle;
Ai is NR1, N, S, CR1 or CHR1;
A2 is NR2, N, O, S, CR2 or CHR2;
A3 is N or C;
A4 is N; and one, two or three of A1-A4 are N, wherein:
each R1 is independently selected from the group consisting of H, halogen, NRaRb, NHC(0)NRaRb, NHS(0)2CH3, C1-C3 alkyl, C3-C7 cycloalkyl, Ci-C3 alkoxy and 3- 11 membered heterocyclyl, wherein the alkyl of R1 is optionally substituted by F, OH, CN, SH, Ci-C3 alkoxy or 3-11 membered heterocyclyl; the cycloalkyl of R1 is optionally substituted by F, OH, CN, SH, CH3 or CF3; the alkoxy of R1 is optionally substituted by F, OH, CN or SH; and the heterocyclyl of R1 is optionally substituted by F, OH, CN, SH, CF3 or Ci-C3 alkyl,
each R2 is independently selected from the group consisting of H, NRaRb Ci-C6 alkyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, phenyl and 3-11 membered heterocyclyl, wherein R is optionally substituted by Rc; or
1 2
R and R" are taken together with the atoms to which they are attached to form a cyclic group selected from the group consisting of C3-C7 cycloalkyl, phenyl and 3- 11 membered heterocyclyl, wherein the cyclic group is optionally substituted by Rd;
R4 is selected from the group consisting of H, Ci-C6 alkyl, CH2F and CH2OH;
R5 is 3-1 1 membered heterocyclyl optionally substituted by Re or -C(=0)N(Ci-C6 alkyl)2; or
R4 and R5 together form a C3-Cn cycloalkyl optionally substituted by Re or a 3- 11 membered heterocyclyl optionally substituted by Re;
one of A5-A8 is N and the remaining are CR6 or all are CR6;
R6, independently at each occurrence, is selected from the group consisting of H, F, CI, NH2, NHCH3, N(CH3)2, OH, OCH3, OCHF2, OCH2F, OCF3, SH, SCH3, SCHF2, SCH2F, CN, CH3, CHF2, CH2F, CH2OH, CF3, N02 and N3;
Ra is selected from the group consisting of H and Ci-C6 alkyl optionally substituted by Ci-C3 alkoxy, F, OH, CN, SH, CH3 or CF3;
Rb is selected from the group consisting of H, Ci-C6 alkyl, Ci-C6 alkoxy, C3-C6 cycloalkyl, C(0)R , phenyl and 3-11 membered heterocyclyl wherein Rb may be optionally substituted by Ci-C3 alkoxy, F, OH, CN, SH, CH3 or CF3;
Rc and Rd are each independently selected from the group consisting of halogen, -(X^o-i- CN, -(x i-NO,, -(x i-SFj, -(X')o-i-OH, -(x i-NH,, -(x i-NCHXR13), -(x i- N(Rlb)(Rla), -(X1)o-i-CF3, Ci_C6 alkyl, Ci_C6 haloalkyl, Ci_C6 heteroalkyl, Ci_C6 alkoxy, Ci_C6 alkylthio, oxo, -(x i-Ci-Ce alkyl, -(x i-Cs-Qo cycloalkyl, -O-C3_Ci0 cycloalkyl, -(Χ Λ-3-11 membered heterocyclyl,
Figure imgf000039_0001
aryl, -C(=O)(X1)i-C3-Ci0 cycloalkyl, -C(=0)(X1)i-3-ll membered heterocyclyl, -(X1)0_i-C(=Y1)N(H)(Rla), -(X1)0_i-C(=Y1)NH2,
Figure imgf000039_0002
Figure imgf000039_0003
-(X1)0-i-N(H)C(=Y1)(Rla),
Figure imgf000039_0004
Figure imgf000039_0005
-(X Vi-S(O)0-iN(Rlb)(Rla), -(X1)0-i-S(O)0-iNH2, -(x i-
Figure imgf000039_0006
NHC(=Y1)N(Rlb)(Rla), -(X1)o-i-N(Rla)C(=Y1)N(H)(Rla), -(X1)0-i-N(Rla)C(=Y1)N(Rla)(Rlb), -(X'k-NCR11)^1)^, -(X1)o-i-OC(=Y1)Rla, -(X1)o-i-OC(=Y1)H, -(X1)0_i-OC(=Y1)ORla, -(X1)o-i-OP(=Y1)(ORla)(ORlb), -(X1)-SC(=Y1)ORla and -(X1)-SC(=Y1)N(Rla)(Rlb) wherein X1 is selected from the group consisting of Ci_C6 alkylene, Ci_C6 heteroalkylene, C2_C6 alkenylene, C2_ C6 alkynylene, Ci_C6 alkyleneoxy, C3_C7 cycloalkylene, 3-11 membered heterocyclylene and phenylene; Rla and Rlb are each independently selected from the group consisting of Ci_C6 alkyl, Ci_C6 haloalkyl, Ci_C6 heteroalkyl, C3_C7 cycloalkyl, (C3_C7 cycloalkylene)Ci_C6 alkyl, 3-11 membered heterocyclyl, (3-11 membered heterocyclylene)Ci-C6 alkyl, C6 aryl, and (C6-Cio arylene)Ci_C6 alkyl, or Rla and Rlb when attached to the same nitrogen atom are optionally combined to form a 3-11 membered heterocyclyl comprising 0-3 additional heteroatoms selected from N, O and S; Y1 is O, NRlc or S wherein Rlc is H or Ci_C6 alkyl; wherein any portion of an Rc or Rd substituent, including Rla, Rlb and Rlc, at each occurrence is each independently further substituted by from 0 to 4 R substituents selected from the group consisting of halogen, CN, N02, SF5, OH, NH2, -N(Ci_C6 alkyl)2, -NH(Ci_C6 alkyl), oxo, Ci_C6 alkyl, -(C2-C6 alkynylene)- (3-11 membered heterocyclyl, wherein the heterocyclyl is optionally substituted by Re), Ci_C6 hydroxyalkyl, Ci_C6 heteroalkyl, Ci_C6 alkoxy, Ci_C6 alkylthio, C3_C7 cycloalkyl, 3-11 membered heterocyclyl, -C(=0)N(H)(Ci_C6 alkyl), -C(=0)N(Ci_C6 alkyl)2, -C(=0)NH2, -C(=0)OCi_C6 alkyl, -C(=0)OH, -N(H)C(=0)(Ci_C6 alkyl), -N(Ci_C6 alkyl)C(=0)(Ci_C6 alkyl),
-N(H)C(=0)OCi_C6 alkyl, -N(Ci_C6 alkyl)C(=0)OCi_C6 (halo)alkyl, -S(0)i_2Ci_C6
alkyl, -N(H)S(0)1.2C1.C6 alkyl, -N(d.C6 alkyl)S(0)1_2C1.C6 alkyl, -S(O)0-1N(H)(Ci.C6 alkyl), - S(0)o-iN(Ci_C6 alkyl)2, -S(O)0-1NH2, -C(=0)Ci_C6 alkyl, -C(=0)C3_C7 cycloalkyl, -C(=NOH)Ci_ C6 alkyl, -C(=NOCi_C6 alkyl)Ci_C6 alkyl, -NHC(=0)N(H)(Ci_C6 alkyl), -NHC(=0)N(C1-C6 alkyl)2, -NHC(=0)NH2, -N(Ci_C6 alkyl)C(=0)N(H)(Ci_C6 alkyl), -N(Ci_C6 alkyl)C(=0)NH2, - OC(=0)Ci_C6 alkyl, -OC(=0)OCi_C6 alkyl, -OP(=0)(OCi_C6 alkyl)2, -SC(=0)OCi_C6 alkyl and -
SC(=0)N(Ci_C6 alkyl)2, wherein any alkyl portion of R is optionally substituted with halogen;
Re is selected from the group consisting of halogen, OH, Ci-C6 alkyl and oxo; and R is selected from the group consisting of Ci-C6 alkyl and C3-C6 cycloalkyl wherein R may be optionally substituted by C1-C3 alkoxy, F, OH, CN, SH, CH3 or CF3.
In some embodiments, the compound is of formula (II), provided that the compound is other than a compound selected from the group consisting of Compound Nos. lx-146x and 148x-199x.
In some embodiments, ring A is a monocycle. Ai is N or CHR1. In some embodiments, Ai is N.
In some embodiments, Ai is N, A2 is S and A3 is C. In some embodiments, A2 is N, O or CHR .
In some embodiments, A2 is N. In some embodiments, Ai is S, A2 is N and A3 is C. In some embodiments, A2 is O, Ai is CR1, A2 is O and A3 is C.
In some embodiments, Ai is CHR 1 and A2 is CHR 2 , and ring A is a non-aromatic heterocyle. In some embodiments, Ai is CHR 1 and A2 is CHR 2 , and ring A is a non-aromatic monocyclic heterocyle. In some embodiments, Ai is CHR 1 and A2 is CHR 2 , and ring A is a fused bicyclic non-aromatic heterocyle. In some embodiments, Ai is CHR 1 ; A2 is CHR 2 ; and R 1 and R2 are taken together with the atoms to which they are attached to form a C3-C7 cycloalkyl optionally substituted by Rd or a 3-11 membered heterocyclyl optionally substituted by Rd. In some embodiments, R 1 and R 2 together form the following cyclic group, wherein the asterisks indicate the points of ring fusion to ring A, and each cyclic group is optionally substituted by Rd:
Figure imgf000040_0001
In some embodiments, R 1 and 2 are taken together with the atoms to which they are attached to form a moiety of the structure:
Figure imgf000040_0002
t , which is optionally substituted by Rd, wherein the asterisks indicate the points of ring fusion to ring A. In some embodiments, Ai is CR1 wherein R1 is selected from the group consisting of NHC(0)NRaRb; NHS(0)2CH3; C1-C3 alkyl substituted by Ci-C3 alkoxy or 3-11 membered heterocyclyl; and 3-11 membered heterocyclyl substituted by Ci-C3 alkyl. In some
embodiments, Ai is CR1 wherein R1 is NHC(0)NRaRb. In some of these embodiments, Ra and Rb are independently selected from the group consisting of H and Ci-C6 alkyl.
In some embodiments, Ai is CR1 wherein R1 is NHS(0)2CH3. In some embodiments, Ai is CR1 wherein R1 is 3-11 membered heterocyclyl substituted by Ci-C3 alkyl. In some embodiments, Ai is CR1 wherein R1 is Ci-C3 alkyl substituted by Ci-C3 alkoxy or 3-11 membered heterocyclyl. In som sisting of:
Figure imgf000041_0001
wherein the wavy line represents the point of attachment of R1 in formula (I) or (II).
In some embodiments of the formula (I) or (II), Ai is NR1, S or CR1; and A2 is NR2, S or CR2.
In some embodiments, A is a monocycle.
In some embodiments, 1 1
Ai is NR . In some embodiments, Ai is 2
NR , A2 is CR and A3 is C. In some of these embodiments, R1 is H or Ci-C3 alkyl. In some embodiments, Ai is CR1. In some embodiments, is 1 2 1
Ai CR , A2 is CR and A3 is N. In some embodiments, Ai is CR and A6 is CR°. In some of these embodiments, A2 is CR where R is H or -OCH3.
In some embodiments, Ai is CR1, A2 is S and A3 is C. In some of these embodiments, R1 is other than -NH2 or -CH3.
In some embodiments, R1 is H, F or CI.
In some embodiments, R1 is NRaRb. In some of these embodiments, Ra is H or Ci-C6 alkyl. In some of these embodiments, Rb is H; Ci-C6 alkyl optionally substituted by Ci-C3 alkoxy, F, OH, CN, SH, CH3 or CF3; or 3-11 membered heterocyclyl optionally substituted by Ci-C3 alkoxy, F, OH, CN, SH, CH3 or CF3. In some of these embodiments, Rb is C(0)R . In some embodiments, R is C3-C6 cycloalkyl optionally substituted by F.
In some embodiments, R1 is Ci-C3 alkyl optionally substituted by F, OH, CN, SH, Ci-C3 alkoxy or 3-11 membered heterocyclyl; C3-C7 cycloalkyl optionally substituted by F, OH, CN, SH, CH3 or CF3; or Ci-C3 alkoxy. In some embodiments, R1 is 3-11 membered heterocyclyl optionally substituted by F, OH, CN, SH, CF3 or Ci-C3 alkyl.
In some embodiments, R1 is a 5-6 membered heteroaryl optionally substituted by F, OH, CN, SH, CF3 or Ci-C3 alkyl.
In some embodiments, R1 is selected from the group consisting of:
Figure imgf000042_0001
wherein the wavy line represents the point of attachment of R1 in formula (I) or (II).
In some embodiments, Ai is S. In some embodiments, Ai is S, A2 is CR and A3 is C. In some embodiments, R is H. In some embodiments,
In some embodiments, Ai is NR 1 or CR1 ; and A2 is NR 2 or CR 2.
In some embodiments, Ai is NR 1 or CR1 ; A2 is NR 2 or CR 2 ; and R 1 and R2 are taken together with the atoms to which they are attached to form a C3-C7 cycloalkyl optionally substituted by Rd, or a 3-11 membered heterocyclyl optionally substituted by Rd. In some of these embodiments, R 1 and R 2 are taken together with the atoms to which they are attached to form a moiety selected from the roup consisting of:
Figure imgf000042_0002
wherein the asterisks indicate the points of ring fusion to ring A.
In some embodiments, A7 is CR6 where R6 is H. In some embodiments, As is CR6 where R6 is H or F. In some embodiments, A5 is CR6 where R6 is H. In some embodiments, A6 is CR6 where R6 is selected from the group consisting of H, F, OCH3 and CH3. In some embodiments, A5, A6, A7 and A8 are each independently CR6 where R6 is, independently at each occurrence, selected from the group consisting of H, F, OCH3 and CH3 and n is 0.
In some embodiments, a compound of formula (I) is further defined as a compound of formula (HI):
Figure imgf000043_0001
wherein ring A, Ai, A2, A3, A4, R and R are as defined for formula (II) or any variation detailed herein, n is 0, 1 or 2, and each R6 is independently selected from the group consisting of F, CI, OCH3, CH3 and CF3. In some embodiments, the compound is of formula (III), provided that the compound is other than a compound selected from the group consisting of Compound Nos. lx- 3x, 12x-14x, 16x, 18x-50x, 53x, 57x, 67x-70x, 73x-77x, 84x-140x, 143x-164x and 167x-199x in Table lx.
In some embodiments of the compound of formula (I), (II) or (III), R4 and R5 are taken together with carbon to which they are attached to form a Cs-Cio cycloalkyl optionally substituted by Re. In some embodiments, R4 and R5 are taken together with carbon to which they are attached to form a 4-9 membered heterocyclyl optionally substituted by Re.
In some embodiments of the compound of formula (I), (II) or (III), wherein the following moiety:
Figure imgf000044_0001
wherein:
A9 is O, NR11 or CRnR12, wherein R11 and R12 are each independently selected from the group consisting of H, halogen, OH and C1-C3 alkyl;
7 8 tly selected from halogen, OH, 7 8
R' and R° are each independen Ci-C6 alkyl, or R and R together form =0, and
R9 and R10 are each independently selected from H and Re, or R9 and R10 are taken together with the atoms to which they are attached to form a C5-C6 cycloalkyl optionally substituted by Re or a 5-6 membered heterocyclyl optionally substituted by Re.
In some of these embodiments, 7 and 8 9 10
R R together form =0; R and R are each H; and A9 is NR11 where R11 is C1-C3 alkyl.
In some embodiments, the moiety
Figure imgf000044_0002
is selected from the group consisting of:
Figure imgf000045_0001
In some embodiments, the moiety is
[0101] It is intended and understood that each and every variation of A1-A4, including variations of R 1 and R 2 where applicable, described for Formula (I), (II) or (III) may be combined with each and every variation of As-Ag described for Formula (I), (II) or (III), and with each and every variation of R4 and R5 described for Formula (I), (II) or (III) as if each and every combination is individually described. For example, in some embodiments, ring A is a monocycle, Ai is NR1, each A5, A6, A7 and A8 is independently CR6, and the -C(R4)(R5)OH moiety is 3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl. In some embodiments, ring A is a monocycle, Ai is CR1 wherein R1 is other than -NH2 or -CH3, A2 is S, A3 is C, each A5, A6, A7 and As is independently CR6, and the -C(R4)(R5)OH moiety is 3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl. In some embodiments, ring 1 2
A is a monocycle, Ai is CR , A2 is CR , A3 is N,
A6 is CR6, and the -C(R4)(R5)OH moiety is 3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl.
[0102] In some embodiments, the compounds of formula (I), (II) or (III), wherein ring A is a monocycle; 1 1 2 2
Ai is NR , S or CR ; and A2 is NR , S or CR . In some embodiments, the compounds of formula (I), (II) or (III), wherein ring A is a monocycle; Ai is NR1, S or CR1; and s NR 2 , 2
A2 i S or CR ; provided that the compound is other than a compound selected from the group consisting of Compound Nos. 55x, 78x-83x, 89x, 195x and 197x.
[0103] In some embodiments, the compound of is formula (I), (II) or (III), wherein the -C(R4)(R5)OH moiety is 3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl. In some embodiments, the compound of is formula (I), (II) or (III), wherein the -C(R4)(R5)OH moiety is 3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl; provided that the compound is other than a compound selected from the group consisting of Compound Nos. lx-25x, 30x-59x, 61x-66x, 68x-71x, 73x-81x, 83x- 114x, 119x-124x, 129x-133x, 136x-162x, 164x-169x, 173x-180x, 182x-184x, 186x, 188x-199x.
[0104] In some embodiments, one of A1-A4 is N. In some embodiments, A4 is N. In some embodiments, two of A1-A4 is N. For example, in some embodiments, Ai and A4 are each N. In other embodiments, A3 and A4 are each N. In any such embodiment, ring B may be phenyl or phenyl independently substituted by one or two R6. In some embodiments, A1 is CR1, A2 is CR2, A3 is N and A4 is N.
[0105] In some embodiments, R1 is selected from the group consisting of H, F and CI. In some embodiments, R is selected from the group consisting of H, NH2, CH3 and cyclopropyl. In other embodiments, R 2 is a 1
C3-C11 heterocycloalkyl. In some embodiments, R and R2 together form the following cyclic group, wherein the asterisks indicate the points of ring fusion to ring A, and each c clic group is optionally substituted by Rd:
Figure imgf000046_0001
Figure imgf000047_0001
[0106] In some embodiments, R 1 and R 2 together form the following cyclic group, wherein the asterisks indicate the points of ring fusion to ring A, and each cyclic group is optionally substituted by Rd:
Figure imgf000047_0002
Figure imgf000047_0003
Figure imgf000048_0001
[0108] In some embodiments, Rd is selected from the group consisting of OH, CN, F, C1-C3 alkoxy, -O-Q-C3 alkyl-phenyl, NRaRb, 4-6 membered heterocyclyl, C(0)R , C(0)2R and Ci-C6 alkyl optionally substituted by OH, CN, or 4-6 membered heterocyclyl.
[0109] In some embodiments, ring B is phenyl.
[0110] In some embodiments, Rc and Rd are each independently selected from the group consisting of halogen, -(XV-CN, -(X1)o-i-N02, -(x i-SFj, -(X')o-i-OH, -(x i-NH,,
Figure imgf000048_0002
i-N(H)(Rla), -(X1)o-i-N(Rlb)(Rla), -(X1)0-i-CF3, Ci_C6 alkyl, Ci_C6 haloalkyl, Ci_C6 heteroalkyl, Ci_C6 alkoxy, Ci_C6 alkylthio, oxo, -(x i-Ci-Ce alkyl,
Figure imgf000048_0003
cycloalkyl,
membered heterocyclyl (e.g., a 4-7 membered heterocycloalkyl or a 5-6 membered heteroaryl), - (x i-Ce-Cio aryl, -C(=0)(X1)i-C3-C7 cycloalkyl, -C(=0)(X1)i-3-ll membered
heterocyclyl, -(X1)0.1-C(=Y1)N(H)(Rla), -(X1)0-i-C(=Y1)NH2,
Figure imgf000048_0004
-
Figure imgf000048_0005
CO 2Rla, -(X1)„.1-N(H)S(0)1.2Rla, -(X1)o-i-N(Rlb)S(0)1.2Rla, -(X1)0-i-S(O)0-iN(H)(Rla), -(X1^- S(O)0-iN(Rlb)(Rla), -(X1)o-i-S(0)o-iNH2,
Figure imgf000048_0006
and - (X1)o-i-C(=Y1)H, wherein X1 is selected from the group consisting of Ci_C6 alkylene, Ci_C6 heteroalkylene, C2_C6 alkenylene, C2_C6 alkynylene, Ci_C6 alkyleneoxy, C3_C7 cycloalkylene, 3- 11 membered heterocyclylene and phenylene; Rla and Rlb are each independently selected from the group consisting of Ci_C6 alkyl, Ci_C6 haloalkyl, Ci_C6 heteroalkyl, C3_C7 cycloalkyl, 3-11 membered heterocyclyl, and phenyl, or Rla and Rlb when attached to the same nitrogen atom are optionally combined to form a 3-11 membered heterocyclyl (e.g., a 4-7 membered
heterocycloalkyl or a 5-6 membered heteroaryl) comprising 0-3 additional heteroatoms selected from N, O and S; Y1 is O, NRlc or S wherein Rlc is H or Ci_C6 alkyl; wherein any portion of an Rc or Rd substituent, including Rla, Rlb and Rlc, at each occurrence is each independently further substituted by from 0 to 4 R substituents selected from the group consisting of halogen, CN, N02, OH, NH2, -N(Ci_C6 alkyl)2, -NH(Ci_C6 alkyl), oxo, Ci_C6 alkyl, Ci_C6 haloalkyl, Ci_C6 hydroxyalkyl, Ci_C6 heteroalkyl, Ci_C6 alkoxy, Ci_C6 alkylthio, C3-C7 cycloalkyl, or 3-11 membered heterocyclyl (e.g., a 4-7 membered heterocycloalkyl or a 5-6 membered heteroaryl).
[0111] In some embodiments, a heterocyclyl group contains one to three nitrogen atoms, one oxygen atom, or one sulfur atom, or any combination thereof.
[0112] In some embodiments, a compound of the present invention is defined as any one or more of the following:
Figure imgf000049_0001
Figure imgf000050_0001
[0113] Some embodiments provide a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable carrier, diluent or excipient. A compound or pharmaceutical composition described herein can be used in therapy, such as the treatment of an inflammatory condition (e.g., lupus, such as systemic lupus erythematosus, extrarenal lupus, or lupus nephritis, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and transplant rejection). Also provided is the use of a compound or a pharmaceutical composition described herein for the preparation of a medicament for the treatment of an inflammatory condition (e.g., lupus, such as systemic lupus
erythematosus, extra-renal lupus, or lupus nephritis, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and transplant rejection).
[0114] Also provided is a method for the treatment of an inflammatory condition in a patient, comprising administering an effective amount of a compound or pharmaceutical composition as described herein to the patient. The inflammatory condition can be selected from the group consisting of lupus, such as systemic lupus erythematosus, extra-renal lupus, or lupus nephritis, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and transplant rejection.
[0115] Further provided is a method of preparing a compound of formula (I):
Figure imgf000051_0001
wherein Q, Ai, A2, A3, A4, A5, A6, A7, As, R4 and R5 are as defined above, contacting a compound of formula (A):
Figure imgf000051_0002
wherein X is CI, Br or I, with a compound of formula (B)
Figure imgf000051_0003
wherein [M] is a boronic acid, a boronic ester, or a trifluoroborate salt, in the presence of (a)(i) a palladium(O) catalyst or (a)(ii) a copper catalyst and (b) a base under Suzuki reaction conditions to yield a compound of formula (I).
[0116] Persons of skill in the art are familiar with Suzuki reactions and the reagents employed in such reactions. See, e.g., Suzuki, J. Organometallic Chem., 576:147-168 (1999). Non- limiting examples of palladium catalysts include Pd(PPh3)4, Pd(OAc)2 and Pd(PPh3)2Cl2. A non- limiting example of a copper catalyst is copper(II) acetate. Non-limiting examples of bases include sodium carbonate, potassium carbonate and cesium carbonate, or mixtures thereof. In some embodiments, copper(II) acetate and pyridine as the base are employed under Chan-Lam coupling conditions, as is known in the art. For example, the carbon-nitrogen bond in an indazole or an aza-indazole can be formed using Chan-Lam coupling conditions. A variety of organic solvents may be employed, including toluene, THF, dioxane, 1 ,2-dichloroethane, DMF, DMSO and acetonitrile. Reaction temperatures vary depending on conditions but typically range from room temperature to 150°C.
[0117] In some embodiments, the invention provides a compound of Table 1 A and Table IB:
Table 1A
Figure imgf000052_0001
4-(ethylamino)- 1 - [3- [2- [(3R)-3-hydroxy- 1 -methyl- 2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]pyrazole-3- carboxamide
2- [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-5- (trifluoromethyl)thiazole-4-carboxamide
1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-4- (trifluoromethyl)pyrazole-3-carboxamide
4-( 1 ,5 -dimethylpyrazol-4-yl)- 1 - [3 - [2- [(3R)-3 - hydroxy- l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazole-3-carboxamide
2- [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3 -yl] ethynyl] phenyl] - 5 - [( 1 - methylpyrazol-4-yl)amino]thiazole-4-carboxamide
5- [2-fluoro-5- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-l,2,4-thiadiazole- 3-carboxamide
Figure imgf000053_0001
°κΝΗ2 <X 1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-4-[(l- methylpyrazol-4-yl)amino]pyrazole-3-carboxamide
1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-4-(2- pyridyl)pyrazole-3-carboxamide
2- [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-5-(oxetan-3- ylamino)thiazole-4-carboxamide
Figure imgf000054_0001
(R)-5-ethyl-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin- 3-yl)ethynyl)phenyl)thiazole-4-carboxamide
1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-6,8-dihydro-5H- imidazo[5,l-c][l,4]oxazine-3-carboxamide
Figure imgf000054_0002
4-(cyclopropanecarbonylamino)-l-[3-[2-[(3R)-3- hydroxy-l-methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazole-3-carboxamide
4-acetamido-l-[3-[2-[(3R)-3-hydroxy-l-methyl-2- oxo-pyrrolidin-3-yl]ethynyl]phenyl]pyrazole-3- carboxamide
Figure imgf000054_0003
Figure imgf000055_0001
Figure imgf000056_0001
5-acetamido-2-[3-[2-[(3R)-3-hydroxy-l-methyl-2- oxo-pyrrolidin-3-yl]ethynyl]phenyl]thiazole-4- carboxamide
1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-4-(l- methylpyrazol-4-yl)pyrazole-3-carboxamide
1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-4-(2- pyridylamino)pyrazole-3-carboxamide
1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-4-[(l- methylpyrazol-3-yl)amino]pyrazole-3-carboxamide
5-(dimethylcarbamoylamino)-2- [3 - [2- [(3R)-3 - hydroxy- 1 -methyl-2-oxo-pyrrolidin-3 - yl]ethynyl]phenyl]thiazole-4-carboxamide
5- [[( 1 R,2R)-2-fluorocyclopropanecarbonyl] amino] - 2- [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]thiazole-4- carboxamide
5-[[(lS,2S)-2-fluorocyclopropanecarbonyl]amino]- 2- [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]thiazole-4- carboxamide
Figure imgf000057_0001
1 - 1 -
Figure imgf000058_0001
2- [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-5- (methylamino)thiazole-4-carboxamide
1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-4-(3- pyridyl)pyrazole-3-carboxamide
1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-4-(2- methylpyrazol-3-yl)pyrazole-3-carboxamide
Figure imgf000059_0001
1 - [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-4-(4- pyridyl)pyrazole-3-carboxamide
3- [2-fluoro-5- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-l,2,4-thiadiazole- 5-carboxamide
Figure imgf000059_0002
2- [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-5- (methanesulfonamido)thiazole-4-carboxamide 2- [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-5-(2,2,2- trifluoroethylamino)thiazole-4-carboxamide
5-(ethylamino)-2-[3-[2-[(3R)-3-hydroxy-l-methyl- 2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]thiazole-4- carboxamide
Table IB
Figure imgf000060_0001
Figure imgf000061_0001
5-(cyclopropanecarbonylamino)-2-[3-[2-[(3R)- 3-hydroxy- l -methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]thiazole-4-carboxamide
2- [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-5- (methoxymethyl)thiazole-4-carboxamide
4- [2-fluoro-5 - [2- [(3R)-3 -hydroxy- 1 -methyl-2- oxo-pyrrolidin-3-yl]ethynyl]phenyl]thiazole-2- carboxamide
4- [3- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]-5-methoxy- thiazole-2-carboxamide
4-(difluoromethyl)- 1 - [3 - [2- [(3R)-3 -hydroxy- 1 - methyl-2-oxo-pyrrolidin-3- yl]ethynyl]phenyl]pyrazole-3-carboxamide
2- [5- [2- [(3R)-3 -hydroxy- 1 -methyl-2-oxo- pyrrolidin-3-yl]ethynyl]-2-methoxy- phenyl]thiazole-4-carboxamide
Figure imgf000062_0001
Figure imgf000063_0001
[0118] In some embodiments, the invention provides a compound in the Examples.
[0119] In some embodiments, the compound is selected from Compounds 1-69, and salts thereof. In some embodiments, the compound is selected from Compounds 4, 5, 12, 16, 20, 26, 37, 43, 49, 52, 55, 65 and 67 and salts thereof.
Synthesis of NIK Inhibitors
[0120] Methods for preparing intermediates and compounds of the present invention are presented in the Examples section below. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the inventive compounds. Although specific starting materials and reagents are depicted in the Schemes and discussed below, other starting materials and reagents can be easily substituted to provide a variety of derivatives or reaction conditions. In addition, many of the compounds prepared by the methods described below can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.
[0121] The starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), or Beilstein's Handbuch der organishcen chemie, 4, Aufl. Ed. Springer- Verlag, Berlin including supplements also included via the Beilstein online database.
[0122] In preparing compounds of formula (I), (II) or (III), protection of remote functionality (e.g., primary or secondary amine) of intermediates may be necessary. The need for such protection will vary depending on the nature of the remote functionality and the conditions of the preparation methods. The need for such protection is readily determined by one skilled in the art. Exemplary protecting groups are provided herein. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.
[0123] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as by chromatography or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Also, some of the compounds of the present invention may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of a chiral HPLC column or supercritical fluid chromatography.
[0124] A single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., J. Chromatogr., 113(3):283-302 (1975)). Racemic mixtures of chiral compounds of the invention can be separated and isolated by any suitable method, including: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. See: Drug Stereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).
[0125] Diastereomeric salts can be formed by reaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, -methyl- -phenylethylamine (amphetamine), and the like with asymmetric compounds bearing acidic functionality, such as carboxylic acid and sulfonic acid. The diastereomeric salts may be induced to separate by fractional
crystallization or ionic chromatography. For separation of the optical isomers of amino compounds, addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid, or lactic acid can result in formation of the diastereomeric salts. [0126] Alternatively, the substrate to be resolved is reacted with one enantiomer of a chiral compound to form a diastereomeric pair (Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994, p. 322). Diastereomeric compounds can be formed by reacting asymmetric compounds with enantiomerically pure chiral derivatizing reagents, such as menthyl derivatives, followed by separation of the diastereomers and hydrolysis to yield the pure or enriched enantiomer. A method of determining optical purity involves making chiral esters, such as a menthyl ester, e.g., (-) menthyl chloroformate in the presence of base, or Mosher ester, a-methoxy-a-(trifluoromethyl)phenyl acetate (Jacob, J. Org. Chem. 47:4165 (1982)), of the racemic mixture, and analyzing the NMR spectrum for the presence of the two atropisomeric enantiomers or diastereomers. Stable diastereomers of atropisomeric compounds can be separated and isolated by normal- and reverse-phase chromatography following methods for separation of atropisomeric naphthyl-isoquinolines (WO 96/15111). By method (3), a racemic mixture of two enantiomers can be separated by chromatography using a chiral stationary phase (Chiral Liquid Chromatography W. J. Lough, Ed., Chapman and Hall, New York, (1989); Okamoto, J. of Chromatogr. 513:375-378 (1990)). Enriched or purified enantiomers can be distinguished by methods used to distinguish other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism. The absolute stereochemistry of chiral centers and enantiomers can be determined by x-ray crystallography.
[0127] Positional isomers, for example E and Z forms, of compounds of formulae (I), (II) and (III) and intermediates for their synthesis, may be observed by characterization methods such as NMR and analytical HPLC. For certain compounds where the energy barrier for interconversion is sufficiently high, the E and Z isomers may be separated, for example by preparatory HPLC.
Pharmaceutical Compositions and Administration
[0128] The compounds with which the invention is concerned are NIK kinase inhibitors, and are useful in the treatment of several diseases, for example, cancer or inflammatory conditions.
[0129] The invention also provides for compositions and medicaments comprising a compound of formula (I), (II), (III) or any variations thereof detailed herein and at least one pharmaceutically acceptable carrier, diluent or excipient. The compositions of the invention can be used for inhibiting NF-kB signaling activity in mammals (e.g., human patients), by for example, inhibiting NIK activity.
[0130] By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
[0131] In one embodiment, the invention provides for pharmaceutical compositions (or medicaments) comprising a compound of formula (I), (II), (III) or any variations thereof detailed herein and a pharmaceutically acceptable carrier, diluent or excipient. In another embodiment, the invention provides for preparing compositions (or medicaments) comprising compounds of the invention. In another embodiment, the invention provides for administering compounds of formula (I), (II), (III) or any variations thereof detailed herein and compositions comprising compounds of formula (I), (II), (III) or any variations thereof detailed herein to a mammal (e.g., a human patient) in need thereof.
[0132] Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit NIK activity as required to prevent or treat the undesired disease or disorder, such as for example, neurodegeneration, amyloidosis, formation of neurofibrillary tangles, or undesired cell growth (e.g., cancer cell growth). For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.
[0133] In one example, the therapeutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.01-100 mg/kg, alternatively about e.g., 0.1 to 20 mg/kg of patient body weight per day, such as 0.3 to 15 mg/kg/day. The daily does is, in certain embodiments, given as a single daily dose or in divided doses two to six times a day, or in sustained release form. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 mg to about 1,400 mg. This dosage regimen may be adjusted to provide the optimal therapeutic response. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day. [0134] The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.
[0135] The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.
[0136] The compositions comprising compounds of formula (I), (II), (III) or any variations thereof detailed herein are normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. A typical formulation is prepared by mixing a compound of the present invention and a diluent, carrier or excipient. Suitable diluents, carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C, et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
[0137] Suitable carriers, diluents and excipients are well known to those skilled in the art and include materials such as carbohydrates, waxes, water soluble or swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like. The particular carrier, diluent or excipient used will depend upon the means and purpose for which a compound of the present invention is being applied. Solvents are generally selected based on solvents recognized by persons skilled in the art as safe (GRAS) to be administered to a mammal. In general, safe solvents are non-toxic aqueous solvents such as water and other non-toxic solvents that are soluble or miscible in water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. The formulations can also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).
[0138] Acceptable diluents, carriers, excipients and stabilizers are nontoxic to recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate and other organic acids; antioxidants including ascorbic acid and methionine; preservatives (such as octadecyldimethylbenzyl ammonium chloride; hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; salt-forming counter-ions such as sodium; metal complexes (e.g., Zn-protein complexes); or non-ionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). A active pharmaceutical ingredient of the invention (e.g., a compound of formula (I), (II), (III) or any variations thereof detailed herein) can also be entrapped in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacrylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005) 21st Edition, Lippincott Williams & Wilkins, Philidelphia, PA. [0139] Sustained-release preparations of a compound of the invention can be prepared.
Suitable examples of sustained-release preparations include semipermeable matrices of solid hydrophobic polymers containing a compound of formula (I), (II), (III) or any variations thereof detailed herein, which matrices are in the form of shaped articles, e.g., films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2- hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides (U.S. Patent No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT™
(injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate) and poly-D-(-)-3-hydroxybutyric acid.
[0140] The formulations include those suitable for the administration routes detailed herein. The formulations can conveniently be presented in unit dosage form and can be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington: The Science and Practice of Pharmacy: Remington the Science and Practice of Pharmacy (2005) 21st Edition, Lippincott Williams & Wilkins, Philadelphia, PA. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients.
[0141] In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers, diluents or excipients or finely divided solid carriers, diluents or excipients, or both, and then, if necessary, shaping the product. A typical formulation is prepared by mixing a compound of the present invention and a carrier, diluent or excipient. The formulations can be prepared using conventional dissolution and mixing procedures. For example, the bulk drug substance (i.e., compound of the present invention or stabilized form of the compound (e.g., complex with a cyclodextrin derivative or other known complexation agent) is dissolved in a suitable solvent in the presence of one or more of the excipients described above. A compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the drug and to enable patient compliance with the prescribed regimen.
[0142] In one example, compounds of formulae (I), (II) and (III) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers. The pH of the formulation depends mainly on the particular use and the concentration of compound, but typically ranges anywhere from about 3 to about 8. In one example, a compound of formula (I), (II), (III) or any variations thereof detailed herein is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formulae (I), (II) and (III) are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.
[0143] Formulations of a compound of the invention suitable for oral administration can be prepared as discrete units such as pills, capsules, cachets or tablets each containing a
predetermined amount of a compound of the invention.
[0144] Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets can optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.
[0145] Tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, e.g., gelatin capsules, syrups or elixirs can be prepared for oral use. Formulations of a compound of the invention intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation.
Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients can be, for example, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets can be uncoated or can be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax can be employed.
[0146] An example of a suitable oral administration form is a tablet containing about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250 mg, 300 mg and 500 mg of the compound of the invention, or any range derivable therein, compounded with about 5-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose, about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using
conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 5-400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.
[0147] For treatment of the eye or other external tissues, e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w. When formulated in an ointment, the active ingredient can be employed with either a paraffinic or a water-miscible ointment base.
Alternatively, the active ingredients can be formulated in a cream with an oil-in-water cream base.
[0148] If desired, the aqueous phase of the cream base can include a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations can desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulfoxide and related analogs.
[0149] The oily phase of the emulsions of this invention can be constituted from known ingredients in a known manner. While the phase can comprise merely an emulsifier, it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations. Emulsifiers and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate. [0150] Aqueous suspensions of a compound of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, croscarmellose, povidone, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.
[0151] Formulations of a compound of the invention can be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils can conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid can likewise be used in the preparation of injectables.
[0152] The amount of active ingredient that can be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans can contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which can vary from about 5 to about 95% of the total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion can contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.
[0153] Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which can contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which can include suspending agents and thickening agents.
[0154] Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of about 0.5 to 20% w/w, for example about 0.5 to 10% w/w, for example about 1.5% w/w.
[0155] Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
[0156] Formulations for rectal administration can be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
[0157] Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration can be prepared according to conventional methods and can be delivered with other therapeutic agents such as compounds heretofore used in the treatment of disorders as described below.
[0158] Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
[0159] The formulations can be packaged in unit-dose or multi-dose containers, for example sealed ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water, for injection immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.
INDICATIONS AND METHODS OF TREATMENT
[0160] The compounds of formulae (I), (II) and (III) inhibit the activity of NIK. Accordingly, in another aspect of the invention the compounds of the invention can be used for the treatment of diseases and disorders in a mammal, for example a human patient, in which the inhibition of NIK in the patient would be therapeutically effective. For example, the compounds of the invention are useful for the treatment of diseases or disorders in a mammal (e.g., a human patient) associated with overactive or undesired NF-kB signaling through, for example, the overactivation of NIK. In one embodiment, the compounds of the invention are used to inhibit the activity of NIK, for example in an in vitro assay setting, by contacting said compound of formula (I), (II), (III) or any variations thereof detailed herein with NIK. For example, compounds of formulae (I), (II) and (III) can be used as a control compound in an in vitro assay setting.
[0161] In another embodiment, the compounds of the invention are used to inhibit the undesired signaling of NF-kB, e.g. in an cell proliferation assay, by introducing into a cell a compound of formula (I), (II), (III) or any variations thereof detailed herein. In another embodiment, the present invention provides the treatment of diseases or disorders in a mammal (e.g., human patient) associated with overactive or undesired NF-kB signaling (e.g., cancer, inflammatory diseases, among others) said method comprising administering to a mammal (e.g., a human patient) in need thereof a therapeutically effective amount of a compound of the invention.
[0162] Diseases and disorders treatable according to the methods of this invention include, cancer, inflammatory conditions, autoimmune disease and proliferation induced after medical procedures (e.g., arthritis, graft rejection, inflammatory bowel disease, cell proliferation induced after surgery angioplasty, among others). In one embodiment, a mammal (e.g., a human patient) is treated with a compound of the invention and a pharmaceutically acceptable carrier, adjuvant, or vehicle, wherein said compound of the invention is present in an amount to inhibit NF-kB signaling through, for example, but not limited to, inhibition of NIK. [0163] In one embodiment, a compound of the invention can be used in the treatment of cell proliferative disorders.
[0164] In one embodiment of the invention, cancers that may be treated by the compounds of formulae (I), (II) and (III) are selected from the group consisting of Lung (bronchogenic carcinoma (non-small cell lung); Gastrointestinal - rectal, colorectal and colon; Genitourinary tract - kidney (papillary renal cell carcinoma); and skin - head and neck squamous cell carcinoma.
[0165] In one embodiment, compounds of formulae (I), (II) and (III) can be use for the treatment of a cancer selected from the group consisting of head and neck squamous cell carcinomas, histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, papillary renal cell carcinoma, liver cancer, gastric cancers, colon cancer, leukemias, lymphomas, multiple myeloma, glioblastomas and breast carcinoma.
[0166] In one embodiment, compounds of formulae (I), (II) and (III) can be used for the treatment of a cancer selected from the group consisting of histiocytic lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, liver cancer, gastric cancer, colon cancer, leukemias, lymphomas, multiple myeloma, glioblastomas and breast carcinoma.
[0167] In one embodiment, compounds of formulae (I), (II) and (III) can be used for the treatment of cancer selected from the group consisting of lymphomas, leukemias and multiple myeloma.
[0168] In one embodiment, the invention provides for the preparation of a medicament comprising a compound of formula (I), (II), (III) or any variations thereof detailed herein for the treatment of lymphoma, leukemia or multiple myeloma.
[0169] In one embodiment, the invention provides for the treatment of lymphoma, leukemia or multiple myeloma, which method comprises administering an effective amount of a compound of formula (I), (II), (III) or any variations thereof detailed herein.
[0170] In one embodiment, compounds of the invention are useful for the treatment of inflammatory diseases and conditions including, but not limited to, lupus (including systemic lupus erythematosus, extra-renal lupus and lupus nephritis), asthma, COPD, rhinitis, multiple sclerosis, IBD, arthritis, gastritis, rheumatoid arthritis, dermatitis, endometriosis, transplant rejection, cardiac infarction, Alzheimer's diseases, diabetes Type II, inflammatory bowel disease, sepsis, and artherosclerosis. [0171] In one embodiment, the invention provides for the use of a compound of formula (I), (II), (III) or any variations thereof detailed herein for the treatment of an inflammatory condition.
[0172] In one embodiment, the invention provideds for the use of a compound of formula (I), (II), (III) or any variations thereof detailed herein for the preparation of a medicament for the treatment of an inflammatory condition.
[0173] In one embodiment, the invention provides for a compound of formula (I), (II), (III) or any variations thereof detailed herein for the treatment of an inflammatory condition.
[0174] In one embodiment, the invention provides for a method for the treatment of an inflammatory condition, which method comprises administering an effective amount of a compound of formula (I), (II), (III) or any variations thereof detailed herein to a patient in need thereof.
[0175] In one embodiment, the invention provides for the the treatment of an inflammatory condition selected from the group consisting of lupus (including systemic lupus erythematosus, extra-renal lupus and lupus nephritis), COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatisis, endometriosis and transplant rejection, which method comprises administering an effective amount of a compound of formula (I), (II), (III) or any variations thereof detailed herein.
Combinations
[0176] The compounds of formulae (I), (II) and (III) may be employed alone or in combination with other therapeutic agents for treatment. In one embodiment, compounds of this invention may be employed alone or in combination with chemotherapeutic agents. In one embodiment, compounds of this invention may be employed alone or in combination with anti-inflammatory agents. The compounds of the present invention can be used in combination with one or more additional drugs, for example an anti-inflammatory compound or anti-cancer compounds, that work by a different mechanism of action. The second compound of the pharmaceutical combination formulation or dosing regimen preferably has complementary activities to the compound of this invention such that they do not adversely affect each other. Such molecules are suitably present in combination in amounts that are effective for the purpose intended. The compounds may be administered together in a unitary pharmaceutical composition or separately and, when administered separately this may occur simultaneously or sequentially in any order. Such sequential administration may be close in time or remote in time.
[0177] In certain embodiments, a compound of formula (I), (II), (III) or any variations thereof detailed herein is combined in a pharmaceutical combination formulation, or dosing regimen as combination therapy, with a second therapeutic compound that has anti-inflammatory or anticancer properties or that is useful for treating an inflammation, immune-response disorder, or hyperproliferative disorder (e.g., cancer). The second therapeutic agent may be a NSAID (Nonsteroidal Anti-Inflammatory Drug) or other anti-inflammatory agent. The second therapeutic agent may be a chemotherapeutic agent. In one embodiment, a pharmaceutical composition of this invention comprises a compound of formula (I), (II), (III) or any variations thereof detailed herein in combination with a therapeutic agent such as an NSAID.
EXAMPLES
[0178] Although the invention has been described and illustrated with a certain degree of particularity, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the combination and arrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of the invention, as defined by the claims.
[0179] The chemical reactions in the Examples described can be readily adapted to prepare a number of other compounds of the invention, and alternative methods for preparing the compounds of this invention are deemed to be within the scope of this invention. For example, the synthesis of non-exemplified compounds according to the invention can be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interferring groups, by utilizing other suitable reagents known in the art other than those described, or by making routine modifications of reaction conditions. Alternatively, other reactions disclosed herein or known in the art will be recognized as having applicability for preparing other compounds of the invention.
General Procedure A: SNAr
Figure imgf000077_0001
[0180] To a solution of nitrogen-containing nucleophile (1 eq.) and cesium carbonate (3.0 eq.) in N,N-dimethylformamide (2 mL/mmol) was added 2-haloheterocycle (1.1 eq.). The reaction was heated to 100 °C and stirred at this temperature for 2 hours. The reaction was then cooled to room temperature and acidified to pH = 1 with 10 % aqueous HC1 solution if product contains a carboxylic acid, or diluted with water if neutral. The solution was extracted with twice with dichloromethane. The organic layers were combined, dried with sodium sulfate and concentrated under vacuum. The crude material was either used directly in subsequent reactions or purified by flash chromatography.
General Procedure B : Amide synthesis from heterocyclic carboxylic acids
Figure imgf000078_0001
[0181] Aromatic or non-aromatic heterocyclic acid (leq) and HATU (1.2eq) were weighed out and transferred to a vial to which DMF and DIPEA (3-5 eq) were subsequently added. The amine (HNRR) was added to the reaction mixture as a free base or HC1 salt after a short period and the reaction was stirred at room temperature or at 50°C for 2-18 hours. Reaction conversion was monitored by LCMS. Upon completion, the reaction was cooled and the crude product was triterated via addition of water and collected by filtration or extracted with sat ammonium chloride and DCM. Trituration or purification by chromatography gave the amide.
General Procedure C: Chan- Lam cross-coupling
Figure imgf000078_0002
[0182] To a small vial was added the nitrogen-containing nucleophile (1 eq.), arylboronic acid (1.5 eq.), copper(II) acetate monohydrate (0.3 eq.) in N,N-dimethylformamide (2 mL/mmol) and pyridine (3.0 eq.). The reaction was stirred under an oxygen atmosphere at 90 °C for 6 hours. The reaction was then cooled to room temperature and diluted with a saturated aqueous sodium bicarbonate solution, and the aqueous phase was extracted with 3 times with dichloromethane. The organic phases were combined, washed with brine, dried with sodium sulfate and concentrated under vacuum. The crude material was purified by flash chromatography. General Procedure D: Hydrolysis of nitrile to primary amide.
O
Ar^
Ar Ar^NH2
[0183] To a solution of an aryl nitrile (1 eq.) in ethanol (0.8 mL/mmol) and water (0.04 mL/mmol) was added hydrido(dimethylphosphinous acid-kp) [hydrogen
bis(dimethylphosphinito-kp)]platinum(II) (0.05 eq.). The reaction was stirred at 90 °C for 2h under air. The solution was then cooled to room temperature and extracted twice with ethyl acetate or dichloromethane. The organic layers were combined, dried with sodium sulfate and concentrated under vacuum. The crude material was either used directly in subsequent reactions or purified by flash chromatography.
General Procedures for aryl-halide (ArX) to terminal alkyne cross-coupling:
Procedure
E, F, G or H
Ar"X ^ Ar = R
X = Br, I
[0184] General Procedure E: Aryl halide was weighed out, transferred to a sealed tube and brought up in Acetontrile (3mL/mmol) and Triethylamine (3mL/mmol). The solution was degassed with nitrogen and Copper(I) Iodide (0.05eq) and
Bis(triphenylphosphine)palladium(II)chloride (0.1 eq) were added. DMF (3mL/mmol) was then added followed by dropwise addition of alkyne (2-3eq). The reaction mixture heated for 3-18h at 80°C and monitored by LCMS for consumption of starting material. Upon completion, the reaction was cooled and the crude product was either triterated via addition of water and collected by filtration or extracted with saturated ammonium chloride and DCM whereupon the organic layer was dried, filtered and concentrated to dryness. Crude products were submitted for reverse phase HPLC purification.
[0185] General Procedure F: Aryl halide (where X = bromide) (1 eq), Copper (I) Iodide (0.06 eq), tri-t-butylphosphonium tetrafluoroborate (0.2 eq) and dichlorobis(phenyl cyanide)palladium (0.1 eq) were weighed out and transferred to a microwave vessel. Upon addition of DMSO ( 3 mL/mmol), the reaction mixture was subsequently degassed whereupon a solution of alkyne (3 eq) in Diisopropylamine (3eq) was added dropwise. The reaction mixture was capped and heated thermally at 80°C and monitored by LCMS for consumption of starting material. Workup is the same for as in procedure E. [0186] General Procedure G: Aryl halide (wherein X = bromide) was weighed out, transferred to a sealed tube and brought up in DMSO or DMF (3 mL/mmol) and Triethylamine (3 mL/mmol). The solution was degassed with nitrogen and
Bis(triphenylphosphine)palladium(II)chloride (0.2eq) and alkyne (2-3eq) were added ("copper- free" conditions). The reaction mixture heated for 2-18hrs at 80°C and monitored by LCMS for consumption of starting material. Workup is the same for as in above procedure E.
ter to Amide Conversion with Sodium Methoxide/Formamide:
Figure imgf000080_0001
[0187] To a solution of Heterocyclic ester in Ν,Ν-Dimethylformamide was added formamide (10 eq) followed by dropwise addition of sodium methoxide (3 eq). The mixture was either stirred at room temperature or heated to 40°C and monitored by LC-MS for completion. The crude reaction mixture was triturated via addition of saturated ammonium chloride or extracted with Dichloromethane in cases where the product did not crash out. In situations where this was an intermediate, the crude material was used directly in subsequent reactions.
er to Amide Conversion with Ammonium Hydroxide in Dioxane:
Figure imgf000080_0002
[0188] To a solution of Heterocyclic ester in Dioxane (lOmL/mmol) was added ammonium hydroxide (25% mass) in water (50 eq., 14 mmol). The reaction mixture was stirred at 40°C and monitored by LC-MS for completion. The crude reaction mixture was concentrated to dryness and purified by reverse phase HPLC to afford product.
Saponification:
Figure imgf000080_0003
[0189] To a solution of heterocylic ester in 1 : 1 Tetrahydrofuran/Water was added lithium hydroxide monohydrate (3-10 eq). The reaction was either stirred at room temperature or heated to 50°C and monitored by LC-MS for completion. The tetrahydrofuran was then evaporated and the pH of the aqueous crude reaction mixture was adjusted to 3 whereupon the product either crashed out and was isolated, or the aqueous layer was extracted with Dichloromethane or ethyl acetate in cases where the product did not crash out. In situations where this was an
intermediate, the crude material was used directly in subsequent reactions.
General Procedure K Ketone/Aldehyde Reduction:
Figure imgf000081_0001
[0190] To a solution of heterocylic ketone/aldehyde in Methanol was added sodium
borohydride (1-3 eq). The reaction was stirred at 0°C or room temperature until bubbling subsided and monitored by LC-MS for completion. The reaction mixture was extracted with dichloromethane and saturated ammonium chloride whereupon the organic layer was dried, filtered and concentrated to afford crude heterocylic alcohol intermediate and was used directly in subsequent reactions.
General Procedure L: Fluorination.
R-i-OH— *~ R— F OR Ri-CHO— *~ R-CH2F OR R-|-C=0— - R1-CF2
R2 R2
[0191] To a solution of alcohol, aldehyde or ketone in Dichloromethane or Dichloroethane was added 4 equivalents of Diethylaminosulfur trifluoride (DAST) or Bis(2- methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor). The reaction was either stirred at room temperature or heated to 45 °C and monitored by LC-MS for completion. The reaction mixture was concentrated to dryness and the crude intermediate was triturated via addition of water which was used in subsequent reactions without further purification.
General Procedure M: Suzuki coupling of boronic acids or boronic esters with aryl halides.
R-B(OH)2
Ar-I *■ Ar-R
Pd(PPh3)4 (cat.)
Acetonitrile
Na2C03(aq)
[0192] Aryl Halide, tetrakis (triphenylphosphine)palladium or Palladium (II)
bis(triphenylphosphine) dichloride (0.05eq) and boronic acid or pinnacol ester (1.2eq) were weighed out into a microwave vessel or sealed tube. Acetonitrile (3mL/mmol) and a 1M aqueous solution of Sodium Carbonate (3eq) were added. The vessel was capped and heated thermally 3-18hrs at 100°C. Upon completion, the reaction was cooled and crude product was either triterated via addition of water and collection by filtration or extracted with sat ammonium chloride and DCM. If the crude product was an intermediate, it was taken into the next step in most cases w/o further purification or alternatively submitted for reverse phase HPLC purification when it was a final product.
General Procedure N: Reductive amination of arylaldehydes.
NHRR
Ar-CHO Ar' NRR
Molecular Sieves
NaCNBH3
10% AcOH in DMF
[0193] To a vial containing aryl aldehyde (1 eq) in 10% Acetic Acid in DMF (6mL/mmol) was added molecular sieves (1 eq by wt), amine (HNRR, 4 eq) then sodium cyanoborohydride (1.2 eq). The reaction was either heated at 45 °C or stirred at room temperature. Upon completion, the reaction was extracted with DCM and saturated ammonium chloride. The organic layer was dried with magnesium sulfate, filtered and concentrated to give crude product which was taken into the next step without purification.
General Procedure O: Carbonylative methanolysis of aryl iodides.
Pd(OAc)2
Xantphos
CO(g) /MeOH
Ar-I ArC02Me
TEA/ DMF
[0194] To a nitrogen-purged solution of aryl iodide in TEA (3mL/mmol), DMF (3mL/mmol) and MeOH (3mL/mmol) was added Palladium (II)Acetate (0.03eq) and Xantphos (0.06eq). The reaction mixture was flushed with Carbon Monoxide gas for several minutes and then sealed with CO balloon attached and heated to 60°C for 3 hours. Upon completion, the reaction was cooled to room temperature and the crude product was triterated via addition of water and collected by filtration. The crude interemediate was taken into the next step w/o further purification.
General Procedure P: Carbonylative amidation with HMDS.
Pd(OAc)2
Pd(ll)(PPh3)2 Cl2
CO(g) / NH[Si(CH3)3]2
Ar-I ArC(0)NH2
DMF [0195] To a nitrogen-degassed solution of generic aryl iodide (Ar-I) in DMF (170eq) was added Palladium(II)bis(triphenylphosphine) dichloride (0.05eq) and hexamethyldisilazane (6eq). The reaction mixture was flushed with Carbon Monoxide gas for several minutes and then sealed with CO balloon attached and heated to 70°C for 18hrs. Upon completion, the reaction was cooled to room temperature and the crude was triterated via addition of water and collected by filtration. The crude interemediate was taken into the next step w/o further purification.
to Amide conversion using Ammonia in Methanol
Figure imgf000083_0001
[0196] To a stirred solution of ester (1 equiv) in methanol was treated with saturated ammonia (>20 eq.) in methanol. The mixture was either stirred at room temperature or heated to 40 °C and the reaction was monitored by LC-MS. The crude reaction mixture was concentrated and purified by reverse phase HPLC.
on with HC1
Figure imgf000083_0002
[0197] The SEM-protected amine or alcohol and 4.0 M hydrochloric acid in dioxane (17.0 eq.) were combined in ethanol (4.0 mL/mmol) and stirred at 50 °C for 2h. The sample was then concentrated under vacuum and used directly in subsequent reactions or purified by flash chromatography.
General Procedures for Suzuki Couplings with Aryltrifluoroborates:
Figure imgf000083_0003
[0198] General Procedure U: A tube containing a solution of arylchloride/bromide (1 eq) and aryltrifluoroborate (1 eq) in Ethanol was purged with nitrogen before addition of Pd(OAc)2 (0.06 eq), RuPhos (0.12 eq), and Sodium Carbonate (2 eq). The tube was sealed with a cap lined with a disposable Teflon septum was heated at 85 °C for 12-20 hours. The reaction mixture was allowed to cool to room temperature and was either filtered thru celite and submitted directly to reverse phase HPLC purification or extracted with dichloromethane and a solution of saturated ammonium chloride before drying, evaporating and submitting to reverse phase purification or using in the subsequent step without purification.
[0199] General Procedure V: A solution of arylchloride/bromide (1 eq) and aryltrifluoroborate (1 eq) in 20% aq dioxane (0.28 M) was degassed before addition of cesium carbonate (3 eq) and tetrakis(triphenylphosphine)palladium(0) (0.05 eq). The reaction mixture was heated at 100°C for 1 hr then cooled to room temperature. Workup same as General Procedure U.
[0200] General Procedure W: A solution of arylchloride/bromide (1 eq) and
aryltrifluoroborate (1 eq) in Acetonitrile (0.25M) was degassed before addition of
tetrakis(triphenylphosphine)palladium(0) (0.05 eq) and a 1: 1 mixture of 1M Sodium Carbonate (2 eq) and 1M Potassium Acetate (2 eq). The reaction was performed in a 5 mL biotage microwave tube and heated to 140°C for 20 - 40 minutes then cooled to room temperature. Workup same as General Procedure U.
General Procedure X: Synthesis of SEM-protected tetrahydroindazoles
Figure imgf000084_0001
Figure imgf000084_0002
[0201] Step 1: A solution of diisopropylamine (1.7 eq.) in THF (4.6 mL/mmol) was cooled to - 78 °C, then a solution of n-butyl lithium in hexanes (1.6 M, 1.5 eq.) was added dropwise. After stirring for 5 minutes, this mixture was added via cannula to a -78 °C solution of ethyl diazoacetate (1.6 eq.) and cycloalkylketone (1.0 eq.) in THF (4.6 mL/mmol). The mixture was stirred for 1 hour at -78 °C, then quenched by the addition of sat. NH4Cl(aq). The mixture was diluted with water and extracted with EtOAc (2 times). The combined organic extracts were dried (MgS04) and concentrated in vacuo. Purification by CombiFlash (heptane: EtO Ac) provided the desired product.
[0202] Step 2: To a solution of product from the previous step (1.0 eq.) in pyridine (4.6 mL/mmol) was added POCI3 (4.35 eq.) and the mixture was allowed to stir at room temperature overnight. After in vacuo concentration, the mixture was poured onto ice, then extracted with EtOAc (3 times). The combined organic extracts were dried (MgS04) and concentrated in vacuo. This residue was diluted with octane (2.1 mL/mmol) and heated to 110 °C for two hours. After in vacuo concentration, purification by CombiFlash (heptane:EtOAc) provided the desired product.
[0203] Step 3: A solution of product from the previous step (1.0 eq.) in THF (20 mL/mmol) was cooled to 0 °C, then sodium hydride (60%, 3.0 eq.) was added. After stirring for 1 hour, SEMC1 (1.2 eq.) was added and the mixture was allowed to warm to room temperature overnight. After excess hydride was quenched by the addition of water at 0 °C, the mixture was extracted with EtOAc (3 times), the organic extracts dried (MgS04) and concentrated in vacuo. Purification by CombiFlash (heptane: EtOAc) provided the desired ester containing product. This ester was diluted with THF (5.4 mL/mmol), acetonitrile (5.4 mL/mmol) and water (5.4 mL/mmol) and lithium hydroxide monohydrate (7.0 eq.) was added and the mixture was stirred overnight. The mixture was diluted with water, acidified to pH 3 with 1 N HCl(aq) and extracted with Et20 (once) and 10% MeOH/CH2Cl2 (3 times). The combined organic extracts were dried (MgS04) and concentrated in vacuo to provide the desired carboxylic acid of sufficient purity to be used directly.
General Procedure Y: Alternative synthesis of SEM-protected tetrahydroindazoles
Figure imgf000086_0001
Figure imgf000086_0002
[0204] Step 1: A solution of cycloalkyl ketone (1.0 eq.) in EtOH (0.5 mL/mmol) was cooled to 0 °C, then sodium ethoxide (21% wt solution in EtOH, 1.1 eq.) was added. To this mixture was added diethyl oxylate (1.0 eq.) and the mixture was allowed to warm to room temperature overnight. In vacuo concentration provided the desired product of sufficient purity to be used directly (yield assumed to be quantitative).
[0205] Step 2: A solution of product from the previous step (1.0 eq.) in glacial acetic acid (0.5 mL/mmol) was cooled to 0 °C, then hydrazine hydrate (1.1 eq.) was added. After warming to room temperature, the mixture was stirred for 1 hour, then diluted with sat. NaHC03(aq) and extracted with 10% MeOH/CH2Cl2. The organic extracts were dried (MgS04) and concentrated in vacuo. Purification by CombiFlash (heptane: EtO Ac) provided the desired tetrahydroindazole- 3-carboxylate.
[0206] Step 3: Performed in an analogous manner to Step 3 General Procedure X.
[0207] In some cases, stereoisomers are separated to give single enantiomers or diastereomers as single, unknown stereoisomers, and are arbitrarily drawn as single isomers. Where appropriate, information is given on separation method and elution time and order.
Example 1
Synthesis of (R)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(l- methyl-lH-pyrazol-4-yl)thiazole-4-carboxamide
Figure imgf000087_0001
Step 1: Synthesis of ethyl 2-amin -5-chlorothiazole-4-carboxylate
Figure imgf000087_0002
[0208] A solution of ethyl 2-amino-l,3-thiazole-4-carboxylate (3 g, 17.421 mmol, 1.00 equiv) and N-chlorosuccinimide (2.783 g, 20.841 mmol, 1.20 equiv) in acetonitrile (50 mL) was stirred for 2 h at 80 °C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (30: 1) to give the title compound (2 g, 56%) as a light yellow solid. LC-MS (ES, m/z): 207 [M+H]+. Step 2: Synthesis of ethyl 2-bromo-5-chlorothiazole-4-carboxylate
Figure imgf000087_0003
[0209] A solution of ethyl 2-amino-5-chloro-l,3-thiazole-4-carboxylate (2.00 g, 9.678 mmol, 1.00 equiv), tert-butyl nitrite (1.20 g, 11.637 mmol, 1.20 equiv), cupric bromide (2.59 g, 11.596 mmol, 1.20 equiv) in acetonitrile (50 mL) was stirred for 2 h at 80 °C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (40:1) to give the title compound (1.2 g, 46%) as a white solid. LC-MS (ES, m/z): 270 [M+H]+.
Step 3: Synthesis of (ii)-ethyl 5-chloro-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxylate
Figure imgf000088_0001
[0210] Similar to the procedure as described in General Procedure U, ethyl 2-bromo-5- chlorothiazole-4-carboxylate was reacted with potassium (ii)-trifluoro(3 -((3 -hydroxy- 1 -methyl - 2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the title compound (180 mg, 40%) as a light yellow solid. LC-MS (ES, m/z): 376 [M+H]+.
Step 4: Synthesis of (ii)-5-chloro-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000088_0002
[0211] Similar to the procedure as described in General Procedure S, (ii)-ethyl 5-chloro-2-(3- ((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxylate was reacted with ammonia to give the title compound (150 mg, 90%) as a light yellow solid. LC-MS (ES, m/z): 376 [M+H]+.
Step 5: Synthesis of (ii)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(l- methyl-lH-pyrazol-4-yl)thiazole-4-carboxamide
Figure imgf000088_0003
[0212] Similar to the procedure as described in General Procedure M, (ii)-5-chloro-2-(3-((3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide was reacted with l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole to give the title compound (33.1 mg, 27%) as a white solid. LC-MS (ES, m/z): 422 [M+H]+. 1H NMR (400MHz, CD3OD): δ 8.38 (s, IH), 8.14 (s, IH), 8.03-8.00 (m, IH), 7.89 (s, IH), 7.59-7.57 (m, IH), 7.52- 7.49 (m, IH), 3.96 (s, 3H), 3.53-3.47 (m, 2H), 2.96 (s, 3H), 2.65-2.59 (m, IH), 2.38-2.31 (m, IH). Example 2
Synthesis of (R)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phi
methyl-lH-pyrazol-5-ylamino)-lH-pyrazole-3-carboxamide
Figure imgf000089_0001
Step 1 : Synthesis of l-(3-methoxyphenyl)-4-[(l-methyl-lH-pyrazol-5-yl)amino]-lH-pyrazole-3- carboxylic acid
Figure imgf000089_0002
[0213] Under nitrogen a solution of methyl 4-bromo-l-(3-methoxyphenyl)-lH-pyrazole-3- carboxylate (600 mg, 1.928 mmol, 1.00 equiv), l-methyl-lH-pyrazol-5-amine (563 mg, 5.797 mmol, 1.00 equiv), t-BuXPhos (82 mg, 0.193 mmol, 0.10 equiv), 3rd Generation t-BuXPhos precatalyst (154 mg, 0.194 mmol, 0.10 equiv), t-BuONa (279 mg, 2.903 mmol, 1.50 equiv) in 1 ,4-dioxane (12 mL) was irradiated with microwave radiation for 90 min at 90 °C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (1 : 1) to give the title compound (425 mg, 70%) as a yellow solid. LC-MS (ES, m/z): 314 [M+H]+.
Step 2: Synthesis of l-(3-methoxyphenyl)-4-[(l-methyl-lH-pyrazol-5-yl)amino]-lH-pyrazole-3- carboxamide
Figure imgf000089_0003
[0214] Similar to the procedure as described in General Procedure B, l-(3-methoxyphenyl)-4- [(l-methyl-lH-pyrazol-5-yl)amino]-lH-pyrazole-3-carboxylic acid was reacted with ammonium chloride to give the title compound (350 mg, 88%) as a yellow solid.
[0215] LC-MS (ES, m z): 313 [M+H]+.
Step 3: Synthesis of 1 -(3 -hydroxyphenyl)-4-[(l -methyl- lH-pyrazol-5 -yl)amino]-l H-pyrazole-3- carboxamide
Figure imgf000090_0001
[0216] To a solution of l-(3-methoxyphenyl)-4-[(l-methyl-lH-pyrazol-5-yl)amino]-lH- pyrazole-3-carboxamide (340 mg, 1.089 mmol, 1.00 equiv) in dichloromethane (20 mL) was added tribromoborane (818 mg, 3.265 mmol, 3.00 equiv) dropwise with stirring at 0°C. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by methanol. The resulting mixture was concentrated under vacuum and the residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (3: 1) to give the title compound (290 mg, 89%) as a yellow solid. LC-MS (ES, mJz): 299 [M+H]+.
Step 4: Synthesis of
Figure imgf000090_0002
[0217] A solution of l-(3-hydroxyphenyl)-4-[(l-methyl-lH-pyrazol-5-yl)amino]-lH-pyrazole- 3-carboxamide (280 mg, 0.939 mmol, 1.00 equiv), 1 ,1 ,1-trifluoro-N-phenyl-N- (trifluoromethane)sulfonylmethanesulfonamide (669 mg, 1.873 mmol, 2.00 equiv) and triethylamine (5 mL) in dichloromethane (50 mL) was stirred for 14 h at room temperature. The pH of the solution was adjusted to 8 and the mixture was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluting with ethyl dichloromethane/methanol (10: 1) to give the title compound (350 mg, 87%) as a yellow solid. LC-MS (ES, m/z): 431 [M+H]+.
Step 5: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(l- methyl-lH-pyrazol-5-ylamino)-lH-pyrazole-3-carboxamide
Figure imgf000091_0001
[0218] Similar to the procedure as described in General Procedure G, 3-[3-carbamoyl-4-[(l- methyl-lH-pyrazol-5-yl)amino]-lH-pyrazol-l-yl]phenyl trifluoromethanesulfonate was reacted with (ii)-3-ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (50.8 mg,
35%) as an off-white solid.
[0219] LC-MS (ES, m/z): 420 [M+H]+.
[0220] 1H NMR (400MHz, CD3OD): δ 8.14 (s, IH), 8.04 (s, IH), 7.93-7.91 (m, IH), 7.53-7.49 (m, IH), 7.45-7.40 (m, 2H), 6.15 (s, IH), 3.78 (s, 3H), 3.52-3.49 (m, 2H), 2.96 (s, 3H), 2.61-2.60 (m, IH), 2.38-2.32 (m, IH).
Example 3
Synthesis of 4-(l,3-diniethyl-lH-pyrazol-4-yl)-l-(3-[2-[(3R)-3-hydroxy-l-niethyl-2- oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000091_0002
Step 1 : Synthesis of methyl 4-(l ,3-dimethyl-lH-pyrazol-4-yl)-lH-pyrazole-3-carboxylate
Figure imgf000091_0003
[0221] Similar to the procedure as described in General Procedure M, methyl 4-bromo-lH- pyrazole-3-carboxylate was reacted with l,3-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole to give the title compound (200 mg, 20%) as yellow oil. LC-MS (ES, m/z): 221 [M+H]+.
Step 2: Synthesis of methyl l-(3-bromophenyl)-4-(l,3-dimethyl-lH-pyrazol-4-yl)-lH-pyrazole- 3-carboxylate
Figure imgf000092_0001
[0222] Similar to the procedure as described in General Procedure C, methyl 4-(l,3-dimethyl- lH-pyrazol-4-yl)-lH-pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to give the title compound (200 mg, 27%) as yellow oil. LC-MS (ES, m/z): 375 [M+H]+.
Step 3: Synthesis of methyl 4-(l,3-dimethyl-lH-pyrazol-4-yl)-l-(3-[2-[(3ii)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate
Figure imgf000092_0002
[0223] Similar to the procedure as described in General Procedure G, methyl l-(3- bromophenyl)-4-(l,3-dimethyl-lH-pyrazol-4-yl)-lH-pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl-3-hydroxy-l-methylpyrrolidin-2-one to give the title compound (150 mg, 65%) as yellow oil. LC-MS (ES, m/z): 434 [M+H]+.
Step 4: Synthesis of 4-( 1,3 -dimethyl- lH-pyrazol-4-yl)-l -(3- [2- [(3R)-3 -hydroxy- l-methyl-2- oxo rrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000092_0003
[0224] Similar to the procedure as described in General Procedure S, methyl 4-(l ,3-dimethyl- lH-pyrazol-4-yl)-l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-lH- pyrazole-3-carboxylate was reacted with ammonia to give the title compound (20.4 mg, 14%) as a white solid. LC-MS (ES, m/z): 419 [M+H]+. XH NMR (300MHz, CD3OD): δ 8.37 (s, IH), 8.06 (s, IH), 7.96-7.93 (m, IH), 7.84 (s, IH), 7.55-7.45 (m, 2H), 3.85 (s, 3H), 3.55-3.48 (m, 2H), 2.94 (s, 3H), 2.65-2.57 (m, IH), 2.37-2.32 (m, IH), 2.29 (s, 3H).
Example 4
Synthesis of l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4- [(methylcarbamoyl)amino]-lH-pyrazole-3-carboxamide
Figure imgf000093_0001
tep 1 : Synthesis of 4-amino-l-(3-bromophenyl)-lH-pyrazole-3-carboxamide
Figure imgf000093_0002
[0225] A solution of l-(3-bromophenyl)-4-acetamido-lH-pyrazole-3-carboxamide (200 mg, 0.619 mmol, 1.00 equiv) in methanol (10 mL) and hydrogen chloride (5 mL) was stirred overnight at room temperature. The pH of the solution was adjusted to 7 with aq. sodium hydroxide and then the mixture was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (10: 1) to give the title compound (115 mg, 63%) as a white solid. LC-MS (ES, m/z): 281
[M+H]+.
Step 2: Synthesis of l-(3-bromophenyl)-4-[(methylcarbamoyl)amino]-lH-pyrazole-3- carboxamide
Figure imgf000094_0001
[0226] A solution of 4-amino-l-(3-bromophenyl)-lH-pyrazole-3-carboxamide (130 mg, 0.462 mmol, 1.00 equiv), N-methylcarbamoyl chloride (129.5 mg, 1.385 mmol, 3.00 equiv) and triethylamine (6 mL) in dichloromethane (12 mL) was stirred for 2 h at room temperature. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (10: 1) to give the title compound (140 mg, 89%) as a white solid. LC-MS (ES, m/z): 338 [M+H]+.
Step 3: Synthesis of l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4- [(methylcarbamoyl)amino]-lH-pyrazole-3-carboxarnide
Figure imgf000094_0002
[0227] Similar to the procedure as described in General Procedure G, l-(3-bromophenyl)-4- [(methylcarbamoyl)amino]-lH-pyrazole-3-carboxarnide was reacted with (ii)-3-ethynyl-3- hydroxy-l-methylpyrrolidin-2-one to give the title compound (23.4 mg, 13 ) as a white solid. LC-MS (ES, m/z): 397 [M+H]+. lH NMR (300MHz, CD3OD): δ 8.42 (s, 1H), 7.86-7.85 (m, 1H), 7.74-7.73 (m, 1H), 7.41-7.30 (m, 2H), 3.40-3.36 (m, 2H), 2.83 (s, 3H), 2.69 (s, 3H), 2.53-2.46 (m, 1H), 2.26-2.17 (m, 1H).
Example 5
Synthesis of (R)-l'-ethyl-l-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-
4,4'-bi(lH-pyrazole)-3-carboxamide
Figure imgf000094_0003
Step 1: Synthesis of ethyl l'-ethyl- '-bi(lH-pyrazole)-3-carboxylate
Figure imgf000095_0001
EtOH , H20, 1 00 °C
[0228] Similar to the procedure as described in General Procedure M, ethyl 4-iodo-lH- pyrazole-3-carboxylate was reacted with 1 -ethyl- lH-pyrazol-4-ylboronic acid to give the title compound (343 mg, 27%) as a yellow oil. LC-MS (ES, m/z): 235 [M+H]+.
Step 2: Synthesis of ethyl l-(3-bromophenyl)-l'-ethyl-4,4'-bi(lH-pyrazole)-3-carboxylate
Figure imgf000095_0002
[0229] Similar to the procedure as described in General Procedure C, ethyl l'-ethyl-4,4'-bi(lH- pyrazole)-3-carboxylate was reacted with 3-bromophenylboronic acid to give the title compound
(311 mg, 57%) as a white solid. LC-MS (ES, m/z): 389 [M+H]+.
Step 3: Synthesis of (ii)-ethyl 1 '-ethyl- l-(3-((3-hydroxy- l-methyl-2-ox opyrrolidin-3- l)ethynyl)phenyl)-4,4'-bi(lH-pyrazole)-3-carboxylate
Figure imgf000095_0003
[0230] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-l'-ethyl-4,4'-bi(lH-pyrazole)-3-carboxylate was reacted with (ii)-3-ethynyl-3- hydroxy-l-methylpyrrolidin-2-one to give the title compound (215 mg, 62%) as yellow oil. LC- MS (ES, m/z): 448 [M+H]+.
Step 4: Synthesis of (ii)-l'-ethyl-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-4,4'-bi(lH-pyrazole)-3-carboxamide
Figure imgf000096_0001
[0231] Similar to the procedure as described in General Procedure S, ethyl l-(3-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(l-methyl-lH-pyrazol-4-yl)-lH- pyrazole-3-carboxylate was reacted with ammonia to give the title compound (19.6 mg, 9%) as a white solid. LC-MS (ES, mJz): 419 [M+H]+. lH NMR (300MHz, CD3OD): δ 8.64 (s, IH), 8.24 (s, IH), 8.06 (s, IH), 7.95-7.94 (m, 2H), 7.62-7.45 (m, 2H), 4.25-4.18 (m, 2H), 3.55-3.47 (m, 2H), 2.94 (s, 3H), 2.65-2.57 (m, IH), 2.38-2.28 (m, IH), 1.50 (t, J = 7.2 Hz, 3H).
Example 6
Synthesis of (R)-4-(ethylamino)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000096_0002
Step 1 : Synthesis of ethyl l-(3-bromophenyl)-4-(N-ethylacetamido)-lH-pyrazole-3-carboxylate
Figure imgf000096_0003
[0232] A solution of ethyl l-(3-bromophenyl)-4-acetamido-lH-pyrazole-3-carboxylate (1 g, 2.839 mmol, 1.00 equiv), sodium hydride (340 mg, 14.168 mmol, 4.99 equiv), and iodoethane (886 mg, 5.681 mmol, 2.001 equiv) in N,N-dimethylformamide (130 mL) was stirred for 1 h at 0 °C. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with dichloromethane/methanol (10: 1) to give the title compound (800 mg,74 ) as a red solid. LC- MS (ES, m/z): 380 [M+H]+.
Step 2: Synthesis of l-(3-bromophenyl)-4-(N-ethylacetamido)-lH-pyrazole-3-carboxamide
Figure imgf000097_0001
[0233] Similar to the procedure as described in General Procedure S, ethyl l-(3-bromophenyl)- 4-(N-ethylacetamido)-lH-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (650 mg, 88%) as a yellow solid. LC-MS (ES, m/z): 351 [M+H]+.
Step 3: Synthesis of l-(3-bromophenyl)-4-(ethylamino)-lH-pyrazole-3-carboxarnide
Figure imgf000097_0002
[0234] A solution of l-(3-bromophenyl)-4-(N-ethylacetamido)-lH-pyrazole-3-carboxamide (650 mg, 1.851 mmol, 1.00 equiv) in methanol (10 mL) and hydrogen chloride (5 mL) was stirred overnight at room temperature. After completion, the solution was adjusted pH to 7 with aq. sodium hydroxide and then extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with dichloromethane/methanol (10: 1) to give the title compound (150 mg, 26%) as a yellow solid. LC-MS (ES, m/z): 309
[M+H]+.
Step 4: Synthesis of 4-(ethylamino)-l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000097_0003
[0235] Similar to the procedure as described in General Procedure G, l-(3-bromophenyl)-4- (ethylamino)-lH-pyrazole-3-carboxamide was reacted with (ii)-3-ethynyl-3-hydroxy-l- methylpyrrolidin-2-one to give the title compound (52.5 mg, 32%) as a white solid. LC-MS (ES, m/z): 368 [M+H]+. 1H NMR (300MHz, CD3OD): δ 7.85 (s, IH), 7.85-7.84 (m, IH), 7.73-7.69 (m, IH), 7.38-7.29 (m, IH), 7.28-7.26 (m, IH), 3.40-3.37 (m, 2H), 3.22-3.20 (m, 2H), 3.06-2.98 (m, 3H), 2.53-2.51 (m, IH), 2.46-2.45 (m,lH), 2.26-2.20 (m,3H).
Example 7
Synthesis of (R)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5- (trifluoromethyl)thiazole-4-carboxamide
Figure imgf000098_0001
Step 1 : Synthesis of ethyl 2-amino-5-iodothiazole-4-carboxylate
Figure imgf000098_0002
[0236] A solution of ethyl 2-amino-l ,3-thiazole-4-carboxylate (3 g, 17.421 mmol, 1.00 equiv) and N-iodosuccinimide (4.689 g, 20.841 mmol, 1.20 equiv) in acetonitrile (50 mL) was stirred for 2 h at 80 °C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (30: 1) to give the title compound (3.5 g, 67%) as a light yellow solid. LC-MS (ES, m/z): 299 [M+H]+. Step 2: Synthesis of ethyl 2-chloro-5-iodothiazole-4-carboxylate
Figure imgf000098_0003
[0237] A solution of ethyl 2-amino-5-iodothiazole-4-carboxylate (3 g, 10.067 mmol, 1.00 equiv), tert-butyl nitrite (1.24 g, 12.080 mmol, 1.20 equiv), cuprous chloride (1.19 g, 12.080 mmol, 1.20 equiv) in acetonitrile (50 mL) was stirred for 2 h at 80 °C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (40:1) to give the title compound (1.8 g, 56%) as a white solid. LC-MS (ES, m/z): 318 [M+H]+.
Step 3: Synthesis of ethyl 2-chloro-5-(trifluoromethyl)thiazole-4-carboxylate
Figure imgf000099_0001
[0238] A solution of ethyl 2-chloro-5-iodothiazole-4-carboxylate (1.05 g, 3.295 mmol, 1.00 equiv), methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (948.21 mg, 4.936 mmol, 1.50 equiv), cuprous iodide (938.74 mg, 4.929 mmol, 1.50 equiv) in NN-dimethylformamide (20 mL) was stirred for 12 h at 70 °C. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1:10) to give the title compound (260 mg, 32%) as colorless oil. LC-MS (ES, m/z): 260 [M+H]+.
Step 4: Synthesis of (ii)-ethyl 2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)- -(trifluoromethyl)thiazole-4-carboxylate
Figure imgf000099_0002
[0239] Similar to the procedure as described in General Procedure U, ethyl 2-chloro-5- (trifluoromethyl)thiazole-4-carboxylate was reacted with potassium (ii)-trifluoro(3-((3-hydroxy- l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the title compound (300 mg, 72%) as a yellow solid. LC-MS (ES, m/z): 439 [M+H]+.
Step 5: Synthesis of (ii)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5- (trifluoromethyl)thiazole-4-carboxamide
Figure imgf000100_0001
[0240] Similar to the procedure as described in General Procedure S, (ii)-ethyl 2-(3-((3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(trifluoromethyl)thiazole-4- carboxylate was reacted with ammonia to give the title compound (180 mg, 67%) as a white solid. LC-MS (ES, m/z): 410 [M+H]+. lH NMR (300MHz, CD3OD): δ 8.24 (s,lH), 8.11-8.08 (m, IH), 7.68-7.65 (m, IH), 7.58-7.54 (m, IH), 3.55-3.47 (m, 2H), 2.96-2.94 (s, 3H), 2.65-2.50 (m, IH), 2.38-2.32 (m, IH).
Example 8
Synthesis of (R)-l-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- (trifluoromethyl)-lH-pyrazole-3-carboxamide
Figure imgf000100_0002
Synthesis of ethyl l-(3-bromophenyl)-4-iodo-lH-pyrazole-3-carboxylate
Figure imgf000100_0003
[0241] Similar to the procedure as described in General Procedure C, ethyl 4-iodo-lH- pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to give the title compound (1.6g, 83%) as a white solid. LC-MS (ES, m/z): 421 [M+H]+.
Step 2: Synthesis of ethyl l-(3-bromophenyl)-4-(trifluoromethyl)-lH-pyrazole-3-carboxylate
Figure imgf000101_0001
[0242] A solution of ethyl l-(3-bromophenyl)-4-iodo-lH-pyrazole-3-carboxylate (500 mg, 1.188 mmol, 1.00 equiv), cuprous iodide (45 mg, 0.236 mmol, 0.20 equiv), methyl 2,2-difluoro- 2-(fluorosulfonyl)acetate (342 mg, 1.782 mmol, 1.50 equiv) in N,N-dimethylformamide (12 mL) was stirred for 14 h at 80 °C. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 :4) to give the title compound (300 mg, 70%) as a yellow solid. LC-MS (ES, m/z): 363 [M+H]+.
Step 3: Synthesis of ethyl l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-4-(trifluoromethyl)-lH-pyrazole-3-carboxylate
Figure imgf000101_0002
[0243] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-(trifluoromethyl)-lH-pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl-3- hydroxy-l-methylpyrrolidin-2-one to give the title compound (180 mg, 78% as a yellow solid. LC-MS (ES, m/z): 422 [M+H]+.
Step 4: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- (trifluoromethyl)-lH-pyrazole-3-carboxamide
Figure imgf000101_0003
[0244] Similar to the procedure as described in General Procedure S, ethyl l-(3-[2-[(3ii)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(trifluoromethyl)-lH-pyrazole-3- carboxylate was reacted with ammonia to give the title compound (53.7 mg, 32%) as a yellow solid. LC-MS (ES, m/z): 393 [M+H]+. 1H NMR (300MHz, CD3OD): δ 8.88 (s, IH), 8.07-8.06 (m, IH), 7.95-7.92 (m, IH), 7.57-7.50 (m, 2H), 3.51-3.47 (m, 2H), 2.94 (s, 3H), 2.64-2.56 (m, IH), 2.37-2.28 (m, IH).
Example 9
Synthesis of 4-(l,5-diniethyl-lH-pyrazol-4-yl)-l-(3-[2-[(3R)-3-hydroxy-l-niethyl-2- oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000102_0001
Step 1 : Synthesis of methyl 4-( 1 ,5 -dimethyl- lH-pyrazol-4-yl)-lH-pyrazole-3 -carboxylate
Figure imgf000102_0002
[0245] Similar to the procedure as described in General Procedure M, methyl 4-bromo-lH- pyrazole-3 -carboxylate was reacted withl,5-dimethyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-
2- yl)-lH-pyrazole to give the title compound (440 mg, 50%) as yellow oil. LC-MS (ES, m/z): 221 [M+H]+.
Step 2: Synthesis of methyl l-(3-bromophenyl)-4-(l,5-dimethyl-lH-pyrazol-4-yl)-lH-pyrazole-
3- carboxylate
Figure imgf000102_0003
[0246] Similar to the procedure as described in General Procedure C, methyl 4-(l,5-dimethyl- lH-pyrazol-4-yl)-lH-pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to give the title compound (300 mg, 40%) as light yellow oil. LC-MS (ES, m/z): 375 [M+H]+. Step 3: Synthesis of methyl 4-( 1 ,5 -dimethyl- lH-pyrazol-4-yl)-l -(3- [2- [(3R)-3 -hydroxy- 1- methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate
Figure imgf000103_0001
[0247] Similar to the procedure as described in General Procedure G, methyl l-(3- bromophenyl)-4-(l ,5-dimethyl-lH-pyrazol-4-yl)-lH-pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl-3-hydroxy-l-methylpyrrolidin-2-one to give the title compound (240 mg, 69%) as yellow oil. LC-MS (ES, m/z): 434 [M+H]+.
Step 4: Synthesis of 4-( 1 ,5 -dimethyl- lH-pyrazol-4-yl)-l -(3- [2- [(3R)-3 -hydroxy- l-methyl-2- oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxarnide
Figure imgf000103_0002
[0248] Similar to the procedure as described in General Procedure S, methyl 4-(l ,5-dimethyl- lH-pyrazol-4-yl)-l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-lH- pyrazole-3-carboxylate was reacted with ammonia to give the title compound (10.8 mg, 5%) as a white solid. LC-MS (ES, m/z): 419 [M+H]+. XH NMR (300MHz, CD3OD): δ 8.34 (s, 1H), 8.06 (m, 1H), 7.96-7.92 (m, 1H), 7.58 (s, 1H), 7.55-7.44 (m, 2H), 3.83 (s, 3H), 3.52-3.45 (m, 2H), 2.94 (s, 3H), 2.64-2.57 (m, 1H), 2.35-2.29 (m, 1H), 2.28 (s, 3H).
Example 10
Synthesis of (R)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(l- methyl-lH-pyrazol-4-ylamino)thiazole-4-carboxamide
Figure imgf000104_0001
Step 1: Synthesis of ethyl 2-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-5 - [( 1 -methyl- 1 H-pyrazol- -yl)amino] - 1 ,3 -thiazole-4-carboxylate
Figure imgf000104_0002
[0249] Under nitrogen a solution of ethyl 5-chloro-2-(3-[2-[(3R)-3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl]ethynyl]phenyl)-l,3-thiazole-4-carboxylate (207 mg, 0.512 mmol, 1.00 equiv), l-methyl-lH-pyrazol-4-amine (240 mg, 2.471 mmol, 4.829 equiv), 2nd RuPhos Pd recatalyst (58 mg, 0.075 mmol, 0.146 equiv), RuPhos (69 mg, 0.148 mmol, 0.289 equiv), cesium carbonate (160 mg, 0.491 mmol, 0.960 equiv) in 1,4-dioxane (10 mL) was stirred for 1 h at 80 °C. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluting with dichloromethane/methanol (30: 1) to give the title compound (190 mg, 82%) as a brown solid. LC-MS (ES, m/z): 466
[M+H]+.
Step 2: Synthesis of 2-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5- [(l-methyl-lH-pyrazol-4-yl)amino]-l,3-thiazole-4-carboxylic acid
Figure imgf000104_0003
[0250] Similar to the procedure as described in General Procedure J, ethyl 2-(3-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-[(l-methyl-lH-pyrazol-4-yl)amino]- l,3-thiazole-4-carboxylate was reacted with potassium hydroxide to give the title compound (150 mg, 86%) as light brown oil. LC-MS (ES, m/z): 438 [M+H]+.
Step 3: Synthesis of (ii)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(l- methyl-lH-pyrazol-4-ylamino)thiazole-4-carboxamide
Figure imgf000105_0001
[0251] Similar to the procedure as described in General Procedure B, 2-(3-[2-[(3R)-3-hydroxy- l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-[(l-methyl-lH-pyrazol-4-yl)amino]-l,3- thiazole-4-carboxylic acid was reacted with ammonium chloride to give the title compound (8.3 mg, 10%) as a light yellow solid. LC-MS (ES, m/z): 437 [M+H]+. 1H NMR (400MHz, CD3OD, ppm): δ 7.95 (s, 1H), 7.83-7.81 (m, 2H), 7.59 (s, 1H), 7.48-7.40 (m, 2H), 3.92 (s, 3H), 3.52-3.46 (m, 2H), 2.95 (s, 3H), 2.64-2.58 (m, 2H), 2.37-2.30 (m, 1H).
Example 11
Synthesis of (R)-5-(2-fluoro-5-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-
1 ,2,4-thiadiazole-3-carboxamide
Figure imgf000105_0002
Step 1 : Synthesis of (3ii)-3-[2-[3-(3-bromo-l ,2,4-thiadiazol-5-yl)-4-fluorophenyl]ethynyl]-3- hydroxy- 1 -methylpyrrolidin-2-one
Figure imgf000105_0003
[0252] Similar to the procedure as described in General Procedure X, 3-bromo-5-chloro-l ,2,4- thiadiazole was reacted with potassium (ii)-trifluoro(2-fluoro-5 -((3 -hydroxy- l-methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the title compound (300 mg, 15%) as a yellow solid. LC-MS (ES, m/z): 396 [M+H]+.
Step 2: Synthesis of 5-(2-fluoro-5-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-l ,2,4-thiadiazole-3-carbonitrile
Figure imgf000106_0001
[0253] Under nitrogen a solution of (3i?)-3-[2-[3-(3-bromo-l,2,4-thiadiazol-5-yl)-4- fluorophenyl]ethynyl]-3-hydroxy-l-methylpyrrolidin-2-one (300 mg, 0.757 mmol, 1.00 equiv) and CuCN (135 mg, 1.507 mmol, 1.99 equiv) in NMP (10 mL) was heated with microwave radiation at 150 °C for lh. After cooling the mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluting with dichloromethane/methanol (10: 1) to give the title compound (160 mg, 62%) as a brown oil. LC-MS (ES, m/z): 343 [M+H]+.
Step 3: Synthesis of (ii)-5-(2-fluoro-5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-l ,2,4-thiadiazole-3-carboxamide
Figure imgf000106_0002
[0254] Similar to the procedure as described in General Procedure D, 5-(2-fluoro-5-[2-[(3ii)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-l,2,4-thiadiazole-3-carbonitrile was reacted with hydrido(dimethylphosphinous acid-kp) [hydrogen bis(dimethylphosphinito- kp)]platinum(II) to give the title compound (15.7 mg, 9%) as a white solid. LC-MS (ES, m/z): 361 [M+H]+. 1H NMR (400MHz, CD3OD): δ 8.50-8.48 (m, 1H), 7.65-7.62 (m, 1H), 7.37-7.32 (m, 1H), 3.41-3.35 (m, 2H), 2.84 (s, 3H), 2.53-2.47 (m, 1H), 2.25-2.20 (m, 1H). Example 12
Synthesis of (R)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phi
methyl-lH-pyrazol-4-ylamino)-lH-pyrazole-3-carboxamide
Figure imgf000107_0001
Synthesis of methyl 4-bromo-l-(3-methoxyphenyl)-lH-pyrazole-3-carboxylate
Figure imgf000107_0002
[0255] Similar to the procedure as described in General Procedure C, methyl 4-bromo-lH- pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to give the title compound (2.1 g, 46%) as a white solid. LC-MS (ES, m/z): 311 [M+H]+.
Step 2: Synthesis of l-(3-methoxyphenyl)-4-[(l-methyl-lH-pyrazol-4-yl)amino]-lH-pyrazole-3- carboxylic acid
Figure imgf000107_0003
[0256] Under nitrogen a solution of ethyl 4-iodo-l-(3-methoxyphenyl)-lH-pyrazole-3- carboxylate (200 mg, 0.537 mmol, 1.00 equiv), 1 -methyl- lH-pyrazol-4-amine (160 mg, 1.647 mmol, 1.00 equiv), t-BuXPhos (20 mg, 0.047 mmol, 0.10 equiv), 3rd Generation t-BuXPhos precatalyst (40 mg, 0.050 mmol, 0.10 equiv), t-BuONa (80 mg, 0.832 mmol, 1.50 equiv) in 1,4- dioxane (12 mL) was irradiated with microwave radiation for 60 min at 90 °C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography eluting with dichloromethane/methanol (10: 1) to give the title compound (120 mg, 71 %) as a red oil. LC-MS (ES, m/z): 314 [M+H]+.
Step 3: Synthesis of l-(3-methoxyphenyl)-4-[(l-methyl-lH-pyrazol-4-yl)amino]-lH-pyrazole-3- carboxamide
Figure imgf000108_0001
[0257] Similar to the procedure as described in General Procedure B, l-(3-methoxyphenyl)-4- [(l-methyl-lH-pyrazol-4-yl)amino]-lH-pyrazole-3-carboxylic acid was reacted with ammonium chloride to give the title compound (400 mg, 89%) as a yellow solid. LC-MS (ES, m/z): 313
[M+H]+.
Step 4: Synthesis of 1 -(3 -hydroxyphenyl)-4-[(l -methyl- lH-pyrazol-4-yl)amino]-lH-pyrazole-3- carboxamide
Figure imgf000108_0002
[0258] To a solution of l-(3-methoxyphenyl)-4-[(l-methyl-lH-pyrazol-4-yl)amino]-lH- pyrazole-3-carboxamide (400 mg, 1.281 mmol, 1.00 equiv) in dichloromethane (30 mL) was added tribromoborane (962 mg, 3.840 mmol, 3.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched by methanol and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (10: 1) to give the title compound (310 mg, 81 %) as a yellow solid. LC-MS (ES, m/z): 299 [M+H]+.
Step 5: Synthesis of 3-[3-carbamoyl-4-[(l-methyl-lH-pyrazol-4-yl)amino]-lH-pyrazol-l- yl]phenyl trifluoromethanesulfonate
Figure imgf000109_0001
[0259] A solution of l-(3-hydroxyphenyl)-4-[(l-methyl-lH-pyrazol-4-yl)amino]-lH-pyrazole- 3-carboxamide (310 mg, 1.039 mmol, 1.00 equiv), 1 ,1,1-trifluoro-N-phenyl-N- (trifluoromethane)sulfonylmethanesulfonamide (740 mg, 2.071 mmol, 2.00 equiv) and triethylamine (3 mL) in dichloromethane (30 mL) was stirred for 14 h at room temperature. The pH of the solution was adjusted to 8 and the mixture was extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (5: 1) to give the title compound (280 mg, 63%) as a light yellow solid. LC-MS (ES, m/z): 431 [M+H]+.
Step 6: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(l- methyl- 1 H-pyrazol-4-ylamino)- 1 H-pyrazole-3-carboxamide
Figure imgf000109_0002
[0260] Similar to the procedure as described in General Procedure G, 3-[3-carbamoyl-4-[(l- methyl-lH-pyrazol-4-yl)amino]-lH-pyrazol-l-yl]phenyl trifluoromethanesulfonate was reacted with (ii)-3-ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (44.5 mg, 30%) as a light yellow solid.
[0261] LC-MS (ES, m/z): 420 [M+H]+.
[0262] 1H NMR (400MHz, CD3OD): δ 7.91-7.90 (m, IH), 7.87 (s, IH), 7.81-7.78 (m, IH), 7.56 (s, IH), 7.39-7.29 (m, 3H), 3.77 (s, 3H), 3.40-3.35 (m, 2H), 2.84 (s, 3H), 2.53-2.47 (m, IH), 2.26-2.19 (m,lH). Example 13
Synthesis of (R)-l-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phi
(pyridin-2-yl)-lH-pyrazole-3-carboxamide
Figure imgf000110_0001
nthesis of methyl l-(3-methoxyphenyl)-4-(pyridin-2-yl)-lH-pyrazole-3-carboxylate
Figure imgf000110_0002
[0263] Similar to the procedure as described in General Procedure Q, methyl 4-bromo-l-(3- methoxyphenyl)-lH-pyrazole-3-carboxylate was reacted with 2-(tributylstannyl)pyridine to give the title compound (500 mg, 72%) as a light yellow solid. LC-MS (ES, m/z): 310 [M+H]+. tep 2: Synthesis of l-(3-methoxyphenyl)-4-(pyridin-2-yl)-lH-pyrazole-3-carboxamide
Figure imgf000110_0003
[0264] Similar to the procedure as described in General Procedure S, methyl l-(3- methoxyphenyl)-4-(pyridin-2-yl)-lH-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (480 mg, 95%) as a light yellow solid. LC-MS (ES, m/z): 295 [M+H]+. tep 3: Synthesis of l-(3-hydroxyphenyl)-4-(pyridin-2-yl)-lH-pyrazole-3-carboxamide
Figure imgf000110_0004
[0265] To a solution of l -(3-methoxyphenyl)-4-(pyridin-2-yl)-lH-pyrazole-3-carboxamide (460 mg, 1.563 mmol, 1.00 equiv) in dichloromethane (50 mL) was added tribromoboron (1.2 g, 4.790 mmol, 3.00 equiv) dropwise with stirring at 0 °C. The resulting mixture was stirred for 2 h at 0 °C. and the reaction was quenched by methanol. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography eluting with dichloromethane/methanol (5: 1) to give the title compound (430 mg, 98%) as a light yellow solid. LC-MS (ES, m/z): 281 [M+H]+.
Step 4: Synthesis of 3-[3-carbamoyl-4-(pyridin-2-yl)-lH-pyrazol-l -yl]phenyl
trifluoromethanesulfonate
Figure imgf000111_0001
[0266] A solution of l-(3-hydroxyphenyl)-4-(pyridin-2-yl)-lH-pyrazole-3-carboxamide (420 mg, 1.498 mmol, 1.00 equiv), 1 , 1 ,1-trifluoro-N-phenyl-N-
(trifluoromethane)sulfonylmethanesulfonamide (1.067 g, 2.987 mmol, 2.00 equiv) and triethylamine (5 mL) in dichloromethane (50 mL) was stirred for 14 h at room temperature. The pH of the reaction solution was adjusted to 8 and the mixture was extracted with
dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with dichloromethane/methanol (10: 1 ) to give the title compound (580 mg, 94%) as a light yellow solid. LC-MS (ES, m/z): 413 [M+H]+.
Step 5: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- (pyridin-2-yl)-lH-pyrazole-3-carboxamide
Figure imgf000111_0002
[0267] Similar to the procedure as described in General Procedure G, 3-[3-carbamoyl-4- (pyridin-2-yl)-lH-pyrazol-l -yl]phenyl trifluoromethanesulfonate was reacted with (R)-3- ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (44.2 mg, 30%) as a white solid. LC-MS (ES, m/z): 402 [M+H]+. XH NMR (400MHz, CD3OD): δ 8.86 (s, IH), 8.61- 8.59 (m, IH), 8.13-8.12 (m, IH), 8.01-7.99 (m, 2H), 7.92-7.88 (m, IH), 7.58-7.50 (m, 2H), 7.40- 7.37 (m, IH), 3.53-3.49 (m,2H), 2.96 (s, 3H), 2.62-2.61(m, IH), 2.38-2.33 (m, IH).
Example 14
Synthesis of (R)-2-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(oxetan-
3-ylamino)thiazole-4-carboxaniide
Figure imgf000112_0001
Step 1 : Synthesis of ethyl 2-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-5-[(oxetan-3-yl)amino]-l,3-thiazole-4-carboxylate
Figure imgf000112_0002
[0268] Under nitrogen a solution of ethyl 5-chloro-2-(3-[2-[(3ii)-3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl]ethynyl]phenyl)-l,3-thiazole-4-carboxylate (207 mg, 0.512 mmol, 1.00 equiv), oxetan-3 -amine (187 mg, 2.558 mmol, 5.00 equiv), RuPhos (24 mg, 0.051 mmol, 0.101 equiv), RuPhos-PdCl-2nd G (40 mg, 0.051 mmol, 0.101 equiv), cesium carbonate (166 mg, 0.511 mmol, 1.00 equiv) in 1 ,4-dioxane (10 mL) was stirred for 1 h at 80 °C. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with dichloromethane/methanol (20: 1) to give the title compound (150 mg, 69%) as an off-white solid. LC-MS (ES, m/z): 442 [M+H]+.
Step 2: Synthesis of 2-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5- [(oxetan-3-yl)amino]-l,3-thiazole-4-carboxylic acid
Figure imgf000113_0001
[0269] Similar to the procedure as described in General Procedure J, ethyl 2-(3-[2-[(3ii)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-[(oxetan-3-yl)amino]-l,3-thiazole-4- carboxylate was reacted with potassium hydroxide to give the title compound (90 mg, 78%) as light brown oil. LC-MS (ES, m/z): 414 [M+H]+.
Step 3: Synthesis of (ii)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-
Figure imgf000113_0002
[0270] Similar to the procedure as described in General Procedure B, 2-(3-[2-[(3R)-3-hydroxy- l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-[(oxetan-3-yl)amino]-l ,3-thiazole-4- carboxylic acid was reacted with ammonium chloride to give the title compound (16.0 mg, 18%) as an off-white solid. LC-MS (ES, m/z): 413 [M+H]+. 1H NMR (400MHz, CD3OD): δ 7.95 (s, IH), 7.84-7.82 (m, IH), 7.47-7.43 (m, 2H), 5.08-4.98 (m, 2H), 4.73-4.68 (m, 3H), 3.50-3.34 (m, 2H), 2.96 (s, 3H), 2.65-2.58 (m, IH), 2.38-2.29 (m, IH).
Example 15
Synthesis of (R)-5-ethyl-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000113_0003
Step 1 : Synthesis of (ii)-ethyl 5-ethyl-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxylate
Figure imgf000114_0001
[0271] In a microwave vial was placed methyl 2-bromo-5-ethyl-thiazole-4-carboxylate (200.0 mg, 0.80 mmol), (3ii)-3-hydroxy-l -methyl-3-[2-[3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)phenyl]ethynyl]pyrrolidin-2-one (355.0 mg, 1.04 mmol), potassium acetate (141 mg, 1.44 mmol), sodium carbonate (144 mg, 1.36 mmol), and l ,l'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (53 mg, 0.064 mmol). Degassed ACN (8 mL) and water (2 mL) were added. The vial was capped, and the reaction mixture was stirred under microwave condition at 1 10°C for 30 min. The reaction mixture was poured into ethyl acetate and water, and then filtered through a pad of Celite. The organic layer was washed with water and brine, dried over Na2S04, filtered, and concentrated in vacuo. The crude material was purified by silica gel column chromatography eluted with heptane / ethyl acetate to give 183.3 mg (59.6%) of the desired product. LC-MS (ES, m/z): 385 [M+H]+.
Step 2: Synthesis of the title compound
Figure imgf000114_0002
[0272] Similar to the procedure as described in General Procedure S, (ii)-ethyl 5-ethyl-2-(3- ((3-hydroxy-l -methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxylate was treated with saturated ammonia in methanol to give the title compound (52.5 mg, 52.4%) as a solid. LC-
MS (ES, m/z): 370 [M+H]+. XH NMR (400 MHz, DMSO-J6) δ 8.07 - 8.05 (m, 1H), 8.00 - 7.94 (m, 1H), 7.92 (s, 1H), 7.55 - 7.49 (m, 3H), 6.49 (s, 1H), 3.37 - 3.34 (m, 3H), 3.30 - 3.29 (m, 1H), 2.80 (s, 3H), 2.48 - 2.42 (m, 1H), 2.24 - 2.15 (m, 1H), 1.27 (t, J = 7.5 Hz, 3H). Example 16
Synthesis of (R)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phi
dihydro-5H-imidazo[5,l-c][l,4]oxazine-3-carboxamide
Figure imgf000115_0001
Step 1 : Synthesis of tert-butyl 3-[methoxy(methyl)carbamoyl]morpholine-4-carboxylate
Figure imgf000115_0002
[0273] Similar to the procedure as described in General Procedure B, 4-[(tert- butoxy)carbonyl]morpholine-3-carboxylic acid was reacted with methoxy(methyl)amine hydrochloride to give the title compound (3.5 g, 59%) as a white solid. LC-MS (ES, m/z): 275 [M+H]+.
Step 2: Synthesis of tert-butyl 3-[(3-bromophenyl)carbonyl]morpholine-4-carboxylate
Figure imgf000115_0003
[0274] n-Butyllithium (8 mL, 2M in THF, 1.10 equiv) was added dropwise into a solution of 1 ,3-dibromobenzene (3.44 g, 14.58 mmol, 1.00 equiv) in tetrahydrofuran (200 mL) under nitrogen. The resulting solution was stirred for 2 h at -78°C and then tert-butyl 3- [methoxy(methyl)carbamoyl]morpholine-4-carboxylate (4.00 g, 14.58 mmol, 1.00 equiv) in tetrahydrofuran (100 mL) was added dropwise at -78°C. The resulting solution was stirred for another 3 h at -78°C. The reaction was then quenched by the addition of aq. saturation ammonium chloride and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1 :3) to give the title compound (2.0 g, 37%) as a white solid. LC-MS (ES, m/z): 370 [M+H]+.
Step 3: Synthesis of 3-(3-bromophenyl)-4H,6H,7H-imidazo[4,3-c][l,4]oxazine
Figure imgf000116_0001
[0275] Under nitrogen a solution of tert-butyl 3-[(3-bromophenyl)carbonyl]morpholine-4- carboxylate (2 g, 5.40 mmol, 1.00 equiv) in formamide (20 niL) and acetic acid (2 niL) was irradiated with microwave radiation for 25 min at 170°C. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1 : 10) to give the title compound (720 mg, 48%) as a yellow solid. LC-MS (ES, m/z): 279 [M+H]+.
Step 4: Synthesis of 3-(3-bromophenyl)-l-iodo-4H,6H,7H-imidazo[4,3-c][l ,4]oxazine
Figure imgf000116_0002
[0276] Under nitrogen to a solution of 3-(3-bromophenyl)-4H,6H,7H-imidazo[4,3- c][l ,4]oxazine (500 mg, 1.79 mmol, 1.00 equiv) in tetrahydrofuran (20 mL) was added lithium diisopropylamide (0.9 mL, 2M in THF, 1.00 equiv). The resulting solution was stirred for 2 h at - 78°C and then iodide (454 mg, 1.79 mmol, 1.00 equiv) in tetrahydrofuran (5 mL) was added. The resulting solution was stirred for another 1 h at -78°C. The reaction was then quenched by the addition of aq. saturation ammonium chloride and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with ethyl
acetate/petroleum ether (1 : 10) to give the title compound (500 mg, 69%) as a light yellow solid. LC-MS (ES, m/z): 405 [M+H]+.
Step 5: Synthesis of methyl 3-(3-bromophenyl)-4H,6H,7H-imidazo[4,3-c][l ,4]oxazine-l- carboxylate
Figure imgf000116_0003
[0277] Similar to the procedure as described in General Procedure O, 3-(3-bromophenyl)-l- iodo-4H,6H,7H-imidazo[4,3-c][l,4]oxazine was reacted with carbon monoxide to give the title compound (210 mg, 56%) as a yellow solid. LC-MS (ES, m/z): 337 [M+H]+.
Step 6: Synthesis of methyl 3-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- l]ethynyl]phenyl)-4H,6H,7H-imidazo[4,3-c][l,4]oxazine-l-carboxylate
Figure imgf000117_0001
[0278] Similar to the procedure as described in General Procedure G, methyl 3-(3- bromophenyl)-4H,6H,7H-imidazo[4,3-c][l ,4]oxazine-l-carboxylate was reacted with (R)-3- ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (90 mg, 38%) as a yellow solid. LC-MS (ES, m/z): 396 [M+H]+.
Step 7: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-6,8- dih dro-5H-imidazo[5 , 1 -c] [1 ,4]oxazine-3-carboxamide
Figure imgf000117_0002
[0279] Similar to the procedure as described in General Procedure S, methyl 3-(3-[2-[(3ii)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4H,6H,7H-imidazo[4,3-c] [l,4]oxazine- 1-carboxylate was reacted with ammonia to give the title compound (38.4 mg, 50%) as an off- white solid. LC-MS (ES, m/z): 381 [M+H]+. XH NMR (300MHz, CD3OD): δ 7.69 (s, 1H ), 7.54 (d, J = 7.5Hz, 1H), 7.41-7.33 (m, 2H), 5.06 (s, 2H), 4.49 (t, / = 5.4Hz, 2H), 4.04 (t, / = 5.1Hz, 2H), 3.48-3.44 (m, 2H), 2.92 (s, 3H), 2.61-2.53 (m, 1H), 2.34-2.25 (m, 1H).
Example 17
Synthesis of (R)-4-(cyclopropanecarboxamido)-l-(3-((3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000118_0001
Synthesis of ethyl l-(3-bromophenyl)-4-cyclopropaneamido-lH-pyrazole-3-carboxylate
Figure imgf000118_0002
[0280] To a stirred solution of ethyl 4-amino-l-(3-bromophenyl)-lH-pyrazole-3-carboxylate (500 mg, 1.612 mmol, 1.00 equiv), triethylamine (323 mg, 3.192 mmol, 1.98 equiv) in dichloromethane (20 mL, 314.601 mmol, 195.15 equiv) was added cyclopropanecarbonyl chloride (254 mg, 2.430 mmol, 1.507 equiv) dropwise at room temperature. The mixture was stirred for 2h at room temperature. After completion, the resulting solution was concentrated under vacuum and the residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). This resulted in the title compound (470 mg, 77%) as an off-white solid. LC-MS (ES, m/z): 378 [M+H]+.
Step 2: Synthesis of ethyl 4-cyclopropaneamido-l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate
Figure imgf000118_0003
[0281] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-cyclopropaneamido-lH-pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl- 3-hydroxy-l-methylpyrrolidin-2-one to give the title compound (185 mg, 80%) as an off-white solid. LC-MS (ES, m/z): 437 [M+H]+.
Step 3: Synthesis of (ii)-4-(cyclopropanecarboxamido)-l-(3-((3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000119_0001
[0282] Similar to the procedure as described in General Procedure S, ethyl 4- cyclopropaneamido-l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)- lH-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (77.2 mg, 49%) as a white solid. LC-MS (ES, m/z): 408 [M+H]+. 1H NMR (300MHz, CD3OD): δ 8.70 (s, 1H), 7.96 (s, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.51-7.41 (m, 2H), 3.49-3.44 (m, 2H), 2.92 (s, 3H), 2.59- 2.49 (m, 1H), 2.39-2.22 (m, 1H), 1.85-1.75 (m, 1H), 0.99-0.91 (m, 4H).
Example 18
Synthesis of (R)-4-acetamido-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000119_0002
te 1 : Synthesis of ethyl 4-acetamido-l-( -bromophenyl)-lH-pyrazole-3-carboxylate
Figure imgf000119_0003
[0283] A solution of ethyl 4-amino-l-(3-bromophenyl)-lH-pyrazole-3-carboxylate (500 mg, 1.612 mmol, 1.00 equiv) and triethylamine (329 mg, 3.251 mmol, 2.017 equiv) in
dichloromethane (20 mL) was stirred for 12 hours at room temperature. The resulting reaction mixture was concentrated under vacuum and the residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 :3). This resulted in the title compound (450 mg, 79%) as an off-white solid. LC-MS (ES, m/z): 352 [M+H]+. Step 2: Synthesis of (ii)-ethyl 4-acetamido-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-lH-pyrazole-3-carboxylate
Figure imgf000120_0001
[0284] Similar to the procedure as described in General Procedure G, ethyl 4-acetamido-l-(3- bromophenyl)-lH-pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl-3-hydroxy-l- methylpyrrolidin-2-one to give the title compound (170 mg, 73%) as an off-white solid. LC-MS (ES, m/z): 411 [M+H]+.
Step 3: Synthesis of (ii)-4-acetamido-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000120_0002
[0285] Similar to the procedure as described in General Procedure S, (ii)-ethyl 4-acetamido-l- (3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (93.7 mg, 59%) as a white solid. LC-MS (ES, m/z): 382 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.77 (s, IH), 7.99 (s, IH), 7.88-7.86 (m, IH), 7.54-7.45 (m, 2H), 3.55-3.46 (m, 2H), 2.95 (s, 3H), 2.65-2.59 (m, IH), 2.37-2.30 (m, IH), 2.27 (s, 3H).
Example 19
Synthesis of (ii)-4-amino-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-lH- pyrazole-3-carboxamide
Figure imgf000120_0003
Step 1 : Synthesis of ethyl l-(3-bromophenyl)-4-nitro-lH-pyrazole-3-carboxylate
Figure imgf000121_0001
[0286] Similar to the procedure as described in General Procedure C, ethyl 4-nitro-lH- pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to give the title compound (11 g, 60%) as an off-white solid. LC-MS (ES, m/z): 340 [M+H]+.
Step 2: Synthesis of ethyl 4-amino-l-(3-bromophenyl)-lH-pyrazole-3-carboxylate
Figure imgf000121_0002
[0287] To a reaction mixture of ethyl l-(3-bromophenyl)-4-nitro-lH-pyrazole-3-carboxylate (6.800 g, 19.992 mmol, 1.00 equiv) and Raney-Ni (3.0 g) in ethanol (50 mL) was added hydrazine hydrate (2.16 g, 43.148 mmol, 2.00 equiv) dropwise with stirring at room temperature for 1 hour. The resulting reaction mixture was diluted with 200 mL of ethanol and 200 mL of dichloromethane. The solids were filtered out and the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl
acetate/petroleum ether (1 : 1) to afford ethyl 4-amino-l-(3-bromophenyl)-lH-pyrazole-3- carboxylate (5.5 g, 89%) as an off-white solid. LC-MS (ES, m z): 310 [M+H]+.
Step 3: Synthesis of ethyl 4-amino-l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate
Figure imgf000121_0003
[0288] Similar to the procedure as described in General Procedure G, ethyl 4-amino-l-(3- bromophenyl)-lH-pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl-3-hydroxy-l- methylpyrrolidin-2-one to give the title compound (185 mg, 78%) as an off-white solid. LC-MS (ES, m/z): 369 [M+H]+.
Step 4: Synthesis of 4-amino-l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000122_0001
[0289] Similar to the procedure as described in General Procedure S, ethyl 4-amino-l-(3-[2- [(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (52.8 mg, 31 ) as an off-white solid. LC-MS (ES, m/z): 340 [M+H]+. lH NMR (300MHz, CD3OD): δ 7.91 (s, 1H), 7.80-7.77 (m, 2H), 7.48- 7.37 (m, 2H), 3.51-3.46 (m, 2H), 2.94 (s, 3H), 2.64-2.56 (m, 1H), 2.37-2.27 (m, 1H).
Examples 20 and 21
Synthesis of 4-((lS,2R)-2-fluorocyclopropanecarboxamido)-l-(3-(((R)-3-hydroxy-l-niethyl- 2-oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide and 4-((lR,2S)-2- fluorocyclopropanecarboxamido)-l-(3-(((R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
(Isolated as single-unknown stereoisomers and assigned as (SJl) or (R.S) arbitrarily)
Figure imgf000122_0002
Step 1 : Synthesis of ethyl l-(3-bromophenyl)-4-[(2-fluorocyclopropane)amido]-lH-pyrazole-3- carboxylate
Figure imgf000123_0001
[0290] Similar to the procedure as described in General Procedure B, ethyl 4-amino-l-(3- bromophenyl)-lH-pyrazole-3-carboxylate was reacted with (trans)-2-fluorocyclopropane-l- carboxylic acid to give the title compound (678 mg, 88%) as a yellow oil. LC-MS (ES, m/z): 396 [M+H]+.
Step 2: Synthesis of ethyl 4-[(trans-2-fluorocyclopropane)amido]-l-(3-[2-[(3R)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)- -pyrazole-3-carboxylate
Figure imgf000123_0002
[0291] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-[(2-fluorocyclopropane)amido]-lH-pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl-3-hydroxy-l-methylpyrrolidin-2-one to give the title compound (530 mg, 68%) as an off-white solid. LC-MS (ES, m z): 455 [M+H]+.
Step 3: Synthesis of 4-((l^,2ii)-2-fluorocyclopropanecarboxarnido)-l-(3-(((ii)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide and 4-((ϋ?,25)-2- fluorocyclopropanecarboxamido)-l-(3-(((ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000123_0003
[0292] Similar to the procedure as described in General Procedure S, ethyl 4-[(2- fluorocyclopropane)amido]-l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate was reacted with ammonia to give 91.0 mg (18%) of the first-eluting (here called lS^ii-isomer) isomer as a white solid and 91.4 mg (18%) of the second-eluting (here called lR,2S-isomer) isomer as a white solid. The stereochemistry of both isomers was arbitrarily assigned. The first-eluting isomer: t = 9.57 min (Chiralcel OJ-H, 0.46*25cm, Hex:IPA=50:50, 1 ml/min); the second-eluting isomer: t = 13.89 min (Chiralcel OJ-H, 0.46*25cm, Hex:IPA=50:50, 1 ml/min); Both isomers showed identical LC-MS and 1H NMR as shown below.
[0293] LC-MS (ES, m/z): 426 [M+H]+. 1H NMR (300MHz, CD3OD): δ 8.85 (s, IH), 7.96 (s, IH), 7.85-7.81 (m, IH), 7.52-7.42 (m, 2H), 4.97-4.75 (m, IH), 3.51-3.47 (m, 2H), 2.94 (s, 3H), 2.64-2.56 (m, IH), 2.40-2.30 (m, 2H), 1.62-1.47 (m,lH), 1.42-1.31 (m, IH).
Example 22
Synthesis of 4-((lR,2R)-2-fluorocyclopropanecarboxamido)-l-(3-(((R)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000124_0001
Step 1: Synthesis of ethyl l-(3-bromophenyl)-4-[[(lR,2R)-2-fluorocyclopropane]amido]-lH- pyrazole-3-carboxylate
Figure imgf000124_0002
[0294] Similar to the procedure as described in General Procedure B, ethyl 4-amino-l-(3- bromophenyl)-lH-pyrazole-3-carboxylate was reacted with (lR,2R)-2-fluorocyclopropane-l- carboxylic acid to give the title compound (350 mg, 91%) as a yellow oil. LC-MS (ES, m/z): 396 [M+H]+.
Step 2: Synthesis of ethyl 4-[[(lR,2R)-2-fluorocyclopropane]amido]-l-(3-[2-[(3R)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate
Figure imgf000125_0001
[0295] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4- [[( 1 R,2R)-2-fluorocyclopropane] amido] - 1 H-pyrazole-3 -carboxylate was reacted with (ii)-3-ethynyl-3-hydroxy-l-methylpyrrolidin-2-one to give the title compound (273 mg, 68%) as yellow oil. LC-MS (ES, m/z): 455 [M+H]+.
Step 3: Synthesis of 4-((lR,2R)-2-fluorocyclopropanecarboxamido)-l-(3-(((R)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-lH- razole-3-carboxamide
Figure imgf000125_0002
[0296] Similar to the procedure as described in General Procedure S, ethyl 4-[[(lR,2R)-2- fluorocyclopropane]amido]-l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (107.6 mg, 42%) as a white solid. LC-MS (ES, m/z): 426 [M+H]+. XH NMR
(300MHz, CD3OD): δ 8.79 (s, IH), 8.00 (s, IH), 7.88 (d, / = 7.5Hz, IH), 7.54-7.43 (m, 2H), 5.01-4.78 (m, IH), 3.52-3.47 (m, 2H), 2.94 (s, 3H), 2.64-2.57 (m, IH), 2.37-2.28 (m, IH), 2.10- 2.04 (m, IH), 1.79-1.70 (m, IH), 1.30-1.23 (m, IH).
Example 23
Synthesis of 4-((lS,2S)-2-fluorocyclopropanecarboxamido)-l-(3-(((R)-3-hydroxy-l-niethyl- 2-oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000125_0003
Step 1: Synthesis of ethyl l-(3-bromophenyl)-4-[[(lS,2S)-2-fluorocyclopropane]amido]-lH- pyrazole-3 -carboxylate
Figure imgf000126_0001
[0297] Similar to the procedure as described in General Procedure B, ethyl 4-amino-l-(3- bromophenyl)-lH-pyrazole-3-carboxylate was reacted with (lS,2S)-2-fluorocyclopropane-l- carboxylic acid to give the title compound (334 mg, 87%) as yellow oil. LC-MS (ES, m/z): 396 [M+H]+.
Step 2: Synthesis of ethyl 4-[[(lS,2S)-2-fluorocyclopropane]amido]-l-(3-[2-[(3R)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate
Figure imgf000126_0002
[0298] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4- [[( 1 S ,2S )-2-fluorocyclopropane] amido] - 1 H-pyrazole-3 -carboxylate was reacted with (J?)-3-ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (239 mg, 62%) as a yellow oil. LC-MS (ES, m z): 455 [M+H]+.
Step 3: Synthesis of 4-((lS,2S)-2-fluorocyclopropanecarboxamido)-l-(3-(((R)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000126_0003
[0299] Similar to the procedure as described in General Procedure S, ethyl 4-[[(lS,2S)-2- fluorocyclopropane]amido]-l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (39.3 mg, 18%) as a white solid. LC-MS (ES, m/z): 426 [M+H]+. 1H NMR (300MHz, CD3OD): δ 8.79 (s, IH), 8.00 (s, IH), 7.88 (d, J = 7.5Hz, IH), 7.54 - 7.44 (m, 2H), 5.03-4.78 (m, IH), 3.52-3.47 (m, 2H), 2.84(s, 3H), 2.64-2.57 (m, IH), 2.37-2.28 (m, IH), 2.10-2.05 (m, IH), 1.85-1.71 (m, IH), 1.30-1.23 (m,lH).
Example 24
Synthesis of (R)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phi
propionamido-lH-pyrazole-3-carboxamide
Figure imgf000127_0001
Synthesis of ethyl l-(3-bromophenyl)-4-propanamido-lH-pyrazole-3-carboxylate
Figure imgf000127_0002
[0300] A solution of ethyl 4-amino-l-(3-bromophenyl)-lH-pyrazole-3-carboxylate (200 mg, 0.645 mmol, 1.00 equiv), propionyl chloride (0.06 mL, 0.648 mmol, 3.35 equiv), and
triethylamine (0.06 mL, 0.432 mmol, 2.23 equiv) in dichloromethane (5 mL) was stirred for 30 min at room temperature. The resulting mixture was concentrated under vacuum and the residue was purified by a silica gel column chromatography and eluted with dichloromethane/methanol (10: 1) to give the title compound (200 mg, 85%) as a white solid. LC-MS (ES, m/z): 366
[M+H]+.
Step 2: Synthesis of ethyl l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-4-propanamido-lH-pyrazole-3-carboxylate
Figure imgf000128_0001
[0301] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-propanamido-lH-pyrazole-3-carboxylate was reacted with (J?)-3-ethynyl-3- hydroxy-l-methylpyrrolidin-2-one to give the title compound (160 mg, 69%) as a brown solid. LC-MS (ES, m/z): 425 [M+H]+.
Step 3: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- propionamido- 1 H-pyrazole-3 -carboxamide
Figure imgf000128_0002
[0302] Similar to the procedure as described in General Procedure S, ethyl l-(3-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-propanamido-lH-pyrazole-3- carboxylate was reacted with ammonia to give the title compound (51.6 mg, 37%) as an off- white solid. LC-MS (ES, m/z): 396 [M+H]+. lH NMR (400MHz, CD3OD): δ 8.78-7.79 (m, IH), 8.00 (s, IH), 7.86-7.88 (m, IH), 7.45-7.54 (m, 2H), 3.47-3.53 (m, 2H), 2.95 (s, 3H), 2.64-2.59 (m, IH), 2.51-2.47 (m, 2H), 2.37-2.30 (m, IH), 2.31 (m, 3H).
Examples 25 and 26
Synthesis of 4-((R)-2,2-difluorocyclopropanecarboxamido)-l-(3-(((R)-3-hydroxy-l-niethyl- 2-oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide and 4-((S)-2,2- difluorocyclopropanecarboxamido)-l-(3-(((R)-3-hydroxy-l-niethyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
(Isolated as single-unknown stereoisomers and assigned as (R) or (S) arbitrarily)
Figure imgf000129_0001
Step 1: Synthesis of ethyl l-(3-bromophenyl)-4-[(2,2-difluorocyclopropane)amido]-lH-pyrazole- 3-carboxylate
Figure imgf000129_0002
[0303] Similar to the procedure as described in General Procedure B, ethyl 4-amino-l-(3- bromophenyl)-lH-pyrazole-3-carboxylate was reacted with 2,2-difluorocyclopropane-l- carboxylic acid to give the title compound (650 mg, 79%) as an off-white solid. LC-MS (ES, m/z): 414 [M+H]+.
Step 2: Synthesis of racemic ethyl 4-[(2,2-difluorocyclopropane)amido]-l-(3-[2-[(3ii)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate
Figure imgf000129_0003
[0304] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-[(2,2-difluorocyclopropane)amido]-lH-pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl-3-hydroxy-l-methylpyrrolidin-2-one to give the title compound (400 mg, 85%) as an off-white solid. LC-MS (ES, m/z): 473 [M+H]+.
Step 3: Synthesis of 4-((ii)-2,2-difluorocyclopropanecarboxamido)-l-(3-(((ii)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide and 4-((5')-2,2- difluorocyclopropanecarboxamido)-l-(3-(((ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000130_0001
[0305] Similar to the procedure as described in General Procedure S, ethyl 4-[(2,2- difluorocyclopropane)amido]-l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate was reacted with ammonia to give 54.1 mg (29%) of first-eluting (here called (lii)-isomer as a white solid and 39.3 mg (21 %) of second-eluting (here called (^-isomer as a white solid. The stereochemistry of both isomers was arbitrarily assigned.
[0306] The first-eluting isomer: tR = 16.40 min ((R,R)WHELK-01, 0.45*25cm,
Hex(0.2%IPA):EtOH=65:35, 1 ml/min); the second-eluting isomer: tR = 18.55 min
((R,R)WHELK-01, 0.45*25cm, Hex(0.2%IPA):EtOH=65:35, 1 ml/min); Both isomers showed identical LC-MS and XH NMR as shown below.
[0307] LC-MS (ES, m/z): 444 [M+H]+. lH NMR (300MHz, CD3OD): δ 8.76 (s, 1H), 7.97 (s, 1H), 7.85-7.82 (d, J = 8.7 Hz, 1H), 7.51-7.41 (m, 2H), 3.53-3.41 (m, 2H), 2.94 (s, 3H), 2.90-2.87 (m, 1H), 2.62-2.54 (m, 1H), 2.35-2.26 (m, 1H), 2.16-2.04 (m, 1H), 1.94-1.84 (m, 1H).
Example 27
Synthesis of (R)-4-(l-fluorocyclopropanecarboxamido)-l-(3-((3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000130_0002
Step 1 : Synthesis of ethyl l-(3-bromophenyl)-4-[(l-fluorocyclopropane)amido]-lH-pyrazole-3- carbox late
Figure imgf000130_0003
[0308] Similar to the procedure as described in General Procedure B, ethyl 4-amino-l-(3- bromophenyl)-lH-pyrazole-3-carboxylate was reacted with l-fluorocyclopropane-l-carboxylic acid to give the title compound (390 mg, 82%) as a white solid. LC-MS (ES, m/z): 396 [M+H]+. Step 2: Synthesis of (ii)-ethyl 4-(l-fluorocyclopropanecarboxamido)-l-(3-((3-hydroxy-l-methyl- -oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxylate
Figure imgf000131_0001
[0309] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-[(l-fluorocyclopropane)amido]-lH-pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl-3-hydroxy-l-methylpyrrolidin-2-one to give the title compound (408 mg, 91%) as a light brown solid. LC-MS (ES, m/z): 455 [M+H]+.
Step 3: Synthesis of (ii)-ethyl 4-(l-fluorocyclopropanecarboxamido)-l-(3-((3-hydroxy-l-methyl- -oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxylate
Figure imgf000131_0002
Sim to the procedure as described in General Procedure S, ethyl 4-[(l- fluorocyclopropane)amido]-l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (56 mg, 16%) as a white solid. LC-MS (ES, m/z): 426 [M+H]+. XH NMR (400MHz, CD3OD): δ 8.83 (s, IH), 8.02 (s, IH), 7.90 (d, / = 1.2 Hz, IH), 7.89-7.51 (m, IH), 7.47 (m, IH), 3.53-3.47 (m, 2H), 2.95 (s, 3H), 2.65-2.59 (m, IH), 2.37-2.30 (m, IH), 1.53-1.51 (m, IH), 1.49- 1.42 (m, 3H).
Example 28
Synthesis of (R)-4-(3,3-dimethylureido)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000132_0001
Step 1 : Synthesis of ethyl l-(3-bromophenyl)-4-[(dimethylcarbamoyl)amino]-lH-pyrazole-3- carboxylate
Figure imgf000132_0002
[0311] A solution of ethyl 4-amino-l-(3-bromophenyl)-lH-pyrazole-3-carboxylate (200 mg, 0.645 mmol, 1.00 equiv), NN-dimethylcarbamoyl chloride (84 mg, 0.781 mmol, 1.20 equiv), and triethylamine (131 mg, 1.295 mmol, 2.00 equiv) in dichloromethane (10 mL) was stirred for 2 h at room temperature. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography and eluted with dichloromethane/methanol (10: 1) to give the title compound (180 mg, 62%) as a yellow solid. LC-MS (ES, m/z): 381
[M+H]+.
Step 2: Synthesis of ethyl 4-[(dimethylcarbamoyl)amino]-l-(3-[2-[(3R)-3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate
Figure imgf000132_0003
[0312] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-[(dimethylcarbamoyl)amino]-lH-pyrazole-3-carboxylate was reacted with (R)- 3-ethynyl-3-hydroxy-l-methylpyrrolidin-2-one to give the title compound (90 mg, 62%) as a yellow solid. LC-MS (ES, m/z): 440 [M+H]+.
Step 3: Synthesis of (ii)-4-(3,3-dimethylureido)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000133_0001
[0313] Similar to the procedure as described in General Procedure S, ethyl 4- [(dimethylcarbamoyl)amino]-l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-lH-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (42.8 mg, 50%) as a yellow solid. LC-MS (ES, m/z): 411 [M+H]+. 1H NMR
(300MHz, DMSO-Je): δ 9.27 (s, 1H), 8.62 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.94 - 7.91 (m, 1H), 7.67 (s, 1H), 7.54 - 7.49 (m, 1H), 7.39 - 7.36 (d, / = 7.8 Hz, 1H), 6.513 (s, 1H), 3.38 - 3.32 (m, 2H), 2.94 (s, 6H), 2.80 (s, 3H), 2.45 - 2.41 (m, 1H), 2.23 - 2.14 (m, 1H).
Example 29
Synthesis of (R)-l-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(2- methoxyacetamido)-lH-pyrazole-3-carboxamide
Figure imgf000133_0002
Step 1 : Synthesis of ethyl l-(3-bromophenyl)-4-(2-methoxyacetamido)-lH-pyrazole-3- carboxylate
Figure imgf000133_0003
[0314] Similar to the procedure as described in General Procedure B, ethyl 4-amino-l-(3- bromophenyl)-lH-pyrazole-3-carboxylate was reacted with 2-methoxyacetic acid to give the title compound (200 mg, 46%) as a yellow solid. LC-MS (ES, m/z): 382 [M+H]+. Step 2: Synthesis of ethyl l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-4-(2-methoxyacetamido)-lH-pyrazole-3-carboxylate
Figure imgf000134_0001
[0315] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-(2-methoxyacetamido)-lH-pyrazole-3-carboxylate was reacted with (R)-3- ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (200 mg, 52%) as a yellow solid. LC-MS (ES, m/z): 441 [M+H]+.
Step 3: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(2- methoxyacetamido)- 1 H-pyrazole-3-carboxamide
Figure imgf000134_0002
[0316] Similar to the procedure as described in General Procedure S, ethyl l-(3-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(2-methoxyacetamido)-lH-pyrazole- 3-carboxylate was reacted with ammonia to give the title compound (54.1 mg, 28%) as a light yellow solid. LC-MS (ES, m/z): 412 [M+H]+. 1H NMR (300MHz, DMSO-J6): δ 10.37 (s, 1H), 8.90 (s, 1H), 8.10 (s, 1H), 8.04 (s, 1H), 8.00 - 7.96 (m, 1H), 7.69 (s, 1H), 7.56 - 7.50 (m, 1H), 7.41 - 7.39 (d, / = 7.5 Hz, 1H), 6.51 (s, 1H), 4.06 (s, 2H), 3.43 (s, 3H), 3.38 -3.30 (m, 2H), 2.80 (s, 3H), 2.45 - 2.41 (m, 1H), 2.24 -2.15 (m, 1H).
Example 30
Synthesis of (R)-l-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- isobutyramido-lH-pyrazole-3-carboxaniide
Figure imgf000135_0001
Step 1 : Synthesis of ethyl l-(3-bromophenyl)-4-(2-methylpropanamido)-lH-pyrazole-3- carboxylate
Figure imgf000135_0002
[0317] A solution of ethyl 4-amino-l-(3-bromophenyl)-lH-pyrazole-3-carboxylate (200 mg, 0.645 mmol, 1.00 equiv), isobutyryl chloride (83 mg, 0.779 mmol, 1.21 equiv), and triethylamine (130 mg, 1.285 mmol, 1.99 equiv) in dichloromethane (15 mL) was stirred for 30 min at room temperature. The resulting solution was concentrated under vacuum and the residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 : 10). This resulted in the title compound (120 mg, 49%) as a yellow solid. LC-MS (ES, m/z): 380 [M+H]+. Step 2: Synthesis of ethyl l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-4-(2-methylpropanamido)-lH-pyrazole-3-carboxylate
Figure imgf000135_0003
[0318] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-(2-methylpropanamido)-lH-pyrazole-3-carboxylate was reacted with (R)-3- ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (120 mg, 87%) as yellow oil. LC-MS (ES, m/z): 439 [M+H]+.
Step 3: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- isobutyramido-lH-pyrazole-3-carboxamide
Figure imgf000136_0001
[0319] Similar to the procedure as described in General Procedure S, ethyl l-(3-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(2-methylpropanamido)-lH-pyrazole- 3-carboxylate was reacted with ammonia to give the title compound (57.5 mg, 62%) as a white solid. LC-MS (ES, m/z): 410 [M+H]+. XH NMR (300MHz, CD3OD): δ 8.77 (s, 1H), 7.99 (s, 1H) , 7.88 - 7.85 (m, 1H), 7.54 - 7.43 (m, 2H), 3.55 - 3.47 (m, 2H), 2.73 (s, 3H), 2.73 - 2.56 (m, 2H), 2.37 - 2.28 (m, 1H), 1.25 (s, 6H).
Example 31
Synthesis of (R)-4-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-l-niethyl- lH-iniidazole-2-carboxaniide
Figure imgf000136_0002
Step 1 : Synthesis of (R)-methyl 4-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-l-methyl-lH-imidazole-2-carboxylate
Figure imgf000136_0003
[0320] A solution of (3^)-3-hydroxy-l-methyl-3-[2-[3-(4,4,5,5-tetramethyl-l ,3,2- dioxaborolan-2-yl)phenyl]ethynyl]pyrrolidin-2-one (73 mg., 0.21 mmol), methyl 4-bromo-l- methyl-lh-imidazole-2-carboxylate (40 mg, 0.18 mmol), cesium fluoride (54 mg, 0.36 mmol) and bis(triphenylphosphine)palladium(II) dichloride (12.5 mg, 0.018 mmol) in ethanol (1.5 mL) and water (1.0 mL) was degassed. The reaction mixture was heated in microwave at 100 °C for 45 min. The reaction was filtered through celite. The crude product was purified by flash chromatography (MeOH/DCM) then submitted for rHPLC to give product (27 mg, 42.7%). [0321] LC-MS (ES, m/z): 354 [M+H]+.
Step 2: Synthesis of (R)-methyl 4-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-l-methyl-lH-imidazole-2-carboxylate
Figure imgf000137_0001
[0322] Similar to the procedure as described in General Procedure S (ii)-methyl 4-(3-((3- hydroxy- 1 -methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)- 1 -methyl- 1 H-imidazole-2-carboxylate was reacted with ammonia to give the title compound (13.4 mg, 42.5%).
[0323] LC-MS (ES, m/z): 339 [M+H]+.
[0324] 1H NMR (400 MHz, DMSO) δ 7.94 - 7.88 (m, 2H), 7.85 - 7.76 (m, 2H), 7.58 - 7.46 (m, 1H), 7.43 - 7.37 (m, 1H), 7.32 - 7.26 (m, 1H), 6.52 - 6.39 (s, 1H), 3.98 - 3.96 (s, 3H), 3.38 - 3.33 (m, 2H), 2.82 - 2.78 (s, 3H), 2.47 - 2.39 (m, 1H), 2.23 - 2.14 (m, 1H).
Example 32
Synthesis of (R)-l-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phi
(methylamino)-lH-pyrazole-3-carboxamide
Figure imgf000137_0002
Step 1 : Synthesis of ethyl l-(3-bromophenyl)-4-(N-methylacetamido)-lH-pyrazole-3- carboxylate
Figure imgf000137_0003
[0325] A solution of ethyl l-(3-bromophenyl)-4-acetamido-lH-pyrazole-3-carboxylate (300 mg, 0.852 mmol, 1.00 equiv), methyl iodide (142 mg, 1.00 mmol, 1.17 equiv), and sodium hydride (61 mg, 2.542 mmol, 2.984 equiv) in N,N-dimethylformamide (10 niL) was stirred for 2 h at 0 °C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:10) to give the title compound (270 mg, 87%) as a yellow solid. LC-MS (ES, m/z): 366 [M+H]+.
Step 2: Synthesis of l-(3-bromophenyl)-4-(N-methylacetamido)-lH-pyrazole-3-carboxamide
Figure imgf000138_0001
[0326] Similar to the procedure as described in General Procedure S, ethyl l-(3-bromophenyl)-
4-(N-methylacetamido)-lH-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (200 mg, 87%) as a yellow solid. LC-MS (ES, m/z): 337 [M+H]+.
Step 3: Synthesis of l-(3-bromophenyl)-4-(methylamino)-lH-pyrazole-3-carboxamide
Figure imgf000138_0002
[0327] A solution of l-(3-bromophenyl)-4-(N-methylacetamido)-lH-pyrazole-3-carboxamide (200 mg, 0.593 mmol, 1.00 equiv) in methanol (10 mL) and hydrogen chloride (5 mL) was stirred overnight at room temperature. After completion, the solution was adjusted pH to 7 with aq. sodium hydroxide and then extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with dichloromethane/methanol (10: 1) to give the title compound (100 mg, 57%) as a white solid. LC-MS (ES, m/z): 295
[M+H]+.
Step 4: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- (methylamino)-lH-pyrazole-3-carboxarnide
Figure imgf000139_0001
[0328] Similar to the procedure as described in General Procedure G, l-(3-bromophenyl)-4- (methylamino)-lH-pyrazole-3-carboxarnide was reacted with (ii)-3-ethynyl-3-hydroxy-l- methylpyrrolidin-2-one to give the title compound (46.7 mg, 44%) as a white solid. LC-MS (ES, m/z): 354 [M+H]+. 1H NMR (300MHz, CD3OD): δ 7.96 - 7.95 (s, 1H), 7.86 -7.82 (m, 1H), 7.77 (s, 1H) , 7.49 - 7.43 (m, 1H), 7.39 - 7.36 (m, 1H), 3.51 - 3.46 (m, 2H), 2.94 (s, 3H), 2.83 (s, 3H), 2.63 -2.36 (m, 1H), 2.34 - 2.27 (m, 1H).
Example 33
Synthesis of (R)-5-acetamido-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000139_0002
Step 1 : Synthesis of (ii)-5-acetamido-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000139_0003
[0329] A solution of 5-amino-2-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-l ,3-thiazole-4-carboxamide (100 mg, 0.281 mmol, 1.00 equiv), acetyl acetate (0.04 mL, 0.426 mmol, 1.52 equiv), triethylamine (0.04 mL, 0.288 mmol, 1.03 equiv) in acetonitrile (10 mL) was stirred for 12 hours at 25 °C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography and eluted with dichloromethane/methanol (20: 1). This resulted in the title compound (14.6 mg, 13%) as a white solid. LC-MS (ES, m/z): 399 [M+H]+. 1H NMR (400MHz, CD3OD): δ 8.10 (s,lH), 7.98- 7.96 (d, J = 8.0 Hz, 1H), 7.55-7.46 (m, 2H), 3.55-3.46 (m, 2H), 2.96 (s, 3H), 2.65-2.59 (m, 1H), 2.37-2.28 (m, 1H), 2.30 (s, 3H).
Example 34
Synthesis of (R)-l-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-2'- methyl-4,4'-bi(lH-pyrazole)-3-carboxamide
Figure imgf000140_0001
Step 1 : Synthesis of ethyl 4-(l -methyl- lH-pyrazol-4-yl)-lH-pyrazole-3-carboxylate
Figure imgf000140_0002
[0330] Similar to the procedure as described in General Procedure M, ethyl 4-iodo-lH- pyrazole-3-carboxylate was reacted with l-methyl-4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2- yl)-lH-pyrazole to give the title compound (352 mg, 18%) as a yellow solid. LCMS was confirmed. LC-MS (ES, m/z): 221 [M+H]+.
Step 2: Synthesis of ethyl l-(2-bromophenyl)-4-(l-methyl-lH-pyrazol-5-yl)-lH-pyrazole-3- carboxylate
Figure imgf000140_0003
[0331] Similar to the procedure as described in General Procedure C, ethyl 4-( 1 -methyl- 1H- pyrazol-4-yl)-lH-pyrrole-3-carboxylate was reacted with 3-bromophenylboronic acid to give the title compound (239 mg, 40%) as yellow oil. LC-MS (ES, m/z): 375 [M+H]+. Step 3: Synthesis of ethyl l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-4-(l-methyl-lH-pyrazol-3-yl)-lH-pyrazole-3-carboxylate
Figure imgf000141_0001
[0332] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-(l-methyl-lH-pyrazol-3-yl)-lH-pyrazole-3-carboxylate was reacted with (R)-3- ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (130 mg, 80%) as yellow oil. LC-MS (ES, m/z): 434[M+H]+.
Step 4: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-2'- methyl-4,4'-bi(lH-pyrazole)-3-carboxamide
Figure imgf000141_0002
[0333] Similar to the procedure as described in General Procedure S, ethyl l-(3-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(l-methyl-lH-pyrazol-4-yl)-lH- pyrazole-3-carboxylate was reacted with ammonia to give the title compound (10.3 mg, 7%) as a white solid. LC-MS (ES, m/z): 405 [M+H]+. 1H NMR (400MHz, CD3OD): δ 8.64 (s, IH), 8.20 (s, IH), 8.07 (s, IH), 7.96-7.93 (m, 2H), 7.54-7.52 (m IH), 7.48-7.47 (m, IH), 3.94 (s, 3H), 3.51 (m, 2H), 2.96 (s, 3H), 2.65-2.61 (m, IH), 2.39-2.31 (m,lH).
Example 35
Synthesis of (R)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- (pyridin-2-ylamino)-lH-pyrazole-3-carboxamide
Figure imgf000141_0003
Step 1 : Synthesis of ethyl l-(3-bromophenyl)-4-[(pyridin-2-yl)amino]-lH-pyrazole-3- carboxylate
Figure imgf000142_0001
[0334] Under nitrogen a solution of ethyl 4-amino-l-(3-bromophenyl)-lH-pyrazole-3- carboxylate (300 mg, 0.967 mmol, 1.00 equiv), 2-iodopyridine (238 mg, 1.161 mmol, 1.20 equiv), RuPhos (90 mg, 0.193 mmol, 0.20 equiv), RuPhos-PdCl-2nd G (150 mg, 0.193 mmol, 0.20 equiv), and cesium carbonate (473 mg, 1.452 mmol, 1.50 equiv) in dimethyl sulfoxide (30 mL) was stirred overnight at 100 °C. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 :50) to give the title compound (50 mg, 13%) as a white solid. LC-MS (ES, m/z): 387 [M+H]+.
Step 2: Synthesis of ethyl l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-4-[(pyridin-2-yl)amino]-lH-pyrazole-3-carboxylate
Figure imgf000142_0002
[0335] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-[(pyridin-2-yl)amino]-lH-pyrazole-3-carboxylate was reacted with (R)-3- ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (40 mg, 70%) as a yellow solid. LC-MS (ES, m/z): 466 [M+H]+.
Step 3: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- (pyridin-2-ylamino)-lH-pyrazole-3-carboxamide
Figure imgf000143_0001
[0336] Similar to the procedure as described in General Procedure S, ethyl l-(3-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-[(pyridin-2-yl)amino]-lH-pyrazole-3- carboxylate was reacted with ammonia to give the title compound (15.6 mg, 42%) as a white solid. LC-MS (ES, m/z): All [M+H]+. 1H NMR (400MHz, CD3OD): δ 8.96 (s, IH), 8.30-8.29 (m, IH), 8.014 (s, IH), 7.92-7.90 (m, IH), 7.62-7.58 (m, IH), 7.54-7.50 (m, IH), 7.44-7.43 (d, J = 7.6 Hz, IH), 6.88-6.86 (d, J = 8.4 Hz, IH), 6.81-6.78 (m, IH), 3.56-3.47 (m, 2H), 2.96 (s, 3H), 2.66-2.56 (m, IH), 2.38-2.31 (m, IH).
Example 36
Synthesis of (R)-l-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(l- methyl-lH-pyrazol-3-ylamino)-lH-pyrazole-3-carboxamide
Figure imgf000143_0002
Synthesis of ethyl 4-iodo-l-(3-methoxyphenyl)-lH-pyrazole-3-carboxylate
Figure imgf000143_0003
[0337] Similar to the procedure as described in General Procedure C, ethyl 4-iodo-lH- pyrazole-3 -carboxylate was reacted with 3-methoxyphenylboronic acid to give the title compound (1.6 g, crude) as red oil. LC-MS (ES, m/z): 373 [M+H]+.
Step 2: Synthesis of ethyl l-(3-methoxyphenyl)-4-[(l-methyl-lH-pyrazol-3-yl)amino]-lH- pyrazole-3 -carboxylate
Figure imgf000144_0001
[0338] Under nitrogen a solution of ethyl 4-iodo-l-(3-methoxyphenyl)-lH-pyrazole-3- carboxylate (1.2 g, 3.224 mmol, 1.00 equiv), l-N,2-N-dimethylcyclohexane-l ,2-diamine (464 mg, 3.262mmol, 1.00 equiv), 1 -methyl- lH-pyrazol-3-amine (1.6 g, 16.475 mmol, 1.00 equiv), potassium phosphate (876 mg, 4.127 mmol, 2.00 equiv), copper(I) iodide (265mg, 1.391mmol, 0.500 equiv) in dimethyl sulfoxide (14 mL) was stirred for 12 h at 80 °C. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 :4) to give the title compound (580mg, 53%) as a light yellow solid. LC-MS (ES, m/z): 342 [M+H]+.
Step 3: Synthesis of l-(3-methoxyphenyl)-4-[(l-methyl-lH-pyrazol-3-yl)amino]-lH-pyrazole-3- carboxamide
Figure imgf000144_0002
[0339] Similar to the procedure as described in General Procedure S, ethyl l-(3- methoxyphenyl)-4- [( 1 -methyl- 1 H-pyrazol-3 -yl)amino] - lH-pyrazole-3 -carboxylate was reacted with ammonia to give the title compound (500 mg, 94%) of l-(3-methoxyphenyl)-4-[(l-methyl- 1 H-pyrazol-3 -yl)arnino]-lH-pyrazole-3-carboxarnide as light yellow oil. LC-MS (ES, m/z): 313 [M+H]+.
Step 4: Synthesis of 1 -(3 -hydroxyphenyl)-4-[(l -methyl- 1 H-pyrazol-3 -yl)amino]-l H-pyrazole-3- carboxamide
Figure imgf000145_0001
[0340] To a solution of l-(3-methoxyphenyl)-4-[(l-methyl-lH-pyrazol-3-yl)amino]-lH- pyrazole-3-carboxamide (500 mg, 1.60 mmol,1.00 equiv) in dichloromethane (20 niL) was added tribromoborane (1.98 g, 7.90mmol, 1.00 equiv) dropwise with stirring at 0°C. The resulting solution was stirred for 2 h at room temperature. The reaction was then quenched with methanol. The resulting mixture was concentrated under vacuum and the residue was purified by a silica gel column chromatography and eluted with dichloromethane/methanol (10: 1) to give the title compound (400 mg, 84%) as a yellow solid. LC-MS (ES, m/z): 299 [M+H]+.
Step 5: Synthesis of 3-[3-carbamoyl-4-[(l -methyl- lH-pyrazol-3-yl)arnino]- lH-pyrazol-l- yl]phenyl trifluoromethanesulfonate
Figure imgf000145_0002
[0341] To a solution of l -(3-hydroxyphenyl)-4-[(l -methyl- lH-pyrazol-3-yl)amino]-lH- pyrazole-3-carboxamide (180 mg, 0.603 mmol, 1.00 equiv) in dichloromethane (30 mL) was added diisopropylethylamine (234 mg, 1.811mmol, 3.00 equiv) dropwise with stirring at 0 °C, followed by addition of trifluoromethanesulfonic anhydride (169 mg, 0.599 mmol, 1.50 equiv) dropwise with stirring at 0°C. The resulting solution was stirred for 2 h at 0 °C. The solution was adjusted to pH 8 and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 : 1) to give the title compound 130 mg (50%) as a light yellow solid. LC-MS (ES, m z): 431 [M+H]+.
Step 6: Synthesis of (ii)-l-(3-((3-hydroxy-l -methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4-(l - methyl-lH-pyrazol-3-ylamino)-lH-pyrazole-3-carboxarnide
Figure imgf000146_0001
[0342] Similar to the procedure as described in General Procedure G, 3-[3-carbamoyl-4-[(l- methyl-lH-pyrazol-3-yl)amino]-lH-pyrazol-l-yl]phenyl trifluoromethanesulfonate was reacted with (ii)-3-ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (20.8 mg, 12%) as an off-white solid. LC-MS (ES, m/z): 420 [M+H]+. lH NMR (300MHz, CD3OD): δ 8.45 (s, 1H), 8.00 (s, 1H), 7.99-7.88 (m, 1H), 7.53-7.49 (t, J = 8Hz, 1H), 7.44-7.41 (m, 2H), 5.90 (s, 1H) 3.83 (s, 3H), 3.55-3.46 (m, 2H), 3.15 (s, 3H), 2.65-2.60 (m, 1H), 2.38-2.31 (m, 1H).
Example 37
Synthesis of (R)-5-(3,3-diniethylureido)-2-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000146_0002
[0343] A solution of ethyl 5-amino-2-(3-iodophenyl)-l,3-thiazole-4-carboxylate (400 mg, 1.069 mmol, 1.00 equiv), triethylamine (6 mL, 43.166 mmol, 40.38 equiv), N,N- dimethylcarbamoyl chloride (137 mg, 1.274 mmol, 1.19 equiv) in dichloromethane (70 mL) was stirred for 2 days at 40 °C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 :5). This resulted in the title compound (300 mg, 63%) as a yellow solid. LC-MS (ES, m/z): 446 [M+H]+.
Step 2: Synthesis of ethyl 5-[(dimethylcarbamoyl)amino]-2-(3-[2-[(3R)-3-hydroxy-l-methyl-2- oxo rrolidin-3-yl]ethynyl]phenyl)-l,3-thi
Figure imgf000147_0001
[0344] Similar to the procedure as described in General Procedure G, ethyl 5- [(dimethylcarbamoyl)amino]-2-(3-iodophenyl)-l ,3-thiazole-4-carboxylate was reacted with (R)- 3 -ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (100 mg, 65%) as yellow oil. LC-MS (ES, m/z): 457 [M+H]+.
Step 3: Synthesis of (ii)-5-(3,3-dimethylureido)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000147_0002
[0345] Similar to the procedure as described in General Procedure S, ethyl 5- [(dimethylcarbamoyl)amino]-2-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-l ,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (55.8 mg, 60%) as a light yellow solid. LC-MS (ES, m/z): 428 [M+H]+. 1H NMR (300MHz, DMSO-Je): δ 11.45 (s, IH), 8.03-8.00 (m, 2H), 7.93-7.89 (m, IH), 7.75 (s, IH), 7.53- 7.45 (m, 2H), 6.49 (s, IH), 3.38-3.31 (m, 2H), 3.00 (s, 6H), 2.81 (s, 3H), 2.46-2.42 (m, IH), 2.27-2.17 (m, IH).
Example 38
Synthesis of 5-((lR,2R)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-l- niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxaniide
Figure imgf000148_0001
Step 1 : Synthesis of ethyl 5-[[(lR,2R)-2-fluorocyclopropane]amido]-2-(3-iodophenyl)-l,3- thiazole-4-carboxylate
Figure imgf000148_0002
[0346] Similar to the procedure as described in General Procedure B, ethyl 5-amino-2-(3- iodophenyl)-l,3-thiazole-4-carboxylate was reacted with (lR,2R)-2-fluorocyclopropane-l- carboxylic acid to give the title compound (390 mg, 63%) as a white solid. LC-MS (ES, m/z): 461 [M+H]+.
Step 2: Synthesis of ethyl 5-[[(lR,2R)-2-fluorocyclopropane]amido]-2-(3-[2-[(3R)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-l,3-thiazole-4-carboxylate
Figure imgf000148_0003
[0347] Similar to the procedure as described in General Procedure G, ethyl 5-[[(lR,2R)-2- fluorocyclopropane]amido]-2-(3-iodophenyl)-l,3-thiazole-4-carboxylate was reacted with (R)-3- ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (180 mg, 88%) as a red solid. LC-MS (ES, m/z): 472 [M+H]+.
Step 3: Synthesis of 5-((lR,2R)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000149_0001
[0348] Similar to the procedure as described in General Procedure S, ethyl 5-[[(lR,2R)-2- fluorocyclopropane]amido]-2-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-l ,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (59.7 mg, 35%) as a white solid. LC-MS (ES, m/z): 443 [M+H]+. lH NMR (300MHz, CD3OD): δ 8.11 (s, IH), 7.99-7.96 (m, IH), 7.56-7.46 (m, 2H), 5.10-5.06 (m, IH), 3.54-3.47 (m, 2H), 2.96 (s, 3H), 2.67-2.59 (m, IH), 2.39-2.30 (m, IH), 2.22-2.17 (m, IH), 1.90-1.80 (m, IH), 1.41-1.32 (m, IH).
Example 39
Synthesis of 5-((lS,2S)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-l-niethyl- 2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000149_0002
Step 1 : Synthesis of ethyl 5-[[(lS,2S)-2-fluorocyclopropane]amido]-2-(3-iodophenyl)-l,3-
Figure imgf000149_0003
[0349] Similar to the procedure as described in General Procedure B, ethyl 5-amino-2-(3- iodophenyl)-l,3-thiazole-4-carboxylate was reacted with (lS,2S)-2-fluorocyclopropane-l- carboxylic acid to give the title compound (450 mg, 73%) as a white solid. LC-MS (ES, m/z): 461 [M+H]+. Step 2: Synthesis of ethyl 5-[[(lS,2S)-2-fluorocyclopropane]amido]-2-(3-[2-[(3R)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-l,3-thiazole-4-carboxylate
Figure imgf000150_0001
[0350] Similar to the procedure as described in General Procedure G, ethyl 5-[[(lS,2S)-2- fluorocyclopropane]amido]-2-(3-iodophenyl)-l,3-thiazole-4-carboxylate was reacted with (R)-3- ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (180 mg, 88%) as a white solid. LC-MS (ES, m/z): 472 [M+H]+.
Step 3: Synthesis of 5-((lS,2S)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-l-
Figure imgf000150_0002
[0351] Similar to the procedure as described in General Procedure S, ethyl 5-[[(lS,2S)-2- fluorocyclopropane]amido]-2-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-l ,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (41.5 mg, 22%) as a white solid. LC-MS (ES, m/z): 443 [M+H]+. lH NMR (300MHz, CD3OD): δ 7.92 (s, IH), 7.81-7.78 (m, IH), 7.38-7.28 (m, 2H), 4.92-4.89 (s, IH), 3.55-3.31 (m, 2H), 2.78 (s, 3H), 2.48-2.41 (m, IH), 2.21-2.14 (m, IH), 2.11-1.99 (m, IH), 1.70-1.61 (m, IH), 1.24-1.14 (m, IH).
Example 40
Synthesis of (R)-5-amino-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)oxazole-4-carboxamide
Figure imgf000151_0001
Step 1 : Synthesis of ethyl 2-(3-bromobenzamido)-2-cyanoacetate
Figure imgf000151_0002
[0352] To a solution of ethyl 2-amino-2-cyanoacetate 4-methylbenzenesulfonate (730 mg, 2.31 mmol) in dichloromethane (9.0 mL) at 0°C was added pyridine (0.47 mL, 5.77 mmol) then 3- bromobenzoyl chloride (0.45 mL, 3.46 mmol). The reaction mixture was stirred at 0 °C for 2h. The reaction was quenched with water and extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (EtOAc/Heptane, eluted at 40 EtOAc) to give product (653 mg, 90%).
[0353] LC-MS (ES, m z): 311 [M+H]+.
Step 2: Synthesis of ethyl 5-amino-2-(3-bromophenyl)oxazole-4-carboxylate
Figure imgf000151_0003
[0354] A solution of ethyl 2-[(3-bromobenzoyl)amino]-2-cyano-acetate (100 mg, 0.32 mmol) in hydrogen chloride (4 mol/L) in 1,4-dioxane (1.60 mL, 6.4 mmol) was stirred at 100°C 4h. The reaction was concentrated and to give crude product (100 mg, 100%).
[0355] LC-MS (ES, m/z): 311.
[M+H]+. Step 3: Synthesis of ethyl 2-(3-bromophenyl)-5-((tert-butoxycarbonyl)amino)oxazole- 4-carboxylate
Figure imgf000152_0001
[0356] To a solution of ethyl 5-amino-2-(3-bromophenyl)oxazole-4-carboxylate (110 mg, 0.35 mmol) in acetonitrile (3.5 mL) was added NN-diisopropylethylamine (0.30 mL, 1.8 mmol), 4- dimethylaminopyridine (4.3 mg, 0.035 mmol) and di-tert-butyl dicarbonate (233 mg, 1.06 mmol). The reaction mixture was stirred at RT 18h. The reaction was quenched with water and extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated via rotovap. The crude product was purified by flash chromatography
(EtOAc/Heptane) to give product (105 mg, 72%).
[0357] LC-MS (ES, m z): 411 [M+H]+.
Step 4: Synthesis of (ii)-ethyl 5-((tert-butoxycarbonyl)amino)-2-(3-((3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)oxazole-4-carboxylate
Figure imgf000152_0002
[0358] A solution of ethyl 2-(3-bromophenyl)-5-(tert-butoxycarbonylamino)oxazole-4- carboxylate (90.0 mg, 0.22 mmol), (3R)-3-ethynyl-3-hydroxy-l-methylpyrrolidin-2-one (36.5 mg, 0.26 mmol), Pd(PPh3)2C12 (15 mg, 0.022 mmol) and TEA (0.75 mL) in dimethyl sulfoxide (4.4 mL) was heat in microwave at 100°C 40min. The reaction was quenched with water and extracted with EtOAc. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by flash chromatography (MeOH/DCM) to give (90 mg, 87.6%).
[0359] LC-MS (ES, mJz): 470 [M+H]+.
Step 5: Synthesis of (R)-5-amino-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)oxazole-4-carboxamide
Figure imgf000153_0001
[0360] Ammonia gas was bubbled into to a solution of ethyl 5-(tert-butoxycarbonylamino)-2- [3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]phenyl]oxazole-4-carboxylate (90 mg, 0.19 mmol) in methanol (4.0 mL) for 5min. The reaction mixture was stirred at 50 °C for 24h. The crude product was concentrated and purified by flash chromatography
(MeOH/DCM) to give tert-butyl-N-[4-carbamoyl-2-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]oxazol-5-yl]carbamate.
[0361] A solution of tert-buty\ N-[4-carbamoyl-2-[3-[2-[(3R)-3-hydroxy-l-methyl-2-oxo- pyrrolidin-3-yl]ethynyl]phenyl]oxazol-5-yl]carbamate (84 mg, 0.19 mmol) in 1,4-dioxane (1.0 mL) and hydrochloric acid (4 mol/L) in 1,4-dioxane (0.95 mL, 3.8 mmol) was stirred at RT 18h. The reaction was concentrated and the residue submitted for rHPLC to give a product (12.8 mg,
18%).
[0362] LC-MS (ES, m z): 341 [M+H]+.
[0363] 1H NMR (400 MHz, DMSO) δ 7.85 - 7.81 (m, 1H), 7.79 - 7.73 (m, 1H), 7.54 - 7.48 (m, 1H), 7.48 - 7.43 (m, 1H), 7.12 - 6.88 (m, 4H), 6.53 - 6.48 (s, 1H), 3.38 - 3.34 (m, 2H), 2.83 - 2.78 (s, 3H), 2.47 - 2.40 (m, 1H), 2.23 - 2.15 (m, 1H).
Examples 41 and 42
Synthesis of 5-((lR,2S)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-l-niethyl- 2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide and 5-((lS,2R)-2- fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-l-niethyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
(Isolated as single-unknown stereoisomers and assigned as (S,R) or (R.S) arbitrarily)
Figure imgf000153_0002
Step 1 : Synthesis of ethyl 5-[(2-fluorocyclopropane)amido]-2-(3-iodophenyl)-l,3-thiazole-4- carboxylate
Figure imgf000154_0001
[0364] Similar to the procedure as described in General Procedure B, ethyl 5-amino-2-(3- iodophenyl)-l,3-thiazole-4-carboxylate was reacted with (trans)-2-fluorocyclopropane-l- carboxylic acid to give the title compound (850 mg, 69%) as a white solid. LC-MS (ES, m/z): 461 [M+H]+.
Step 2: Synthesis of ethyl 5-[trans-(2-fluorocyclopropane)amido]-2-(3-[2-[(3R)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-l,3-thiazole-4-carboxylate
Figure imgf000154_0002
[0365] Similar to the procedure as described in General Procedure G, ethyl 5-[(2- fluorocyclopropane)amido]-2-(3-iodophenyl)-l,3-thiazole-4-carboxylate was reacted with (R)-3- ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (450 mg, 88%) as a light yellow solid. LC-MS (ES, m/z): 472 [M+H]+.
Step 3: Synthesis of 5-((lR,2S)-2-fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide and 5-((l S,2R)-2- fluorocyclopropanecarboxamido)-2-(3-(((R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000154_0003
[0366] Similar to the procedure as described in General Procedure S, ethyl 5-[(2- fluorocyclopropane)arnido] -2-(3 - [2- [(3ii)-3 -hydroxy- 1 -methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-l ,3-thiazole-4-carboxylate was reacted with ammonia to give 25.6 mg (6%) of the first-eluting (here called lR,2S-isomer) isomer as a white solid and 21.8 mg (5%) of the second-eluting (here called lS,2R-isome,r) isomer as a white solid.
[0367] The stereochemistry of both (single isomers of unknown absolute stereochemistry) isomers was arbitrarily assigned. The first-eluting isomer: t = 12.26 min (Chiralcel OJ-3, 0.46*15cm, Hex (0,1 DEA):IPA = 50:50, 1 ml/min); the second-eluting isomer: tR = 19.00 min (Chiralcel OJ-3, 0.46*15cm, Hex (0,1 DEA):IPA = 50:50, 1 ml/min); Both isomers showed identical LC-MS and XH NMR as shown below.
[0368] LC-MS (ES, m/z): 443 [M+H]+. XH NMR (300MHz, DMSO-J6): δ 11.86 (s, IH), 8.10 (s, IH), 8.06 (s, IH), 7.96-7.92 (m, IH), 7.84 (s, IH), 7.51-7.50 (m, 2H), 6.49 (s, IH), 4.95 (d, J = 60 Hz, IH), 3.38-3.32 (m, 2H), 2.90-2.81 (m, IH), 2.81 (s, 3H), 2.45-2.43 (m, IH), 2.21-2.17 (m, IH), 1.68-1.55 (m, IH), 1.37-1.30 (m, IH).
Example 43
Synthesis of (R)-3-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-l,2,4- thiadiazole-5-carboxamide
Figure imgf000155_0001
Step 1: Synthesis of 3-bromo-5-(l-ethoxyethenyl)-l,2,4-thiadiazole
Figure imgf000155_0002
[0369] Similar to the procedure as described in General Procedure Q, 3-bromo-5-chloro-l,2,4- thiadiazole was reacted with tributyl(l-ethoxyethenyl)stannane to give the title compound (1.5 g, 64%) as a yellow solid. LC-MS (ES, m/z): 235 [M+H]+.
Step 2: Synthesis of ethyl 3-bromo-l,2,4-thiadiazole-5-carboxylate
Figure imgf000156_0001
[0370] Similar to the procedure as described in General Procedure R, 3-bromo-5-(l- ethoxyethenyl)-l,2,4-thiadiazole was reacted with sodium periodate and potassium
permanganate to give the title compound (650 mg, 43%) as colorless oil. LC-MS (ES, m/z): 237 [M+H]+.
Step 3: Synthesis of 3-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)- -thiadiazole-5-carboxylic acid
Figure imgf000156_0002
[0371] Similar to the procedure as described in General Procedure U, ethyl 3-bromo- 1,2,4- thiadiazole-5-carboxylate was reacted with potassium (ii)-trifluoro(3-((3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the title compound (90 mg, 27%) as a brown solid. LC-MS (ES, m/z): 344 [M+H]+.
Step 4: Synthesis of 3-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)- 1 ,2,4-thiadiazole-5-carboxamide
Figure imgf000156_0003
[0372] Similar to the procedure as described in General Procedure B, 3-(3-[2-[(3R)-3-hydroxy- l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-l,2,4-thiadiazole-5-carboxylic acid was reacted with ammonium chloride to give the title compound (12.1 mg, 15%) as a white solid. LC-MS (ES, m/z): 343 [M+H]+. lH NMR (300MHz, CD3OD): δ 8.43 (s, 1H), 8.34-8.31 (m, 1H), 8.60- 8.53 (m, IH), 8.50-8.48 (m, IH), 3.49-3.45 (m, 2H), 2.92 (s, 3H), 2.63-2.55 (m, IH), 2.36-2.26 (m, IH).
Example 44
Synthesis of (R)-5-(difluoromethyl)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000157_0001
Step 1: Synthesis of (ii)-5-(difluoromethyl)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000157_0002
[0373] Similar to the procedure as described in General Procedure U, 2-bromo-5- (difluoromethyl)-l,3-thiazole-4-carboxamide was reacted with potassium (R)-trifluoro(3-((3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the title compound (43.2 mg, 14%) as a white solid. LC-MS (ES, m/z): 392 [M+H]+. 1H NMR (300MHz, CD3OD): δ 8.22 (s, IH), 8.10-8.04 (m, IH), 7.86 (s, IH), 7.68-7.63 (m, IH), 7.56-7.51 (m, IH), 3.55-3.48 (m, 2H), 2.95 (s, 3H), 2.66-2.58 (m, IH), 2.38-2.29 (m,lH).
Example 45
Synthesis of (R)-5-amino-2-(2-fluoro-5-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000158_0001
Synthesis of ethyl 2-[(5-bromo-2-fluorophenyl)formamido]-2-cyanoacetate
Figure imgf000158_0002
[0374] To a solution of l-cyano-2-ethoxy-2-oxoethan-l-aminium 4-methylbenzene-l- sulfonate (5.00 g, 16.648 mmol, 1.00 equiv) in dichloromethane (150 mL) was added pyridine (2.68 mL, 33.295 mmol, 2.00 equiv). This was followed by the addition of 5-bromo-2- fluorobenzoyl chloride (4.00 g, 16.845 mmol, 1.01 equiv) dropwise with stirring at 0 °C. After beingas stirred for 30 min at 0 °C the reaction mixture was diluted with dichloromethane, washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1 :2) to give the title compound (4.0 g, 73%) as a white solid. LC-MS (ES, m/z): 329 [M+H]+.
Step 2: Synthesis of ethyl 5-amino-2-(5-bromo-2-fluorophenyl)-l,3-thiazole-4-carboxylate
Figure imgf000158_0003
[0375] Under nitrogen a suspension of ethyl 2-[(5-bromo-2-fluorophenyl)formamido]-2- cyanoacetate (3.80 g, 11.546 mmol, 1.00 equiv), Lawesson's reagent (5.14 g, 12.708 mmol, 1.10 equiv) in toluene (100 mL) was stirred for 12 h at 90 °C. The resulting solution was diluted with ethyl acetate. The pH value of the solution was adjusted to 3 with IN hydrochloric acid and then was adjusted to pH of 8 with aq. sodium bicarbonate. The resulting mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/petroleum ether (1:3) to give the title compound (2 g, crude) as a yellow solid. LC-MS (ES, m/z): 345 [M+H]+.
Step 3: Synthesis of ethyl 5-[bis[(tert-butoxy)carbonyl]amino]-2-(5-bromo-2-fluorophenyl)-l,3-
Figure imgf000159_0001
[0376] A solution of ethyl 5-amino-2-(5-bromo-2-fluorophenyl)-l,3-thiazole-4-carboxylate (2.0 g, 5.794 mmol, 1.00 equiv), 4-dimethylaminopyridine (530 mg, 4.338 mmol, 0.75 equiv) and di-tert-butyl dicarbonate (2.58 g, 11.821 mmol, 2.04 equiv) in acetonitrile (50 mL) was stirred for 3 h at 60 °C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:5). This resulted in the title compound (500 mg, 16%) as a yellow solid. LC-MS (ES, m/z): 545 [M+H]+.
Step 4: Synthesis of tert-butyl N-[2-(5-bromo-2-fluorophenyl)-4-carbamoyl-l,3-thiazol-5-yl]-N- [(tert-butoxy)carbonyl] carbamate
Figure imgf000159_0002
[0377] Similar to the procedure as described in General Procedure S, ethyl 5-[bis[(tert- butoxy)carbonyl] amino] -2-(5-bromo-2-fluorophenyl)-l ,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (450 mg, crude) as a yellow solid. LC-MS (ES, m/z): 546 [M+H]+.
Step 5: Synthesis of 5-amino-2-(5-bromo-2-fluorophenyl)-l,3-thiazole-4-carboxamide
Figure imgf000160_0001
[0378] A solution of tert-butyl N-[2-(5-bromo-2-fluorophenyl)-4-carbamoyl-l,3-thiazol-5-yl]- N-[(tert-butoxy)carbonyl]carbamate (450 mg, 0.871 mmol, 1.00 equiv) in 1,4-dioxane (10 niL, saturated with hydrogen chloride) was stirred overnight at room temperature. After completion, the solution was adjusted pH to 7 with aq. sodium hydroxide and then extracted with
dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with dichloromethane/methanol (10: 1) to give the title compound (200 mg, 73%) as yellow oil. LC-MS (ES, m/z): 316 [M+H]+.
Step 6: Synthesis of 5-amino-2-(2-fluoro-5-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-l ,3-thiazole-4-carboxamide
Figure imgf000160_0002
[0379] Similar to the procedure as described in General Procedure G, 5-amino-2-(5-bromo-2- fluorophenyl)-l,3-thiazole-4-carboxamide was reacted with (ii)-3-ethynyl-3 -hydroxy- 1- methylpyrrolidin-2-one to give the title compound (14 mg, 6%) as an off-white solid. LC-MS (ES, m/z): 375 [M+H]+. XH NMR (400MHz, DMSO-J6): δ 8.30 (dd, / = 7.2, 5.1 Hz, IH), 7.57 (s, IH), 7.45-7.32 (m, 4H), 7.09 (s, IH), 6.45 (s, IH), 3.37-3.33 (m, 2H), 2.80 (s, 3H), 2.44-2.40 (m, IH), 2.23-2.14 (m, IH).
Example 46
Synthesis of (R)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phi
(methylamino)thiazole-4-carboxamide
Figure imgf000161_0001
Step 1 : Synthesis of ethyl 5-[[(tert-butoxy)carbonyl](methyl)amino]-2-(3-iodophenyl)-l,3-
Figure imgf000161_0002
[0380] A solution of ethyl 5-[[(tert-butoxy)carbonyl]amino]-2-(3-iodophenyl)-l,3-thiazole-4- carboxylate (500.00 mg, 1.054 mmol, 1.00 equiv), cesium carbonate (685.56 mg, 2.104 mmol, 2.00 equiv), methyl iodide (298.05 mg, 2.100 mmol, 1.99 equiv) in dimethyl sulfoxide (30 mL) was stirred for 1 h at 45 °C. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 : 10) to give the title compound (500 mg, 97%) as light yellow oil. LC-MS (ES, m/z): 489 [M+H]+.
Step 2: Synthesis of tert-butyl N-[4-carbamoyl-2-(3-iodophenyl)-l,3-thiazol-5-yl]-N- methylcarbamate
Figure imgf000161_0003
[0381] Similar to the procedure as described in General Procedure S, ethyl 5-[[(tert- butoxy)carbonyl]amino]-2-(3-iodophenyl)-l ,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (200 mg, 40%) as a yellow solid. LC-MS (ES, m/z): 460 [M+H]+. Step 3: Synthesis of
Figure imgf000162_0001
[0382] A solution of tert-butyl N-[4-carbamoyl-2-(3-iodophenyl)-l,3-thiazol-5-yl]-N- methylcarbamate (190.00 mg, 0.414 mmol, 1.00 equiv) in 1,4-dioxane (10 niL, saturated with hydrogen chloride) was stirred overnight at room temperature. After completion, the solution was adjusted pH to 7 with aq. sodium hydroxide and then extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with
dichloromethane/methanol (10: 1) to give the title compound (130 mg, 87%) as a light yellow solid. LC-MS (ES, m/z): 360 [M+H]+.
Step 4: Synthesis of (ii)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5- methylamino)thiazole-4-carboxamide
Figure imgf000162_0002
[0383] Similar to the procedure as described in General Procedure G, 2-(3-iodophenyl)-5- (methylamino)-l,3-thiazole-4-carboxamide was reacted with (ii)-3-ethynyl-3-hydroxy-l- methylpyrrolidin-2-one to give the title compound (42.3 mg, 41%) as a white solid. LC-MS (ES, m/z): 371 [M+H]+. lH NMR (400MHz, CD3OD): δ 7.94 (s, 1H), 7.83-7.08 (m, 1H), 7.46-7.40 (m, 2H), 3.54-3.47 (m, 2H), 3.09 (s, 3H), 2.95 (s, 3H), 2.64-2.58 (m, 1H), 2.37-2.30 (m, 1H).
Example 47
Synthesis of (R)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- (pyridin-3-yl)-lH-pyrazole-3-carboxamide
Figure imgf000163_0001
Step 1 : Synthesis of ethyl 4-(pyridin-3-yl)-lH-pyrazole-3-carboxylate
Figure imgf000163_0002
EtOH , H20, 1 00 °C
[0384] Similar to the procedure as described in General Procedure M, ethyl 4-iodo-lH- pyrazole-3-carboxylate was reacted with pyridin-3-ylboronic acid to give the title compound (390 mg, 18%) as yellow oil. LC-MS (ES, m/z): 218 [M+H]+.
Step 2: Synthesis of ethyl l-(3-bromophenyl)-4-(pyridin-3-yl)-lH-pyrazole-3-carboxylate
Figure imgf000163_0003
[0385] Similar to the procedure as described in General Procedure C, ethyl 4-(pyridin-3 lH-pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to give the title compound (210 mg, 36%) as yellow oil. LC-MS (ES, m/z): 372 [M+H]+.
Step 3: Synthesis of ethyl l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-
Figure imgf000163_0004
[0386] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-(pyridin-3-yl)-lH-pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl-3- hydroxy- l-methylpyrrolidin-2-one to give the title compound (150 mg, 65%) as a yellow solid. LC-MS (ES, m/z): 431 [M+H]+.
Step 4: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- (pyridin-3-yl)-lH-pyrazole-3-carboxamide
Figure imgf000164_0001
[0387] Similar to the procedure as described in General Procedure S, ethyl l-(3-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(pyridin-3-yl)-lH-pyrazole-3- carboxylate was reacted with ammonia to give the title compound (28.8 mg, 28%) as a white solid. LC-MS (ES, m/z): 402 [M+H]+. XH NMR (300MHz, CD3OD): δ 8.82 (s, 1H), 8.66 (s, 1H), 8.48-8.47 (m,lH), 8.17-8.10 (m, 2H), 7.99-7.95 (m, 1H), 7.57-7.45 (m, 3H), 3.55-3.45 (m, 2H), 2.94 (s, 3H), 2.65-2.57 (m, 1H), 2.38-2.31 (m, 1H).
Example 48
Synthesis of l-(3-[2-[(3R)-3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(l- methyl-lH-pyrazol-5-yl)-lH-pyrazole-3-carboxamide
Figure imgf000164_0002
Step 1 : Synthesis of ethyl 4-(l -methyl- lH-pyrazol-5-yl)-lH-pyrazole-3-carboxylate
Figure imgf000164_0003
[0388] Similar to the procedure as described in General Procedure M, ethyl 4-iodo-lH- pyrazole-3-carboxylate was reacted with l-methyl-lH-pyrazol-5-ylboronic acid to give the title compound (500 mg, 45%) as yellow oil. LC-MS (ES, m/z): 221 [M+H]+. Step 2: Synthesis of ethyl l-(3-bromophenyl)-4-(l-methyl-lH-pyrazol-5-yl)-lH-pyrazole-3- carboxylate
Figure imgf000165_0001
m ar to t e proce ure as escr e n enera roce ure C, ethyl 4-( 1 -methyl- 1H- pyrazol-5-yl)-lH-pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to give the title compound (410 mg, 48%) as a brown solid. LC-MS (ES, m/z): 375 [M+H]+.
Step 3: Synthesis of ethyl l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-4-(l-meth l-lH-pyrazol-5- l)-lH-pyrazole-3-carboxylate
Figure imgf000165_0002
[0390] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-(l-methyl-lH-pyrazol-5-yl)-lH-pyrazole-3-carboxylate was reacted with (R)-3- ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (350 mg, 76%) as a yellow solid. LC-MS (ES, m/z): 434 [M+H]+.
Step 4: Synthesis of l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4- ( 1 -methyl- 1 H-pyrazol-5 -yl)- 1 H-pyrazole-3 -carboxamide
Figure imgf000165_0003
[0391] Similar to the procedure as described in General Procedure S, ethyl l-(3-[2-[(3ii)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(l-methyl-lH-pyrazol-5-yl)-lH- pyrazole-3-carboxylate was reacted with ammonia to give the title compound (27.6 mg, 7.6%) as a white solid. LC-MS (ES, m/z): 405 [M+H]+. XH NMR (300MHz, CD3OD): δ 8.55 (s, 1H), 8.09 (d, J = 1.5 Hz, IH), 7.99-7.95 (m, IH), 7.58-7.49 (m, 3H), 6.39 (d, J = 2.1 Hz, IH), 3.79 (s, 3H), 3.56-3.34 (m, 2H), 2.94 (s, 3H), 2.65-2.57 (m, IH), 2.38-2.29 (m, IH).
Example 49
Synthesis of (R)-l-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phi
(pyridin-4-yl)-lH-pyrazole-3-carboxamide
Figure imgf000166_0001
Step 1 : Synthesis of ethyl 4-(pyridin-4-yl)-lH-pyrazole-3-carboxylate
Figure imgf000166_0002
EtOH, H20, 100 °C
[0392] Similar to the procedure as described in General Procedure M, ethyl 4-iodo-lH- pyrazole-3-carboxylate was reacted with pyridin-4-ylboronic acid to give the title compound (596 mg, 36%) as a yellow solid. LC-MS (ES, m/z): 218 [M+H]+.
Step 2: Synthesis of ethyl l-(3-bromopheny -4-(pyridin-4-yl)-lH-pyrazole-3-carboxylate
Figure imgf000166_0003
[0393] Similar to the procedure as described in General Procedure C, ethyl 4-(pyridin-4 lH-pyrazole-3-carboxylate was reacted with 3-bromophenylboronic acid to give the title compound (572 mg, 56%) as a white solid. LC-MS (ES, m/z): 372 [M+H]+.
Step 3: Synthesis of ethyl l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-4-(pyridin-4-yl)-lH-pyrazole-3-carboxylate
Figure imgf000167_0001
[0394] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-(pyridin-4-yl)-lH-pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl-3- hydroxy-l-methylpyrrolidin-2-one to give the title compound (290 mg, 46%) as a yellow solid. LCMS was confirmed. LC-MS (ES, m/z): 431 [M+H]+.
Step 4: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-4- (pyridin-4-yl)-lH-pyrazole-3-carboxamide
Figure imgf000167_0002
[0395] Similar to the procedure as described in General Procedure S, ethyl l-(3-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-4-(pyridin-4-yl)-lH-pyrazole-3- carboxylate was reacted with ammonia to give the title compound (39.6 mg, 15%) as a white solid. LC-MS (ES, m/z): 402 [M+H]+. lH NMR (300MHz, CD3OD): δ 8.80 (s, IH), 8.55 (d, / = 6.3 Hz, 2H), 8.10 (d, / = 1.8 Hz, IH), 8.00-7.96 (m, IH), 7.84-7.81 (m, 2H), 7.59-7.49 (m, 2H), 3.56-3.48 (m, 2H), 2.95 (s, 3H), 2.65-2.58 (m, IH), 2.39-2.29 (m, IH).
Example 50
Synthesis of (R)-3-(2-fluoro-5-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-
1 ,2,4-thiadiazole-5-carboxamide
Figure imgf000167_0003
Step 1 : Synthesis of 3-(2-fluoro-5-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-l ,2,4-thiadiazole-5-carboxylic acid
Figure imgf000168_0001
[0396] Similar to the procedure as described in General Procedure U, ethyl 3-bromo- 1,2,4- thiadiazole-5-carboxylate was reacted with potassium (R)-trifluoro(2-fluoro-5-((3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the title compound (120 mg, 33%) as a red solid. LC-MS (ES, m/z): 362 [M+H]+.
Step 2: Synthesis of (ii)-3-(2-fluoro-5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-l,2,4-thiadiazole-5-carboxamide
Figure imgf000168_0002
[0397] Similar to the procedure as described in General Procedure B, 3-(2-fluoro-5-[2-[(3R)- 3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-l,2,4-thiadiazole-5-carboxylic acid was reacted with ammonium chloride to give the title compound (15.6 mg, 13%) as a white solid. LC-MS (ES, m/z): 361 [M+H]+. lH NMR (300 MHz, CD3OD): δ 8.39-8.36 (m, IH), 7.65- 7.60 (m, IH), 7. ,32-7.26 (m, IH), 3.49-3.30 (m, 2H), 2.92 (s, 3H), 2.62-2.53 (m, IH), 2.35-2.25 (m, IH).
Example 51
Synthesis of (R)-2-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phi
(methylsulfonamido)thiazole-4-carboxamide
Figure imgf000168_0003
Step 1 : Synthesis of 2-(3-iodophenyl)-5-methanesulfonamido-l,3-thiazole-4-carboxamide
Figure imgf000169_0001
[0398] A solution of 5-amino-2-(3-iodophenyl)-l ,3-thiazole-4-carboxamide (300 mg, 0.869 mmol, 1.00 equiv), triethylamine (101 mg, 0.998 mmol, 1.15 equiv) and methanesulfonyl methanesulfonate (227 mg, 1.303 mmol, 1.50 equiv) in dichloromethane (20 mL) was stirred for 5 h at room temperature. The resulting solution was concentrated under vacuum. The crude product was purified by reverse phase chromatography to give the title compound (195 mg, 53%) as an off-white solid. LC-MS (ES, m/z): 424 [M+H]+.
Step 2: Synthesis of (ii)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5- (methylsulfonamido)thiazole-4-carboxamide
Figure imgf000169_0002
[0399] Similar to the procedure as described in General Procedure G, 2-(3-iodophenyl)-5- methanesulfonamido-l,3-thiazole-4-carboxamide was reacted with (ii)-3-ethynyl-3-hydroxy-l- methylpyrrolidin-2-one to give the title compound (65.7 mg, 43%) as an off-white solid. LC-MS (ES, m/z): 435 [M+H]+. lH NMR (400MHz, CD3OD): δ 8.01 (s, 1H), 7.92-7.90 (d, / = 7.2 Hz, 1H), 7.45-7.39 (m, 2H), 3.55-3.42 (m, 2H), 2.99 (s, 3H), 2.95 (s, 3H), 2.64-2.59 (m, 1H), 2.36- 2.29 (m, 1H).
Example 52
Synthesis of (R)-2-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-(2,2,2- trifluoroethylamino)thiazole-4-carboxamide
Figure imgf000170_0001
Step 1 : Synthesis of ethyl 5-[[(tert-butoxy)carbonyl](2,2,2-trifluoroethyl)amino]-2-(3- iodophenyl)-l,3-thiazole-4-carboxylate
Figure imgf000170_0002
[0400] A solution of ethyl 5-[[(tert-butoxy)carbonyl]amino]-2-(3-iodophenyl)-l,3-thiazole-4- carboxylate (500.00 mg, 1.054 mmol, 1.00 equiv), 2,2,2-trifluoroethyl trifluoromethanesulfonate (489.34 mg, 2.108 mmol, 2.00 equiv), cesium carbonate (686.93 mg, 2.108 mmol, 2.00 equiv) in dimethyl sulfoxide (20 mL) was stirred for 12 h at 55 °C. The resulting solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 : 10) to give the title compound (400 mg, 68%) as yellow oil. LC-MS (ES, m/z): 557 [M+H]+.
Step 2: Synthesis of tert-butyl N-[4-carbamoyl-2-(3-iodophenyl)-l,3-thiazol-5-yl]-N-(2,2,2- trifluoroethyl)carbamate
Figure imgf000170_0003
[0401] Similar to the procedure as described in General Procedure S, ethyl 5-[[(tert- butoxy)carbonyl](2,2,2-trifluoroethyl)amino]-2-(3-iodophenyl)-l,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (180 mg, 47%) as yellow oil. LC-MS (ES, m/z): 528 [M+H]+.
Step 3: Synthesis of 2-(3-iodophenyl)-5-[(2,2,2-trifluoroethyl)amino]-l ,3-thiazole-4- carboxamide
Figure imgf000171_0001
[0402] A solution of tert-butyl N-[4-carbamoyl-2-(3-iodophenyl)-l,3-thiazol-5-yl]-N-(2,2,2- trifluoroethyl)carbamate (180 mg, 0.341 mmol, 1.00 equiv) in 1,4-dioxane (10 niL, saturated with hydrogen chloride) was stirred overnight at room temperature. After completion, the solution was adjusted pH to 7 with aq. sodium hydroxide and then extracted with
dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with dichloromethane/methanol (10: 1) to give the title compound (140 mg, 96%) as a yellow solid. LC-MS (ES, m/z): 428 [M+H]+.
Step 4: Synthesis of (ii)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5- (2,2,2-trifluoroethylamino)thiazole-4-carboxarnide
Figure imgf000171_0002
[0403] Similar to the procedure as described in General Procedure G, 2-(3-iodophenyl)-5- [(2,2,2-trifluoroethyl)amino]-l,3-thiazole-4-carboxamide was reacted with (ii)-3-ethynyl-3- hydroxy-l-methylpyrrolidin-2-one to give the title compound (63.4 mg, 44%) as a white solid. LC-MS (ES, m/z): 439 [M+H]+. XH NMR (400MHz, CD3OD): δ 7.98 (s, 1H), 7.86-7.84 (d, / = 7.6 Hz, 1H), 7.50-7.42 (m, 2H), 4.13-4.06 (m, 2H), 3.54-3.47 (m, 2H), 2.95 (s, 3H), 2.64-2.58 (m, 1H), 2.37-2.30 (m, 1H).
Example 53
Synthesis of (R)-5-(ethylamino)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000172_0001
Step 1 : Synthesis of ethyl 5-[[(tert-butoxy)carbonyl](ethyl)amino]-2-(3-iodophenyl)-l,3-thiazole- -carboxylate
Figure imgf000172_0002
[0404] A solution of ethyl 5-[[(tert-butoxy)carbonyl]amino]-2-(3-iodophenyl)-l,3-thiazole-4- carboxylate (500.00 mg, 1.054 mmol, 1.00 equiv), iodoethane (197.29 mg, 1.265 mmol, 1.20 equiv), cesium carbonate (686.93 mg, 2.108 mmol, 2.00 equiv) in dimethyl sulfoxide (30 mL) was stirred for 4 h at 40 °C. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 : 10) to give the title compound 490 mg (93%) as light yellow oil. LC- MS (ES, m/z): 503 [M+H]+.
Step 2: Synthesis of tert-buty\ N-[4-carbamoyl-2-(3-iodophenyl)-l ,3-thiazol-5-yl]-N-(2,2,2- trifluoroethyl)carbamate
Figure imgf000172_0003
[0405] Similar to the procedure as described in General Procedure S, ethyl 5-[[(tert- butoxy)carbonyl](2,2,2-trifluoroethyl)amino]-2-(3-iodophenyl)-l,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (180 mg, 93%) as yellow oil. LC-MS (ES, m/z): 474 [M+H]+.
Step 3: Synthesis of 5-(ethylamino)-2-(3-iodophenyl)-l,3-thiazole-4-carboxamide
Figure imgf000173_0001
[0406] A solution of ethyl 5-[[(ieri-butoxy)carbonyl](ethyl)amino]-2-(3-iodophenyl)-l,3- thiazole-4-carboxylate (180 mg, 0.358 mmol, 1.00 equiv) in 1,4-dioxane (10 niL, saturated with hydrogen chloride) was stirred overnight at room temperature. After completion, the solution was adjusted pH to 7 with aq. sodium hydroxide and then extracted with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with
dichloromethane/methanol (10: 1) to give the title compound (130 mg, 97%) as a light yellow solid. LC-MS (ES, m/z): 374 [M+H]+.
Step 4: Synthesis of (ii)-5-(ethylamino)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000173_0002
[0407] Similar to the procedure as described in General Procedure G, 5-(ethylamino)-2-(3- iodophenyl)-l,3-thiazole-4-carboxamide was reacted with (ii)-3-ethynyl-3-hydroxy-l- methylpyrrolidin-2-one to give the title compound (31.2 mg, 23%) as a white solid. LC-MS (ES, m/z): 385 [M+H]+. 1H NMR (400MHz, CD3OD): δ 7.94 (s,lH), 7.81 (d, / = 7.2 Hz, 1H), 7.46- 7.40 (m, 2H), 3.54-3.49 (m, 2H), 3.39-3.36 (m, 2H), 2.95 (s, 3H), 2.64-2.58 (m, 1H), 2.37-2.30 (m, 1H), 1.35 (t, / = 7.2 Hz, 3H).
Example 54
Synthesis of (R)-2-(5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)-2- methylphenyl)thiazole-4-carboxamide
Figure imgf000174_0001
Synthesis of ethyl 2-(5-hydroxy-2-methylphenyl)-l ,3-thiazole-4-carboxylate
Figure imgf000174_0002
[0408] Similar to the procedure as described in General Procedure M, ethyl 2-bromo-l,3- thiazole-4-carboxylate was reacted with 4-methyl-3-(tetramethyl-l,3,2-dioxaborolan-2-yl)phenol to give the title compound (4.48 g, 96%) as yellow oil. LC-MS (ES, m/z): 264 [M+H]+.
Step 2: Synthesis of ethyl 2-[2-methyl-5-[(trifluoromethane)sulfonyloxy]phenyl]-l ,3-thiazole-4- carboxylate
Figure imgf000174_0003
[0409] A solution of ethyl 2-(5-hydroxy-2-methylphenyl)-l ,3-thiazole-4-carboxylate (4.48 g, 17.014 mmol, 1.00 equiv), 1,1 ,1-trifluoro-N-phenyl-N-
(trifluoromethane)sulfonylmethanesulfonamide (9.1 g, 25.472 mmol, 1.50 equiv) and triethylamine (8 mL) in dichloromethane (50 mL) was stirred for 12 h at room temperature. The pH of the solution was adjusted to 8 and the mixture was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluted with ethyl acetate/petroleum ether (1 : 1) to give the title compound (3.85 g, 57%) as a white solid. LC-MS (ES, m/z): 396 [M+H]+.
Step 3: Synthesis of ethyl 2-(5-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]-2- methylphenyl)- 1 ,3-thiazole-4-carboxylate
Figure imgf000175_0001
[0410] Similar to the procedure as described in General Procedure G, ethyl 2-[2-methyl-5- [(trifluoromethane)sulfonyloxy]phenyl]-l,3-thiazole-4-carboxylate was reacted with (R)-3- ethynyl-3 -hydroxy- 1 -methylpyrrolidin-2-one to give the title compound (111 mg, 57%) as a white solid. LC-MS (ES, m/z): 385 [M+H]+.
Step 4: Synthesis of (ii)-2-(5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)-2- methylphenyl)thiazole-4-carboxamide
Figure imgf000175_0002
[0411] Similar to the procedure as described in General Procedure S, ethyl 2-(5-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]-2-methylphenyl)-l ,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (18 mg, 18%) as a white solid. LC-MS (ES, m/z): 356 [M+H]+. lH NMR (300MHz, CD3OD): δ 8.33 (s, 1H), 7.90 (d, / = 1.5Hz, 1H), 7.48 (dd, J = 7.8Hz, 1.5Hz, 1H), 7.38 (d, J = 8.1Hz, 1H), 3.51-3.45 (m, 2H), 2.94 (m, 3H), 2.63 (s, 3H), 2.60-2.55 (m, 1H), 2.36-2.27 (m, 1H).
Example 55
Synthesis of l-(3-(((R)-3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)- 3a,4,6,6a-tetrahydro-lH-furo[3,4-c]pyrazole-3-carboxamide
Figure imgf000175_0003
Step 1 : Synthesis of ethyl l-(3-iodophenyl)-lH,3aH,4H,6H,6aH-furo[3,4-c]pyrazole-3- carboxylate
Figure imgf000176_0001
[0412] To a solution of ethyl 2-chloro-2-[(E)-2-(3-iodophenyl)diazen-l-yl]acetate (3.6 g, 10.21 mmol, 1.00 equiv) in 2,5-dihydrofuran (10 niL) was added triethylamine (1.03 g, 10.18 mmol, 1.00 equiv) dropwise with stirring at -15°C. The resulting solution was stirred overnight at room temperature, diluted with water, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 : 10). This resulted in the title compound (300 mg, 7%) as a yellow solid. LC-MS (ES, m/z): 387 [M+H]+.
Step 2: Synthesis of ethyl l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- l]ethynyl]phenyl)-lH aH,4H,6H,6aH-furo[3,4-c]pyrazole-3-carboxylate
Figure imgf000176_0002
[0413] Similar to the procedure as described in General Procedure G, ethyl l-(3-iodophenyl)- lH,3aH,4H,6H,6aH-furo[3,4-c]pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl-3- hydroxy-l-methylpyrrolidin-2-one to give the title compound (170 mg, 64%) as yellow oil. LC- MS (ES, m/z): 398 [M+H]+.
Step 3: Synthesis of l-(3-(((ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)- 3a,4,6,6a-tetrahydro-lH-furo[3,4-c]pyrazole-3-carboxamide
Figure imgf000176_0003
[0414] Similar to the procedure as described in General Procedure S, ethyl l-(3-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-lH,3aH,4H,6H,6aH-furo[3,4- c]pyrazole-3-carboxylate was reacted with ammonia to give the title compound (72.6 mg, 37%) as a mixture of stereoisomers. LC-MS (ES, m/z): 369 [M+H]+. XH NMR (300MHz, DMSO-J6): δ 7.72 (s, 1H), 7.31-7.13 (m, 3H), 7.10-7.10 (m, 1H), 6.93-6.91 (m, 1H), 6.42 (s, 1H), 5.06-5.01 (m, 1H), 4.15-3.97 (m, 3H), 3.80-3.75 (m, 2H), 3.38-3.31 (m, 2H), 2.79 (s, 3H), 2.50-2.37 (m, 1H), 2.22-2.15 (m, 1H).
Example 56
Synthesis of (R)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-6,7- dihydro-5H-pyrrolo[l,2-e]imidazole-3-carboxamide
Figure imgf000177_0001
Step 1 : Synthesis of pent-4-yn-l-yl methanesulfonate
Figure imgf000177_0002
[0415] To a solution of pent-4-yn-l-ol (3 g, 35.66 mmol, 1.00 equiv), triethylamine (5.77 g, 57.02 mmol, 1.60 equiv) in dichloromethane (20 mL) was added methanesulfonyl chloride (4.9 g, 42.78 mmol, 1.20 equiv) dropwise with stirring for 1 h at 0 °C. After completion the resulting solution was diluted with dichloromethane and then washed with brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound (3.1 g, 54%) as an off-white solid. LC-MS (ES, m/z): 163 [M+H]+.
Step 2: Synthesis of 5-azidopent-l-yne
Figure imgf000177_0003
[0416] To a solution of pent-4-yn-l-yl methanesulfonate (3 g, 18.495 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL) was added sodium azide (2.4 g, 36.917 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at room temperature, diluted with aq. sodium bicarbonate, and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in the title compound (2.5 g, crude) as a brown solid. LC-MS (ES, m z): HO [M+H]+. Step 3: Synthesis of ethyl 5H,6H,7H-pyrrolo[l ,2-c]imidazole-3-carboxylate
Figure imgf000178_0001
[0417] A solution of 5-azidopent-l-yne (1.0 g, 9.16 mmol, 1.00 equiv), 2-ethoxy-2- oxoacetonitrile (5 mL, 50.46 mmol, 5.50 equiv), gold(iii) trichloride (139 mg, 0.46 mmol, 0.05 equiv), and methanesulfonic acid (969 mg, 10.08 mmol, 1.10 equiv) in methyl cyanoformate (5 mL) was stirred for 12 h at room temperature. The resulting solution was concentrated under vacuum. The residue was dissolved with ethyl acetate and then was washed with aq. sodium bicarbonate and brine. The organic layer was dried over anhydrous sodium sulfate and
concentrated under vacuum. The residue was purified by a silica gel column chromatography eluting with dichloromethane/methanol (10: 1) to give the title compound (350 mg, crude) as a light yellow solid. LC-MS (ES, m/z): 167 [M+H]+.
tep 4: Synthesis of ethyl l-iodo-5H,6H,7H-pyrrolo[l,2-c]imidazole-3-carboxylate
Figure imgf000178_0002
[0418] A solution of ethyl 5H,6H,7H-pyrrolo[l,2-c]imidazole-3-carboxylate (350.00 mg, 1.94 mmol, 1.00 equiv), N-iodosuccinimide (436.98 mg, 1.94 mmol, 1.00 equiv) in acetonitrile (5 mL) was stirred for 6 h at 70 °C. The reaction was quenched with aq. sodium thiosulfate and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 : 1). This resulted in the title compound (70 mg, 12%) as a light yellow solid. LC-MS (ES, m/z): 293 [M+H]+.
Step 5: Synthesis of ethyl l-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-5H,6H,7H-pyrrolo[l ,2-c]imidazole-3-carboxylate
Figure imgf000179_0001
[0419] Similar to the procedure as described in General Procedure U, ethyl l-iodo-5H,6H,7H- pyrrolo[l,2-c]imidazole-3-carboxylate was reacted with potassium (ii)-trifluoro(3-((3-hydroxy- l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the title compound (20 mg, 52%) as a white solid. LC-MS (ES, m/z): 380 [M+H]+.
Step 6: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-6,7- dihydro-5H-pyrrolo[l ,2-e]imidazole-3-carboxamide
Figure imgf000179_0002
[0420] Similar to the procedure as described in General Procedure S, ethyl l-(3-[2-[(3ii)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5H,6H,7H-pyrrolo[l ,2-c]imidazole-3- carboxylate was reacted with ammonia to give the title compound (5.8 mg, 25%) as a white solid. LC-MS (ES, m/z): 365 [M+H]+. lH NMR (300MHz, CD3OD): δ 7.84 (s, 1H), 7.77-7.70 (m, 1H), 7.41-7.31 (m, 2H), 4.38-4.33 (m, 2H), 3.54-3.46 (m, 2H), 3.15-3.10 (m, 2H), 2.94 (s, 3H), 2.80- 2.73 (m, 2H), 2.63-2.55 (m, 1H), 2.36-2.26 (m, 1H).
Example 57
Synthesis of (R)-5-((lH-pyrazol-l-yl)methyl)-2-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000179_0003
Step 1 : Synthesis of methyl 2-bromo-5- bromomethyl)-l,3-thiazole-4-carboxylate
Figure imgf000180_0001
[0421] A solution of methyl 2-bromo-5-methyl-l,3-thiazole-4-carboxylate (500.00 mg, 2.118 mmol, 1.00 equiv), N-bromosuccinimide (570 mg, 3.203 mmol, 1.51 equiv) and benzoyl peroxide (217.08 mg, 0.847 mmol, 0.40 equiv) in carbon tetrachloride (80 mL) was stirred for 14 h at 80 °C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 :30). This resulted in the title compound 650 mg (97%) as yellow oil. LC-MS (ES, m/z): 314 [M+H]+. Step 2: Synthesis of methyl 2-bromo-5-(lH-pyrazol-l-ylmethyl)-l ,3-thiazole-4-carboxylate
Figure imgf000180_0002
[0422] A solution of methyl 2-bromo-5-(bromomethyl)-l,3-thiazole-4-carboxylate (600.00 mg, 1.905 mmol, 1.00 equiv), cesium carbonate (1861.93 mg, 5.715 mmol, 3.00 equiv), and 1H- pyrazole (389.04 mg, 5.715 mmol, 3.00 equiv) in acetonitrile (50 mL) was stirred for 3 h at room temperature. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 :5). This resulted in the title compound (85 mg, 15%) as a yellow solid. LC-MS (ES, m/z): 302 [M+H]+. Step 3: Synthesis of methyl 2-(3-[2-[(3ii)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-5-(lH-pyrazol-l-ylmethyl)-l,3-thiazole-4-carboxylate
Figure imgf000180_0003
[0423] Similar to the procedure as described in General Procedure U, methyl 2-bromo-5-(lH- pyrazol-l-ylmethyl)-l,3-thiazole-4-carboxylate was reacted with potassium (ii)-trifluoro(3-((3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the title compound (70 mg, 61%) as a red solid. LC-MS (ES, m/z): 437 [M+H]+.
Step 4: Synthesis of (ii)-5-((lH-pyrazol-l-yl)methyl)-2-(3-((3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000181_0001
[0424] Similar to the procedure as described in General Procedure S, methyl 2-(3-[2-[(3ii)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-(lH-pyrazol-l-ylmethyl)-l,3- thiazole-4-carboxylate was reacted with ammonia to give the title compound (8.9 mg, 13%) as a white solid. LC-MS (ES, m z): 422 [M+H]+. XH NMR (300MHz, CD3OD): δ 8.07 (t, / = 1.2 Hz, IH), 7.96-7.90 (m, IH), 7.85 (s, IH), 7.58-7.54 (m, 2H), 7.46 (t, J = 7.5 Hz, IH), 6.36 (t, / = 2.1 Hz, IH), 6.07 (s, 2H), 3.48-3.46 (m, 2H), 2.93 (s, 3H), 2.65-2.55 (m, IH), 2.35-2.25 (m, IH).
Example 58
Synthesis of (R)-2-(2,4-difluoro-5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-5-methylthiazole-4-carboxamide
Figure imgf000181_0002
Synthesis of ethyl 2-(5-bromo-2,4-difluorophenyl)-5-methylthiazole-4-carboxylate
Figure imgf000181_0003
[0425] Similar to the procedure as described in General Procedure M, ethyl 2-bromo-5- methylthiazole-4-carboxylate was reacted with 2-(5-bromo-2,4-difluorophenyl)-4,4,5,5- tetramethyl-l ,3,2-dioxaborolane to give the title compound (510 mg, 69%) as a white solid. LC- MS (ES, m/z): 362 [M+H]+.
Step 2: Synthesis of (R)-ethyl 2-(2,4-difluoro-5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-5-methylthiazole-4-carboxylate
Figure imgf000182_0001
[0426] Similar to the procedure as described in General Procedure G, ethyl 2-(5-bromo-2,4- difluorophenyl)-5-methylthiazole-4-carboxylate was reacted with (ii)-3-ethynyl-3-hydroxy-l- methylpyrrolidin-2-one to give the title compound (200 mg, 86%) as a white solid. LC-MS (ES, m/z): 421 [M+H]+.
Step 3: Synthesis of (ii)-2-(2,4-difluoro-5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-5-methylthiazole-4-carboxamide
Figure imgf000182_0002
[0427] Similar to the procedure as described in General Procedure S, (ii)-ethyl 2-(2,4- difluoro-5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-methylthiazole-4- carboxylate was reacted with ammonia to give the title compound (55.5 mg, 29%) as a white solid. LC-MS (ES, m/z): 392 [M+H]+. lH NMR (300MHz, DMSO-J6): δ 8.61-8.57 (m, IH), 8.15 (s, IH), 7.70-7.65 (m, IH), 7.53 (s, IH), 6.58 (s, IH), 3.38-3.32 (m, 2H), 2.80 (s, 3H), 2.78 (s, 3H), 2.49-2.44 (m, IH), 2.25-2.20 (m, IH).
Example 59
Synthesis of (R)-5-(difluoroniethyl)-2-(2-fluoro-5-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000183_0001
Step 1 : Synthesis of methyl 2-bromo 5-(dibromomethyl)-l,3-thiazole-4-carboxylate
Figure imgf000183_0002
[0428] To a solution of methyl 2-bromo-5-methyl-l,3-thiazole-4-carboxylate (350.00 mg, 1.483 mmol, 1.00 equiv) and N-bromosuccinimide (790 mg, 4.439 mmol, 2.99 equiv) in carbon tetrachloride (20 mL) was added benzoyl peroxide (73 mg, 0.285 mmol, 0.19 equiv). The resulting solution was stirred for 3 h at 80 °C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 : 10). This resulted in the title compound (760 mg, crude) as colorless oil. LC-MS (ES, m/z): 394 [M+H]+.
Step 2: Synthesis of methyl 2-bromo-5-formyl-l,3-thiazole-4-carboxylate
Figure imgf000183_0003
[0429] A solution of methyl 2-bromo-5-(dibromomethyl)-l,3-thiazole-4-carboxylate (700.00 mg, 1.777 mmol, 1.00 equiv) and silver nitrate (610 mg, 3.591 mmol, 2.02 equiv) in ethanol (20 mL)/water (2 mL) was stirred for 3 h at 80 °C. The precipitates were filtered out and the filtrate was concentrated under vacuum to give the title compound (560 mg, crude) as a yellow solid. LC-MS (ES, m/z): 250 [M+H]+.
Step 3: Synthesis of methyl 2-bromo-5-(difluoromethyl)-l,3-thiazole-4-carboxylate
Figure imgf000183_0004
[0430] Similar to the procedure as described in General Procedure L, methyl 2-bromo-5- formyl-l,3-thiazole-4-carboxylate was reacted with bis(2-methoxyethyl)aminosulfur trifluoride to give the title compound (270 mg, 44%) as a yellow solid. LC-MS (ES, m/z): 272 [M+H]+. Step 4: Synthesis of 2-bromo-5-(difluoromethyl)-l,3-thiazole-4-carboxamide
Figure imgf000184_0001
[0431] Similar to the procedure as described in General Procedure S, methyl 2-bromo-5- (difluoromethyl)-l,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (250 mg, 95%) as a yellow solid. LC-MS (ES, m z): 257 [M+H]+.
Step 5: Synthesis of (R)-5-(difluoromethyl)-2-(2-fluoro-5-((3-hydroxy-l-methyl-2- oxopyrrolidin- -yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000184_0002
[0432] Similar to the procedure as described in General Procedure U, 2-bromo-5- (difluoromethyl)-l,3-thiazole-4-carboxamide was reacted with potassium (ii)-trifluoro(2-fluoro- 5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the title compound (52.0 mg, 14%) as a pink solid. LC-MS (ES, m/z): 410 [M+H]+. 1H NMR (300MHz, DMSO-J6): δ 8.60-8.57 (m, 1H), 8.52 (s, 1H), 8.03 (s, 1H), 7.93 (t, / = 47.2 Hz, 1H), 7.70-7.65 (m, 1H), 7.58-7.51 (m, 1H), 3.38-3.30 (m, 2H), 2.81(s, 3H), 2.50-2.42 (m, 1H), 2.27-2.18 (m, 1H).
Example 60
Synthesis of (R)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5- methyloxazole-4-carboxamide
Figure imgf000185_0001
Step 1 : Synthesis of 2-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-
Figure imgf000185_0002
[0433] Similar to the procedure as described in General Procedure U, ethyl 2-bromo-5-methyl- l,3-oxazole-4-carboxylate was reacted with potassium (ii)-trifluoro(3-((3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the title compound (403 mg, 55%) as a light yellow solid. LC-MS (ES, m/z): 369 [M+H]+.
Step 2: Synthesis of (ii)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5- methyloxazole-4-carboxamide
Figure imgf000185_0003
[0434] Similar to the procedure as described in General Procedure S, ethyl 2-(3-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-methyl-l ,3-oxazole-4-carboxylate was reacted with ammonia to give the title compound (51 mg, 16%) as a white solid. LC-MS (ES, m/z): 340 [M+H]+. XH NMR (300 MHz, DMSO-J6): δ 8.02-7.95 (m, 2H), 7.63-7.57 (m, 3H), 7.48 (s, IH), 6.53 (s, IH), 3.38-3.31 (m, 2H), 2.81 (s, 3H), 2.65 (s, 3H), 2.47-2.43 (m, IH), 2.28-2.12 (m, IH).
Example 61
Synthesis of (R)-l-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5- niethoxy-lH-pyrazole-3-carboxaniide
Figure imgf000186_0001
Synthesis of methyl l-(3-bromophenyl)-5-hydroxy-lH-pyrazole-3-carboxylate
Figure imgf000186_0002
[0435] A solution of (3-bromophenyl)hydrazine hydrochloride (11 g, 49.217 mmol, 1.00 equiv), dimethyl but-2-ynedioate (7.1 g, 49.952 mmol, 1.02 equiv) and triethylamine (10 g, 98.824 mmol, 2.01 equiv) in ethanol (100 mL) was heated to reflux for 5 hr. The resulting mixture was concentrated under vacuum. The residue was purified by a silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 :2) to give the title compound (8.5 g, 58%) as an off-white solid. LC-MS (ES, m/z): 297 [M+H]+.
Step 2: Synthesis of methyl l-(3-bromophenyl)-5-methoxy-lH-pyrazole-3-carboxylate
Figure imgf000186_0003
[0436] A solution of methyl l-(3-bromophenyl)-5-hydroxy-lH-pyrazole-3-carboxylate (4.00 g, 12.86 mmol, 1.00 equiv), methyl iodide (2.74 g, 19.30 mmol, 1.50 equiv), cesium carbonate (6.28 g, 19.27 mmol, 1.50 equiv) in N,N-dimethylformamide (60 mL) was stirred for 3 h at room temperature. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under vacuum. The residue was purified by a silica gel column chromatography eluting with ethyl acetate/petroleum ether (1 :20) to give the title compound (2.3 g, 55%) as light yellow oil. LC-MS (ES, m/z): 311 [M+H]+.
Step 3: Synthesis of methyl l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-5-methoxy-lH-pyrazole-3-carboxylate
Figure imgf000187_0001
[0437] Similar to the procedure as described in General Procedure G, methyl l-(3- bromophenyl)-5-methoxy-lH-pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl-3-hydroxy- l-ethylpyrrolidin-2-one to give the title compound (200 mg, 84%) as red oil. LC-MS (ES, m/z): 384 [M+H]+.
Step 4: Synthesis of (ii)-l-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5- methoxy-lH-pyrazole-3-carboxamide
Figure imgf000187_0002
[0438] Similar to the procedure as described in General Procedure S, methyl l-(3-[2-[(3ii)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-methoxy-lH-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (40.6 mg, 21 %) as a white solid. LC-MS (ES, m/z): 355 [M+H]+. XH NMR (300MHz, CD3OD): δ 7.78 (s, 1H), 7.72 - 7.68 (m, 1H), 7.40 - 7.33 (m, 2H), 6.18 (s, 1H), 3.94 (s, 3H), 3.94 - 3.33 (m, 2H), 2.84 (s, 3H), 2.53 - 2.46 (m, 1H), 2.27 - 2.17 (m, 1H).
Example 62
Synthesis of (R)-4-(cyclobutanecarboxaniido)-l-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin- 3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000187_0003
Synthesis of ethyl l-(3-bromophenyl)-4-cyclobutaneamido-lH-pyrazole-3-carboxylate
Figure imgf000188_0001
[0439] A solution of ethyl 4-amino-l -(3-bromophenyl)-lH-pyrazole-3-carboxylate (300 mg, 0.967 mmol, 1.00 equiv), cyclobutanecarbonyl chloride (138 mg, 1.164 mmol, 1.20 equiv), and triethylamine (1.5 mL, 10.792 mmol, 11.16 equiv) in dichloromethane (8 mL) was stirred for 30 min at room temperature. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 : 10). This resulted in the title compound (320 mg, 84%) as a yellow solid. LC-MS (ES, m/z): 392 [M+H]+.
Step 2: Synthesis of ethyl 4-cyclobutaneamido-l -(3-[2-[(3R)-3-hydroxy- l-methyl-2- oxopyrrolidin-3-yl]ethynyl]phenyl)-lH-pyr
Figure imgf000188_0002
[0440] Similar to the procedure as described in General Procedure G, ethyl l-(3- bromophenyl)-4-cyclobutaneamido-lH-pyrazole-3-carboxylate was reacted with (ii)-3-ethynyl- 3-hydroxy-l -methylpyrrolidin-2-one to give the title compound (200 mg, 87%) as yellow oil. LC-MS (ES, m/z): 451 [M+H]+.
Step 3: Synthesis of (ii)-4-(cyclobutanecarboxamido)-l -(3-((3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000188_0003
[0441] Similar to the procedure as described in General Procedure S, ethyl 4- cyclobutaneamido-l -(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-lH- pyrazole-3-carboxylate was reacted with ammonia to give the title compound (80.7 mg, 43%) as a white solid. LC-MS (ES, m/z): 422 [M+H]+. 1H NMR (300MHz, CD3OD): δ 8.79 (s, 1H), 7.99 (s, 1H), 7.88 - 7.86 (m, 1H), 7.55 - 7.44 (m, 2H), 3.53 - 3.47 (m, 2H), 3.42 - 3.31 (m, 1H), 2.66 (s, 3H), 2.65 - 2.58 (m, 1H), 2.43 - 2.32 (m, 5H), 2.31 - 2.26 (m, 1H), 2.17 - 2.15 (m, 1H).
Example 63
Synthesis of (R)-5-(cyclopropanecarboxamido)-2-(3-((3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000189_0001
Synthesis of ethyl 2-(3-bromophenyl)-5-cyclopropaneamido-l,3-thiazole-4-carboxylate
Figure imgf000189_0002
[0442] A solution of ethyl 5-amino-2-(3-bromophenyl)-l,3-thiazole-4-carboxylate (100 mg, 0.306 mmol, 1.00 equiv), cyclopropanecarbonyl chloride (30 mg, 0.287 mmol, 0.94 equiv), triethylamine (0.1 mL, 0.719 mmol, 2.35 equiv) in dichloromethane (5 mL) was stirred for 30 min at room temperature. The resulting solution was concentrated under vacuum and the residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1: 10). This resulted in the title compound (100 mg, 83%) as a yellow solid. LC-MS (ES, m/z): 381 [M+H]+.
Step 2: Synthesis of ethyl 5-cyclopropaneamido-2-(3-[2-[(3R)-3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl]ethynyl]phenyl)-l,3-th
Figure imgf000189_0003
[0443] Similar to the procedure as described in General Procedure G, ethyl 2-(3- bromophenyl)-5-cyclopropaneamido-l,3-thiazole-4-carboxylate was reacted with (ii)-3-ethynyl- 3-hydroxy-l-methylpyrrolidin-2-one to give the title compound (100 mg, 87%) as a white solid. LC-MS (ES, m/z): 440 [M+H]+.
Step 3: Synthesis of (ii)-5-(cyclopropanecarboxamido)-2-(3-((3-hydroxy- l-methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000190_0001
[0444] Similar to the procedure as described in General Procedure S, ethyl 5- cyclopropaneamido-2-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)- l,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (35.4 mg, 25%) as a white solid. LC-MS (ES, m/z): 425 [M+H]+. 1H NMR (300MHz, CD3OD): δ 7.98 (s, 1H), 7.85 (d, / = 7.5 Hz, 1H), 7.43-7.33 (m, 2H), 3.44-3.38 (m, 2H), 2.98 (s, 3H), 2.60-2.46 (m, 1H), 2.26-2.17 (m, 1H), 1.90 -1.78 (m, 1H), 0.98-0.89 (m, 4H).
Example 64
Synthesis of (R)-2-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3-yl)ethynyl)phi
(methoxymethyl)thiazole-4-carboxamide
Figure imgf000190_0002
Synthesis of methyl 2-bromo-5-(hydroxymethyl)-l,3-thiazole-4-carboxylate
Figure imgf000190_0003
[0445] Similar to the procedure as described in General Procedure K, methyl 2-bromo-5- formyl-l,3-thiazole-4-carboxylate was reacted with sodium borohydride to give the title compound (2.2 g, 73%) as a white solid. LC-MS (ES, m/z): 252 [M+H]+.
Step 2: Synthesis of methyl 2-bromo-5-(methoxymethyl)-l,3-thiazole-4-carboxylate
Figure imgf000191_0001
[0446] A solution of methyl 2-bromo-5-(hydroxymethyl)-l ,3-thiazole-4-carboxylate (1 g, 3.967 mmol, 1.00 equiv), sodium hydride (320 mg, 8.001 mmol, 2.02 equiv, 60%), methyl iodide (0.3 mL, 4.82 mmol, 1.215 equiv) in N,N-dimethylformamide (40 mL) was stirred for 2 min at 0 °C. The reaction was quenched with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 : 10) to give the title compound (0.2 g, 19%) as yellow oil. LC-MS (ES, m/z): 266
[M+H]+.
Step 3: Synthesis of 2-bromo-5-(methoxymethyl)-l ,3-thiazole-4-carboxamide
Figure imgf000191_0002
[0447] Similar to the procedure as described in General Procedure S, methyl 2-bromo-5-
(methoxymethyl)-l,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (0.19 g, 95%) as a white solid. LC-MS (ES, m/z): 251 [M+H]+.
Step 4: Synthesis of (ii)-2-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)-5-
(methoxymethyl)thiazole-4-carboxamide
Figure imgf000191_0003
m ar to t e proce ure as escr e n enera roce ure , - romo- - (methoxymethyl)-l,3-thiazole-4-carboxamide was reacted with potassium (ii)-trifluoro(3-((3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the title compound (73.9 mg, 25%) as a white solid. LC-MS (ES, m/z): 386 [M+H]+. lH NMR (300MHz, CD3OD): δ 8.12 (s, IH), 8.00-7.97 (m, IH), 7.58-7.46 (m, 2H), 5.08 (s, 2H), 3.51-3.47 (m, 5H), 2.94 (s, 3H), 2.63-2.57 (m, IH), 2.37-2.31 (m, IH).
Example 65
Synthesis of (R)-4-(2-fluoro-5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-2-carboxamide
Figure imgf000192_0001
Step 1 : Synthesis of methyl 4-bromo-l,3-thiazole-2-carboxylate
Figure imgf000192_0002
[0449] Similar to the procedure as described in General Procedure O, 2,4-dibromo-l,3- thiazole was reacted with carbon monoxide to give the title compound (1.2 g, 13%) as a Hi yellow solid. LC-MS (ES, m/z): 222 [M+H]+.
Step 2: Synthesis of 4-bromo-l ,3-thiazole-2-carboxamide
Figure imgf000192_0003
[0450] Similar to the procedure as described in General Procedure S, methyl 4-bromo-l,3- thiazole-2-carboxylate was reacted with ammonia to give the title compound (410 mg, 88%) as a light yellow solid. LC-MS (ES, m/z): 207 [M+H]+.
Step 3: Synthesis of (ii)-4-(2-fluoro-5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)thiazole-2-carboxamide
Figure imgf000193_0001
[0451] Similar to the procedure as described in General Procedure U, 4-bromo-l ,3-thiazole-2- carboxamide was reacted with potassium (R)-trifluoro(2-fluoro-5-((3-hydroxy-l-methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the title compound (46.1 mg, 19%) as a white solid. LC-MS (ES, m/z): 361 [M+H]+. lH NMR (300MHz, CDC13): δ 8.46-8.43 (m, IH), 8.18 (s, IH), 7.52-7.48 (m, IH), 7.28-7.22(m, IH), 3.48-3.45 (m, 2H), 2.94 (s, 3H), 2.63-2.53 (m, IH), 2.36-2.29 (m, IH).
Example 66
Synthesis of (R)-4-(3-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)phi
methoxythiazole-2-carboxamide
Figure imgf000193_0002
Synthesis of ethyl [(2-methoxy-2-oxoethyl)carbamoyl]formate
Figure imgf000193_0003
[0452] A solution of ethyl 2-chloro-2-oxoacetate (20.1 g, 147.216 mmol, 1.00 equiv), methyl 2-aminoacetate hydrochloride (12.6 g, 100.355 mmol, 0.68 equiv), triethylamine (30.3 g, 299.437 mmol, 2.03 equiv) in dichloromethane (800 mL) was stirred for 4 h at 25°C. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:4). This resulted in the title compound (17.5 g, 63%) as yellow oil. LC-MS (ES, m/z): 190 [M+H]+.
Step 2: Synthesis of ethyl 5-methoxy-l,3-thiazole-2-carboxylate
Figure imgf000194_0001
[0453] A solution of ethyl 2-(2-methoxy-2-oxoacetamido)acetate (5 g, 26.432 mmol, 1.00 equiv), phosphorus pentasulfide (6.45 g, 29.018 mmol, 1.10 equiv) in 1,4-dioxane (150 mL) was stirred for 12 h at 110 °C. The solid was removed and the filtrate was concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:4) to give the title compound (0.24 g, 5%) as brown oil. LC-MS (ES, m/z): 188 [M+H]+.
Step 3: Synthesis of ethyl 4-bromo-5-methoxy-l,3-thiazole-2-carboxylate
Figure imgf000194_0002
[0454] A solution of ethyl 5-methoxy-l,3-thiazole-2-carboxylate (188 mg, 1.004 mmol, 1.00 equiv), N-bromosuccinimide (356 mg, 2.00 mmol, 1.99 equiv) in acetonitrile (20 mL) was stirred for 4 h at 20 °C. The resulting solution was concentrated under vacuum and the residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1:3). This resulted in the title compound (200 mg, 75%) as a yellow solid. LC-MS (ES, m/z): 266 [M+H]+.
Step 4: Synthesis of ethyl 4-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-5-methoxy-l,3-thiazole-2-carboxylate
Figure imgf000194_0003
[0455] Similar to the procedure as described in General Procedure U, ethyl 4-bromo-5- methoxy-l,3-thiazole-2-carboxylate was reacted with potassium (ii)-trifluoro(3-((3-hydroxy-l- methyl-2-oxopyrrolidin-3-yl)ethynyl)phenyl)borate to give the title compound (84 mg, 28%) as a yellow solid. LC-MS (ES, m/z): 401 [M+H]+.
Step 5: Synthesis of 4-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5- methoxy-l,3-thiazole-2-carboxamide
Figure imgf000195_0001
[0456] Similar to the procedure as described in General Procedure S, ethyl 4-(3-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-5-methoxy-l ,3-thiazole-2-carboxylate was reacted with ammonia to give the title compound (28.3 mg, 36%) as a white solid. LC-MS (ES, m/z): 372 [M+H]+. XH NMR (400MHz, CD3OD): δ 8.17 (s, IH), 8.09-8.08 (d, J = 7.2 Hz, IH), 7.44-7.38 (m, 2H), 4.20 (s, 3H), 3.54-3.47 (m, 2H), 2.95 (s, 3H), 2.64-2.58 (m, IH), 2.37- 2.30 (m, IH).
Example 67
Synthesis of (R)-4-(difluoroniethyl)-l-(3-((3-hydroxy-l-niethyl-2-oxopyrrolidin-3- yl)ethynyl)phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000195_0002
Synthesis of ethyl l-(3-bromophenyl)-4-methyl-lH-pyrazole-3-carboxylate
Figure imgf000196_0001
[0457] Similar to the procedure as described in General Procedure C, ethyl 4-methyl-lH- pyrazole-3 -carboxylate was reacted with 3-bromophenylboronic acid to give the title compound (6.24 g, 67%) as a white solid. LC-MS (ES, m/z): 309 [M+H]+.
Step 2: Synthesis of ethyl l-(3-bromophenyl)-4-(dibromomethyl)-lH-pyrazole-3-carboxylate
Figure imgf000196_0002
[0458] A solution of ethyl l-(3-bromophenyl)-4-methyl-lH-pyrazole-3-carboxylate (1.236 g, 3.998 mmol, 1.00 equiv), AIBN (262.7 mg, 1.60 mmol, 0.40 equiv) and N-bromosuccinimide (2.136 g, 12.00 mmol, 3.00 equiv) in carbon tetrachloride (100 mL) was stirred for 12 h at 80 °C. The solution was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 : 10) to give the title compound (1.99 g, crude) as a light yellow solid. LC-MS (ES, m/z): 465 [M+H]+.
Step 3: Synthesis of ethyl l-(3-bromophenyl)-4-formyl-lH-pyrazole-3-carboxylate
Figure imgf000196_0003
[0459] To a solution of ethyl l-(3-bromophenyl)-4-(dibromomethyl)-lH-pyrazole-3- carboxylate (1.167 g, 2.499 mmol, 1.00 equiv) in 1 ,4-dioxane (10 mL) was added a solution of silver nitrate (1.062 g, 6.252 mmol, 1.00 equiv) in water (4 mL). The resulting solution was stirred for 12 h at 70 °C and then was diluted with water and extracted with ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by a silica gel column chromatography and eluted with ethyl acetate/petroleum ether (1 : 10). This resulted in the title compound (613 mg, 76%) as a light yellow solid. LC-MS (ES, m/z): 323 [M+H]+.
Step 4: Synthesis of ethyl l-(3-bromophenyl)-4-(difluoromethyl)-lH-pyrazole-3-carboxylate
Figure imgf000197_0001
[0460] Similar to the procedure as described in General Procedure L, ethyl l-(3- bromophenyl)-4-formyl-lH-pyrazole-3-carboxylate was reacted with bis(2- methoxyethyl)aminosulfur trifluoride to give the title compound (539 mg, 82%) as a white solid. LC-MS (ES, m/z): 345 [M+H]+.
Step 5: Synthesis of l-(3-bromophenyl)-4-(difluoromethyl)-lH-pyrazole-3-carboxamide
Figure imgf000197_0002
[0461] Similar to the procedure as described in General Procedure S, ethyl l-(3- bromophenyl)-4-(difluoromethyl)-lH-pyrazole-3-carboxylate was reacted with ammonia to give the title compound (493 mg, 75%) as a white solid. LC-MS (ES, m/z): 316 [M+H]+.
Step 6: Synthesis of 4-(difluoromethyl)-l-(3-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3- yl]ethynyl]phenyl)-lH-pyrazole-3-carboxamide
Figure imgf000198_0001
[0462] Similar to the procedure as described in General Procedure G, l-(3-bromophenyl)-4- (difluoromethyl)-lH-pyrazole-3-carboxamide was reacted with (ii)-3-ethynyl-3-hydroxy-l- methylpyrrolidin-2-one to give the title compound (89.1 mg, 18%) as a white solid. LC-MS (ES, m/z): 375 [M+H]+. 1H NMR (300MHz, CD3OD): δ 8.73-8.72 (m, IH), 8.09-8.08 (m, IH), 7.97- 7.93 (m, IH), 7.58-7.14 (m, 3H), 3.54-3.50 (m, 2H), 2.96 (s, 3H), 2.66-2.58 (m, IH), 2.39-2.30 (m, IH).
Example 68
Synthesis of (R)-2-(5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)-2- methoxyphenyl)thiazole-4-carboxamide
Figure imgf000198_0002
Synthesis of ethyl 2-(5-bromo-2-methoxyphenyl)-l ,3-thiazole-4-carboxylate
Figure imgf000198_0003
[0463] Similar to the procedure as described in General Procedure M, ethyl 2-bromo-l,3- thiazole-4-carboxylate was reacted with 5-bromo-2-methoxyphenylboronic acid to give the title compound (381 mg, 33%) as a white solid. LC-MS (ES, m/z): 342 [M+H]+.
Step 2: Synthesis of ethyl 2-(5-[2-[(3R)-3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]-2- methoxyphenyl)-l,3-thiazole-4-carboxylate
Figure imgf000199_0001
[0464] Similar to the procedure as described in General Procedure G, ethyl 2-(5-bromo-2- methoxyphenyl)-l,3-thiazole-4-carboxylate was reacted with (ii)-3-ethynyl-3-hydroxy-l- methylpyrrolidin-2-one to give the title compound (279 mg, 66%) as yellow oil. LC-MS (ES, m/z): 401 [M+H]+.
Step 3: Synthesis of (ii)-2-(5-((3-hydroxy-l-methyl-2-oxopyrrolidin-3-yl)ethynyl)-2- methoxyphenyl)thiazole-4-carboxamide
Figure imgf000199_0002
[0465] Similar to the procedure as described in General Procedure S, ethyl 2-(5-[2-[(3R)-3- hydroxy-l-methyl-2-oxopyrrolidin-3-yl]ethynyl]-2-methoxyphenyl)-l ,3-thiazole-4-carboxylate was reacted with ammonia to give the title compound (35.8 mg, 13%) as a white solid. LC-MS (ES, m/z): 372 [M+H]+. lH NMR (300MHz, CD3OD): δ 8.61(s, 1H), 8.27(s, 1H), 7.60-7.56 (m, 1H), 7.23 (d, J = 8.7 Hz, 1H), 4.11 (s, 3H), 3.57-3.45 (m, 2H), 2.95 (s, 3H), 2.65-2.57 (m, 1H), 2.37-2.28 (m, 1H).
Example 69
Synthesis of (R)-5-(3,3-difluorocyclobutanecarboxamido)-2-(3-((3-hydroxy-l-niethyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000199_0003
Step 1 : Synthesis of (ii)-5-(3,3-difluorocyclobutanecarboxamido)-2-(3-((3-hydroxy-l -methyl-2- oxopyrrolidin-3-yl)ethynyl)phenyl)thiazole-4-carboxamide
Figure imgf000200_0001
Similar to the procedure as described in General Procedure B, 5-amino-2-(3-[2-[(3R)-3- hydroxy-l -methyl-2-oxopyrrolidin-3-yl]ethynyl]phenyl)-l ,3-thiazole-4-carboxarnide was reacted with 3,3-difluorocyclobutane-l -carboxylic acid to give the title compound (45 mg, 17%) as an off-white solid. LC-MS (ES, m/z): 475 [M+H]+. 1H NMR (300MHz, CD3OD): δ 8.12 (s, IH), 7.99-7.96 (m, IH), 7.57-7.46 (m, 2H), 3.55-3.47 (m, 2H), 3.37-3.34 (m, IH), 2.98 (s, 3H), 2.94-2.87 (m, 4H), 2.66-2.61 (m, IH), 2.60-2.34 (m, IH).
BIOLOGICAL EXAMPLES
[0466] NIK Enzyme Inhibition Assay: The ability of the nuclear factor-kappa B (NF-kB)- inducing kinase (NIK) to catalyze the hydrolysis of adenosine-5'-triphosphate (ATP) was monitored using the Transcreener ADP (adenosine-5 '-diphosphate) assay (BellBrook Labs). Purified NIK (0.5 nM) derived from a baculovirus-infected insect cell expression system was incubated with test compounds for 1-3.5 hours in 50 mM 2-[4-(2-hydroxyethyl)piperazin-l - yl]ethanesulfonic acid buffer (pH 7.2) containing 10 mM MgCl2, 2 mM dithiothreitol, 10 μΜ ATP, 0.01 % Triton X-100, 0.1 % gamma-globulins from bovine blood, 1 % dimethylsulfoxide (DMSO), 7 μg/mL ADP antibody and 5 nM ADP-MR121 633 tracer. Reactions were quenched by the addition of 20 mM 2,2',2",2"'-(ethane-l ,2-diyldinitrilo)tetraacetic acid and 0.01 % Brij 35. The tracer bound to the antibody was displaced by the ADP generated during the NIK reaction, which causes a decrease in fluorescence polarization that was measured by laser excitation at 633 nm with a Fluorescence Correlation Spectroscopy Plus reader (Evotec AG). Equilibrium dissociation constant (Ki) values for NIK inhibitors are calculated from plots of activity vs.
inhibitor concentration using Morrison's quadratic equation that accounts for the potential of tight binding, and by also applying the conversion factor that accounted for competitive inhibition and the concentration of substrate used in the assay relative to its Michaelis constant (Km). The compounds in listed in Table 1 have the corresponding inhibitory value (NIK ADP- FP, Kj in micromolar) for NIK described in Table 2 below. [0467] Cellular Assay: Several assays were developed to profile the cellular activities of NIK inhibitors.
[0468] (1) The first assay that can be used to profile whether a test compound can inhibit the NF-kB signal through NIK inhibition without affecting cell viability. In this assay, human embryonic kidney 293 cells are stably transfected with a tetracycline-inducible NIK DNA construct containing a cytomegalovirus promoter plus two reporter DNA constructs. One reporter encodes firefly luciferase under the control of three repeats of an NF-kB response element from the ELAM-1 gene and reflects the level of NIK activity in the cells, whereas the other reporter constitutively expresses Renilla luciferase under the control of the herpes simplex virus thymidine kinase promoter and serves as a general measure of cell viability. Cells are incubated with different concentrations of compounds (0.2% DMSO final) in medium containing 1 μg/mL doxycycline and 10% tet-system approved fetal bovine serum (Clontech) for 24 hours, after which the reporters' signals are detected using the Dual Glo luciferase detection system (Promega) according to the vendor's protocol.
[0469] (2) A second set of cell assay are used to define the selectivity of NIK inhibitors toward inhibition of classical vs. non-classical NF-kB signaling and rely on quantification of the nuclear translocation of p52 (NF-kB2) and REL-A (p65) using high content cellular imaging. For the p52 (non-classical NF-kB signaling) nuclear translocation assay, HeLa cells are treated with different concentrations of compounds (0.2% DMSO final) in medium containing 10% fetal bovine serum and then stimulated with 100 ng/mL of an anti-lymphotoxin beta receptor antibody (R&D Systems) for 5 hours. In the REL-A nuclear translocation assay, HeLa cells are incubated with compounds (0.2% DMSO final) for 4.5 hours in medium containing 10% fetal bovine serum before stimulating them with 10 ng/mL tumor necrosis factor (TNF)-a (R&D Systems) for 30 minutes. Cells are fixed with 4% paraformaldehyde, permeabilized by adding 0.1% Triton X- 100 in phosphate buffered saline, and then are incubated with either 2 ug/mL anti-p52 antibody (Millipore) or 400 ng/mL anti-REL-A (p65) antibody (Santa Cruz Biotechnology). Finally, the cells are incubated with an Alexa488-labeled secondary antibody (Invitrogen) and DRAQ5 DNA stain (Biostatus). Imaging is carried out using an Opera reader (Perkin Elmer) and data are analyzed with the aid of Acapella software (Perkin Elmer). The p52 or REL-A translocation into the nucleus is quantified by the ratio of the nuclear to cytoplasmic signal intensity. The concentration of inhibitor required for 50% inhibition (IC50 values) in these cell assays are derived from the plots of signal vs. inhibitor concentration. The compounds in listed in 1A and IB have the corresponding inhibitory value (IC50 in micromolar) for NIK p52 Translocation Assay as set forth in Table 2.
Table 2
Figure imgf000202_0001
0.00053 5 0.1
0.00005 5 0.036
0.00005 5 0.042
0.00005 5 0.053
0.096
0.00005 5 0.039
0.00005 5 0.034
0.028
0.00005 5 0.13
0.00005 5 0.065
0.000059 5 0.079
0.00047
0.016
0.0002
0.028
0.21
0.00011 5 0.13
0.00005 5 0.08
0.0011 5 0.29
0.024
0.0065
0.00034 5 0.34
0.00005 5 0.063
0.00019 5 0.063
0.27
0.0087
0.00058 5 0.17
0.00005 5 0.015
0.00015 5 0.24
0.0006 5 0.24
0.00006 5 0.22
0.0019
0.0019 5 0.37
0.00061 5 0.13

Claims

1. A compound of formula I):
Figure imgf000204_0001
or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein:
ring A is a monocycle or a fused bicycle;
Q is N or C, wherein when Q is N, then the bond between Ai and Q is not a double bond and the bond between Q and A4 is not a double bond;
Ai is NR1, N, S, CR1 or CHR1;
A2 is NR2, N, O, S, CR2 or CHR2;
A3 is N or C;
A4 is N; and
one, two or three of Ai-A4 are N, wherein:
each R1 is independently selected from the group consisting of H, halogen, NRaRb, NHC(0)NRaRb, NHS(0)2CH3, C1-C3 alkyl, C3-C7 cycloalkyl, C1-C3 alkoxy and 3-11 membered heterocyclyl, wherein the alkyl of R1 is optionally substituted by F, OH, CN, SH, C1-C3 alkoxy or 3-11 membered heterocyclyl; the cycloalkyl of R1 is optionally substituted by F, OH, CN, SH, CH3 or CF3; the alkoxy of R1 is optionally substituted by F, OH, CN or SH; and the heterocyclyl of R1 is optionally substituted by F, OH, CN, SH, CF3 or C1-C3 alkyl,
each R2 is independently selected from the group consisting of H, NRaRb, Ci-C6 alkyl, C3-C7 cycloalkyl, Ci-C6 alkoxy, phenyl and 3-11 membered heterocyclyl, wherein R is optionally substituted by Rc; or
1 2
R and R" are taken together with the atoms to which they are attached to form a cyclic group selected from the group consisting of C3-C7 cycloalkyl, phenyl and 3-11 membered heterocyclyl, wherein the cyclic group is optionally substituted by Rd; R4 is selected from the group consisting of H, Ci-C6 alkyl, CH2F and CH2OH;
R5 is 3-1 1 membered heterocyclyl optionally substituted by Re or -C(=0)N(C1-C6 alkyl)2; or
R4 and R5 together form a C3-C11 cycloalkyl optionally substituted by Re or a 3- 11 membered heterocyclyl optionally substituted by Re;
one of A5-A8 is N and the remaining are CR6 or all are CR6;
R6, independently at each occurrence, is selected from the group consisting of H, F, CI, NH2, NHCH3, N(CH3)2, OH, OCH3, OCHF2, OCH2F, OCF3, SH, SCH3, SCHF2, SCH2F, CN, CH3, CHF2, CH2F, CH2OH, CF3, N02 and N3;
Ra is selected from the group consisting of H and Ci-C6 alkyl optionally substituted by C1-C3 alkoxy, F, OH, CN, SH, CH3 or CF3;
Rb is selected from the group consisting of H, Ci-C6 alkyl, Ci-C6 alkoxy, C3-C6 cycloalkyl, C(0)R , phenyl and 3-11 membered heterocyclyl wherein Rb may be optionally substituted by C1-C3 alkoxy, F, OH, CN, SH, CH3 or CF3;
Rc and Rd are each independently selected from the group consisting of halogen, -(X^o-i- CN, -(XVi-NO,, -(xVi-SFs, -(X')o-i-OH, -(X -NH,, -(X -NCHXR13), -(X i- N(Rlb)(Rla), -(X1)o-i-CF3, Ci_C6 alkyl, Ci_C6 haloalkyl, Ci_C6 heteroalkyl, Ci_C6 alkoxy, Ci_C6 alkylthio, oxo, -(x i-Q.Ce alkyl, -(x i-Cs-Qo cycloalkyl, -O-C3-C10 cycloalkyl,
Figure imgf000205_0001
membered heterocyclyl, -(x i-Ce-Qo aryl, -C(=O)(X1)i-C3-Ci0 cycloalkyl, -C(=0)(X1)i-3-ll membered heterocyclyl, -(X1)0_i-C(=Y1)N(H)(Rla), -(X1)0_i-C(=Y1)NH2, -(Xl)0A-
Figure imgf000205_0002
-(X1)o-i-N(H)C(=Y1)(Rla),
Figure imgf000205_0003
C(=NORlb)Rla, -(X1)o-i-NHC(=Y1)N(H)(Rla), -(X1)0.1-NHC(=Y1)NH2, -(x i- NHC(=Y1)N(Rlb)(Rla), -(X1)o-i-N(Rla)C(=Y1)N(H)(Rla), -(X1)0-i-N(Rla)C(=Y1)N(Rla)(Rlb), -(X'k-NCR11)^1)^, -(X1)o-i-OC(=Y1)Rla, -(X1)o-i-OC(=Y1)H, -(X1)0_i-OC(=Y1)ORla, -(X1)o-i-OP(=Y1)(ORla)(ORlb), -(X1)-SC(=Y1)ORla and -(X1)-SC(=Y1)N(Rla)(Rlb) wherein X1 is selected from the group consisting of Ci_C6 alkylene, Ci_C6 heteroalkylene, C2_C6 alkenylene, C2_ C6 alkynylene, Ci_C6 alkyleneoxy, C3-C7 cycloalkylene, 3-11 membered heterocyclylene and phenylene; Rla and Rlb are each independently selected from the group consisting of Ci_C6 alkyl, Ci_C6 haloalkyl, Ci_C6 heteroalkyl, C3-C7 cycloalkyl, (C3-C7 cycloalkylene)Ci_C6 alkyl, 3-11 membered heterocyclyl, (3-11 membered heterocyclylene)Ci-C6 alkyl, C6 aryl, and (C6-Cio arylene)Ci-C6 alkyl, or Rla and Rlb when attached to the same nitrogen atom are optionally combined to form a 3-11 membered heterocyclyl comprising 0-3 additional heteroatoms selected from N, O and S; Y1 is O, NRlc or S wherein Rlc is H or Ci_C6 alkyl; wherein any portion of an Rc or Rd substituent, including Rla, Rlb and Rlc, at each occurrence is each independently further substituted by from 0 to 4 R substituents selected from the group consisting of halogen, CN, N02, SF5, OH, NH2, -N(Ci_C6 alkyl)2, -NH(Ci_C6 alkyl), oxo, Ci_C6 alkyl, -(C2-C6 alkynylene)- (3-11 membered heterocyclyl, wherein the heterocyclyl is optionally substituted by Re), Ci_C6 hydroxyalkyl, Ci_C6 heteroalkyl, Ci_C6 alkoxy, Ci_C6 alkylthio, C3-C7 cycloalkyl, 3-11 membered heterocyclyl, -C(=0)N(H)(Ci_C6 alkyl), -C(=0)N(Ci_C6 alkyl)2, -C(=0)NH2, -C(=0)OCi_C6 alkyl, -C(=0)OH, -N(H)C(=0)(Ci_C6 alkyl), -N(Ci_C6 alkyl)C(=0)(Ci_C6 alkyl),
-N(H)C(=0)OCi_C6 alkyl, -N(Ci_C6 alkyl)C(=0)OCi_C6 (halo)alkyl, -S(0)i_2Ci_C6
alkyl, -N(H)S(0)1.2C1.C6 alkyl, -N(d_C6 alkyl)S(0)1_2C1.C6 alkyl, -S(O)0-1N(H)(Ci.C6 alkyl), - S(0)o-iN(Ci_C6 alkyl)2, -S(O)0-1NH2, -C(=0)Ci_C6 alkyl, -C(=0)C3-C7 cycloalkyl, -C(=NOH)Ci_ C6 alkyl, -C(=NOCi_C6 alkyl)Ci_C6 alkyl, -NHC(=0)N(H)(Ci_C6 alkyl), -NHC(=0)N(C1-C6 alkyl)2, -NHC(=0)NH2, -N(Ci_C6 alkyl)C(=0)N(H)(Ci_C6 alkyl), -N(Ci_C6 alkyl)C(=0)NH2, - OC(=0)Ci_C6 alkyl, -OC(=0)OCi_C6 alkyl, -OP(=0)(OCi_C6 alkyl)2, -SC(=0)OCi_C6 alkyl and - SC(=0)N(Ci_C6 alkyl)2, wherein any alkyl portion of R is optionally substituted with halogen;
Re is selected from the group consisting of halogen, OH, Ci-C6 alkyl and oxo; and R is selected from the group consisting of Ci-C6 alkyl and C3-C6 cycloalkyl wherein R may be optionally substituted by C1-C3 alkoxy, F, OH, CN, SH, CH3 or CF3;
provided that the compound is other than a compound selected from the group consisting of Compound Nos. lx - 199x.
2. The compound of claim 1, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein Q is C, and the compound is of the formula (II):
Figure imgf000207_0001
wherein ring A, Ai, A2, A3, A4, A5, A6, A7, As, R4 and R5 are as defined in claim 1.
3. The compound of claim 1 or claim 2, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein ring A is a monocycle.
4. The compound of claim 1 or claim 2, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein Ai is N or CHR1.
5. The compound of claim 4, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein Ai is N, A2 is S and A3 is C.
6. The compound of claim 1 or claim 2, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein A2 is N, O or CHR .
7. The compound of claim 6, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein Ai is S, A2 is N and A3 is C.
8. The compound of claim 1 or claim 2, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein A2 is O.
9. The compound of claim 8, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein Ai is CR1, A2 is O and A3 is C.
10. The compound of claim 1 or claim 2, or a stereoisomer, tautomer, solvate,
1 1 2 2
prodrug or salt thereof, wherein Ai is NR , S or CR ; and A2 is NR , S or CR .
11. The compound of claim 10, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein ring A is a monocycle.
12. The compound of claim 11, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein Ai is NR .
13. The compound of claim 12, or a stereoisomer, tautomer, solvate, prodrug or salt
2
thereof, wherein A2 is CR and A3 is C.
14. The compound of claim 11, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein Ai is CR1.
15. The compound of claim 14, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein A2 is CR and A3 is N.
16. The compound of claim 10, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein Ai is S.
17. The compound of claim 11, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein A2 is CR and A3 is C.
18. The compound of any one of claims 1 to 17, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein A5, A6, A7 and A8 are each independently CR6 where R6 is, independently at each occurrence, selected from the group consisting of H, F, OCH3 and CH3 and n is 0.
19. The compound of any one of claims 1 to 17, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein ring B is a substituted phenyl and Q is C; and the compound is of the formula (III):
Figure imgf000208_0001
wherein n is 0, 1 or 2, and each R6 is independently selected from the group consisting of F, CI, OCH3, CH3 and CF3.
20. The compound of any one of claims 1 to 19, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R4 and R5 are taken together with carbon to which they are attached to form a Cs-Cio cycloalkyl optionally substituted by Re.
21. The compound of any one of claims 1 to 19, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R4 and R5 are taken together with carbon to which they are attached to form a 4-9 membered heterocyclyl optionally substituted by Re.
22. The compound of any one of claims 1 to 19, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein the following moiety:
Figure imgf000209_0001
wherein:
A9 is O, NR11 or CRnR12, wherein R11 and R12 are each independently selected from the group consisting of H, halogen, OH and Ci-C3 alkyl;
R 7' and R 8° are each independently selected from halogen, OH, Ci-C6 alkyl, or R 7 and R 8 together form =0, and
R9 and R10 are each independently selected from H and Re, or R9 and R10 are taken together with the atoms to which they are attached to form a C5-C6 cycloalkyl optionally substituted by Re or a 5-6 membered heterocyclyl optionally substituted by Re.
23. The compound of claim 22, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein R7 and R8 together form =0; R9 and R10 are each H; and A9 is NR11 where R11 is Ci-C3 alkyl.
24. The compou , solvate, prodrug or salt
Figure imgf000210_0001
thereof, wherein the moiety is
25. The compound of claim 1, or a stereoisomer, tautomer, solvate, prodrug or salt thereof, wherein the compound is selected from:
Figure imgf000210_0002
Figure imgf000211_0001
210
Figure imgf000212_0001
211
Figure imgf000213_0001
212
Figure imgf000214_0001
213
26. A pharmaceutical composition comprising a compound of any one of claims 1 to 25, or a stereoisomer, tautomer, solvate or prodrug thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
27. A compound or pharmaceutical composition as in any one of claims 1 to 26 for use in therapy.
28. The use of a compound or pharmaceutical composition as in any one of claims 1 to 26 for the treatment of an inflammatory condition.
29. The use of a compound or pharmaceutical composition as in any one of claims 1 to 26 for the preparation of a medicament for the treatment of an inflammatory condition.
30. The use as in claim 28 or 29, wherein the inflammatory condition is selected from the group consisting of lupus, systemic lupus erythematosus, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and transplant rejection.
31. A method for the treatment of an inflammatory condition in a patient, comprising administering an effective amount of a compound or pharmaceutical composition as in any one of claims 1 to 26 to the patient.
32. The method of claim 31 , wherein the inflammatory condition is selected from the group consisting of lupus, systemic lupus erythematosus, COPD, rhinitis, multiple sclerosis, IBD, arthritis, rheumatoid arthritis, dermatitis, endometriosis and transplant rejection.
33. A method of reparing a compound of formula (I) of claim 1,
Figure imgf000215_0001
wherein Q, Ai-Ag, R4 and R5 are as defined in any one of claims 1 to 25, comprising: contacting a compound of formu
Figure imgf000216_0001
wherein X is CI, Br or I,
with a compound of formula (B)
Figure imgf000216_0002
wherein [M] is a boronic acid, a boronic ester, or a trifluoroborate salt,
in the presence of (a)(i) a palladium(O) catalyst or (a)(ii) a copper catalyst and (b) a base under Suzuki reaction conditions
to yield a compound of formula (I).
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