CA2673000A1 - Pyrrolo [2, 3-b] pyridine derivatives as kinase modulators - Google Patents

Abstract

Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

Description

Atty. Dkt. No.: 039363-3550 PYRROLO[2,3-B]PYRIDINE DERIVATIVES AS KINASE MODULATORS

RELATED PATENT APPLICATIONS
[0001] This application claims priority to U.S. Provisional App. No.
60!876,953, entitled "Compounds and Methods for Kinase Modulation, and Indications Therefor", filed December 21, 2006, and is related to U.S. Patent App. No. 11/473,347, entitled "Compounds and Methods for Kinase Modulation, and Indications Therefor", filed June 21, 2006, which claims the benefit of U.S.
Provisional App. No. 60/731,528, entitled "Compounds and Methods for Kinase Modulation, and Indications Therefor", filed October 28, 2005, and U.S. Provisional App. No.
60/692,960, entitled "Compounds and Methods for Kinase Modulation, and Indications Therefor", filed June 22, 2005, all of which are incorporated herein by reference in their entireties and for all purposes.

FIELD OF THE INVENTION

100021 The present invention relates to kinases and compounds which modulate kinases, and uses therefor. Particular embodiments contemplate disease indications which are amenable to treatment by modulation of kinase activity by the compounds of the present invention.

BACKGROUND OF THE INVENTION

[0003] The information provided herein is intended solely to assist the understanding of the reader.
None of the information provided nor references cited is admitted to be prior art to the present invention. Each of the references cited herein is incorporated herein by reference in its entirety.
100041 Receptor protein kinases regulate key signal transduction cascades that control or are involved in the control of a plethora of physiological functions including cellular growth and proliferation, cell differentiation, cellular development, cell division, cell adhesion, stress response, short-range contact-mediated axonal guidance, transcription regulation, aberrant mitogenesis, angiogenesis, abnormal endothelial cell-cell or cell-matrix interactions during vascular development, inflammation, lymphohematopoictic stem cell activity, protective immunity against specific bacteria, allergic asthma, aberrant tissue-specific responses to the activation of the JNK signal transduction pathway, cell transformation, memory, apoptosis, competitive activity-dependent synapse modification at the neuromuscular synapse, immunological mediation of disease, and calcium regulation.

[0005] Specific disease states associated with aberrant regulation of protein kinases include, for example without limitation, acrocephalo-syndactyly type I, acute myeloid leukemia, AIDS-induced DLMR 329323.5 1 Atty. Dkt. No.: 039363-3550 non-Hodgkin's lymphoma, Alzheimer's disease, amyotrophic lateral sclerosis, arthritis, asthma, atherosclerosis, atopic dermatitis, autoimmune diseases, bacterial infection, bladder cancer, cancer of the breast, cancer of the central nervous svstem, cancer of the colon, cancer of the endometrium, cancer of the fallopian tube, cancer of the gastrointestinal tract, cancer of the ovary, heart failure, chronic myeloid leukemia, colon carcinoma, colorcctal cancer, chronic obstructive pulmonary disease (COPD), Crouzon Syndrome, diabetes, diabetic nephropathy, emphysema, endometriosis, epidermoid cancer, fibrotic disorders, gastrointestinal stromal tumor (GIST), glomerulonephritis, Graves' disease, hcad injury, hepatocellular carcinoma, Hirschsprung's disease, human gliomas, immunodcficiency diseases, inflammatory disorders, ischemic stroke, Jackson-Weiss syndrome, leiomyosarcoma, leukemias, lupus nephritis, malignant melanoma, malignant nephrosclerosis, mastocytosis, mast cell tumors, melanoma of the colon, MEN2 syndromes, metabolic disorders, migraine, multiple sclerosis, myeloproliferative disorders, nephritis, neurodegenerative diseases, neurotraumatic diseases, non small cell lung cancer, organ transplant rejection, osteoporosis, pain, Parkinson's disease, Pfeiffcr Syndrome, polycystic kidney disease, primary lymphoedema, prostate cancer, psoriasis, vascular restenosis, rheumatoid arthritis, dermal and tissue scarring, selective T-cell defect (STD), severe combined immunodeficiency (SCID), small cell lung cancer, spinal cord injury, squamous cell carcinoma, systemic lupus erythematosis, testicular cancer, thrombotic microangiopathy syndromes, Wegener's granulomatosis, X-linked agammaglobulinemia, viral infection, diabetic retinopathy, alopecia, erectile dysfunction, macular degeneration, clironic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), neurofibromatosis, and tuberous sclerosis.

[0006] This application is related to the following published patent applications: WO 2004024895, US 20040142864, WO 2004078923, US 20050170431, WO 2005028624, US 20050164300, and WO
2005062795, each of which are hereby incorporated by reference herein in their entireties including all specifications, figures, and tables, and for all purposes.

SUMMARY OF THE INVENTION
[0007] Compounds are contemplated that are active on protein kinases in general, including, but not limited to, Abl, Aktl, Akt2, Akt3, ALK, Alk5, A-Raf, B-Raf, Brk, Btk, Cdk2, CDK4, CDK5, CDK6, CHK1, c-Raf-l, Csk, EGFR, EphAl, EphA2, EphB2, EphB4, Erk2, Fak, FGFR1, FGFR2, FGFR3, FGFR4, Fltl, F1t3, F1t4, Fms, Frk, Fyn, Gsk3a5 Gsk3(3, HCK, Hcr2/Erbb2, Her4/Erbb4, IGFIR, IKK beta, Irak4, Itk, Jakl, Jak2, Jak3, Jnkl, Jnk2, Jnk3, Kdr, Kit, Lck, Lyn, MAP2K1, MAP2K2, MAP4K4, MAPKAPK2, Met, Mnkl, MLK1, p38, PDGFRA, PDGFRB, PDPK1, Piml, Pim2, Pim3, PKC alpha, PKC beta, PKC theta, Plk1, Pyk2, Ret, ROCKI, ROCK2, Ron, Src, Stk6, Syk, TEC, Tie2, TrkA, TrkB, Yes, and/or Zap70, including any mutations of these kinases.
In sorne aspects, the compounds are active on protein kinases including A-Raf, B-Raf and/or c-Raf-1, including any mutations thereof. In some aspects, compounds are of Fonnula I, Fornlula H, or Formula Ill, as DLMR 329323.5 2 Atty. Dkt. No.: 039363-3550 described below.

[00081 Also contemplated in accordance with the present invention are methods for the use of the above-described compounds in treating diseases and conditions associated with regulation of the activity of the above-described kinases. Thus, the use of compounds for therapeutic methods involving modulation of protein kinases are provided, as well as compounds that can be used for therapeutic methods involving modulation of protein kinases.

[00091 In some embodiments, compounds have the structure according to the following Formula 1:

O O ~ R2 ~
R' ~ ~_~Si ~
O
N N
H
Formula I
all salts, prodrugs, tautomers and isoniers thereof, wherein:
R' is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NII_, -CN, -NO2, -C(O)OH, -S(O)2NHI, -C(O)NHz, -C(S)NH2i -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NI12, -OR', -SR7, -NRgR', -C(O)R7, -C(S)R7, -C(O)OR', -C(O)NReR', -C(S)NRSR', -S(O)2NRBR', -NRBC(O)R', -NRgC(S)R', -NRBS(O)zR', -NRgC(O)NH2, -NRBC(O)NRaR', -NRBC(S)NH,, -NReC(S)NRBR', -NR8S(O)2NH,, -NRsS(O)2NRaR', -S(O)R', and -S(O)zR', wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, -OH, -NH2, -C(O)OII, -C(O)NH2, -OR', -NR'R', -C(O)OR', -C(O)NR$R', cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and lieteroaryl as R' or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2,, -CN, -NOz, -S(O)2NH2, -C(O)NH2, -OR9, -SR , -NR'R4, -NRgC(O)R', -NRBS(O)2R', -S(O)2R", -S(O)zNRgR', -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R2 is selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NHZ, -CN, NO7i -C(O)OH, -S(O)2NH2, -C(O)NH1-, -C(S)NHz, -NHC(O)NH-2, -NHC(S)NH2, -NHS(O)2NHz, -OR', -SR', -NR'R', -C(O)R', -C(S)R', -C(O)OR', -C(O)NRsR', -C(S)NRBR', -S(O)yNRsR', -NRSC(O)R', -NRBC(S)R', -NR'S(O)zR', -NRgC(O)NHt, -NR$C(O)NReR', -NRsC(S)NHy, -NR~`C(S)NR'R', DLMR_329323.5 Atty. Dkt. No.: 039363-3550 NRgS(O)zNH,, -NRsS(O)zNRsR', -S(O)R7 , and -S(O)2R7, wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, -OR7, -NRBR', cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NOz, -S(O)2NH2, -C(O)?,4H2, -OR9, -SR9, -NR'R', -NR'C(O)R', -NRgS(O)2R9, -S(O),R9, -S(O)zNRsR", -C(O)R9, C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R3 is selected from the group consisting of hydrogen, fluoro and chloro;
R is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R' or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH', -C(O)NH2, -OR9, -SR9, -NR$R9, -NRsC(O)R', -NRgS(O)2R9, -S(O)2R9, -S(O)xNRaR", -C(O)R9, -C(O)NRgR9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R8 at each occurrence is independently hydrogen or lower alkyl; and R~ at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy, provided, however, the compound is not F F F r-r ~ t a o ~ t o -CF3 ~ / o 0 , l~ F ~~ ~ ~ F H F ~ S6 N H NJ H N H

F p F
G e~U ~~ - " C4 ~ C p _ O F H ~~'~/ Ct F HN-~ j p C! HN-S CF, N N N~ N C7 ~~ ~ N O
H H H
) 3 ) DLMR 329323.5 4 Atty. Dkt. No.: 039363-3550 F F

p O_ ( p \/ O
p \ ~ F HN O CF3 p n ; F HN-o N H H

F F F
CI O~`~ p V I CFs O V t O ~
F H ~ \~ /J C' F HN-O/ \ F HN O ~ CF3 N H ~ ~
H N H
s s >

F F F
O~ _ O 0 p CI / HN S CN CI i HN S GI HN-S F
N ~ N F \/ N( H F o NH F p~
, , O~N
F
F F
O O O
p J1 CI F HN o\/ (~ \ F H op GI \' \ F HNO \p N H N H N N
> > >
F

F HN ~ F ~O ~ ~ F N ~ F HN-5; p N H O N~ H N N O
F F
NN p 0 p HN o \ /~-CF, CI o ~~ p ( ~ \ HN
( -5 NH
F HN S \ / GF3 f ~ 0 F
N ~ O 0 N H N ~ p p >
O'\\N
F F F
~
o ~~
o a o ~ HN N4 l HNi C ~ HN F
p \ / ~F ~ \ / F `p ( F
N H \ H F NH 0 N H
> > >
F
C /O O
QCF
F HN O \ / OJ` F H O ~ / 3 N N N
H , C7r H

[00101 In some embodiments of compounds of Formula 1, R' is selected from the group consisting of hydrogen, -CN, -OR', -sR', -NR'R`, -NRSC(O)R', -NRgS(0)2R7, -C(O)NRsR', -C(O)R', -S(O)2NR'R7, -S(O)R', -S(O)zR", halogcn, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and hetcroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, ary l, and DLMR 329323.5 5 Atty. Dkt. No.: 039363-3550 heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R' or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH,, -CN, -NO2, -S(O)2NH1, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR'C(O)R', -NTR'S(O),R4, -S(O)2R9, -S(O),NRgR9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and R2 is selected from the group consisting of -CN, -OR7, -SR7, -NRV, -NR'C(O)R', -NRBS(O)zR`', -C(O)NRBR', -C(O)R', -S(O)zNR'R', -S(O)R', -S(O),R', halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lotiver alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2 or as a substituent of lower alkyl are optionally substituted witli one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)IN112, -C(O)NH2, -OR9, -SR', -NRSR9, -NRSC(O)R9, -NR$S(O)zR9, -S(O)IRg, -S(O),NR'R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.
[00111 In some embodiments of compounds of Formula I, Ri is hydrogen, -CN, -NR'R', -OR', -S(O)zR', fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected froin the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NRBR', -OR' and -S(O)zR', and R2 is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR$R', -OR' or -S(O),R'.

100121 In some embodiinents of compounds of Formula I, R' is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substitutcd lower alkoxy, lower alkoxy substituted C-1_6alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and R2 is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, inono-alkylamino, di-alkylamino, or cycloalkylamino.

100131 In one cmbodiment of compounds of Formula I, the compound is selected from the group consisting of;
4-Butoxy-N-[3 -(5-chloro-1 H-pyrrolo[2,3 -b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide(P-0007), N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phcnyl]-4-pyraxol-l-yl-benzenesulfonamide (P-0008), N-[3-(5 -Chloro-1 H-pyrrolo[2,3-b] pyridine-3-carbonyl)-2,4-di fl uoro-phenyl]-4-isopropoxy-DLMR 329323.5 6 Atty. Dkt. No.: 039363-3550 benzenesulfonamide (P-0011), 4-tert-Butyl-N-[3-(5-chloro-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfon.amide (P-0014), N-[3-(5-Chloro-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-propyl-benzenesulfonamide (P-0015), N- { 2,4-Difluoro-3-[ 5-(2-methoxy-ethoxy)-1 H-pyrrolo [2, 3-b]pyridine-3 -carbonyl]-phenyl }-4-isopropyl-benzenesulfonamide (PR0018), N- {2,4-Difluoro-3-[5-(4-methyl-1 H-imidazol-2-yl)-]H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide (P-0019), 4-Difluoromethoxy-N- {2,4-difluoro-3-[5-(1-methyl-1 H-pyrazol-4-yl)-]H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide (P-0020), N- {2,4-Difluoro-3-[5-(1-methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo [2,3-b]pyridi.ne-3-carbonyl]-phenyl} -4-propyl-bcnzenesulfonainide (P-0021), N- {2,4-Difluoro-3-[5-(1-methyl-1 H-pyrazol-4-yl)-1 H-pyrrolo[2,3-b]pyridine-3 -carbonyl]-phenyl } -4-isopropyl-benzenesulfonamide (P-0022), N- {2,4-Di fluoro-3-[5-(5-methyl-1 H-imidazol-2-yl)-1 H-pyrrolo[2,3-b]pyridine-3-earbonyl]-phenyl}-4-propyl-benzenesulfonamide (P-0023), N- {2,4-Difluoro-3-[5-(5-methyl-1 H-im idazol-2-yl)-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl } -4-trifluoromethyl-benzenesulfonamide (P-0025), N- {2,4-Difluoro-3-[5-(1-methyl-1 H-imidazol-2-yl)-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl} -4-propyl-benzenesulfonamide (P-0026), N- { 3-[5 -(1, 5-Dimethyl-1 H-imidazol-2-yl)-1 H-pyrrolo [2, 3-b]pyridine-3 -carbonyl]-2,4-difluoro-phenyl}-4-propyl-benzenesulfonamide (P-0027), N-[2,4-Difluoro-3-(5-methyl-1 H-pyrrolo [2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-0030), N-[3-(5-Cyano-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-0031), (E)-3 -{ 3-[2, 6-Difluoro-3 -(4-trifluoromethyl-benzenesulfonyl amino)-benzoyl]-1 H-pyrrolo [2, 3-b]pyridin-5-yl}-acrylic acid methyl ester (P-0032), 3- { 3 -[2, 6-Difluoro-3 -(4-trifluoromethyl-benzenesulfonylamino)-benzoyl] -1 H-pyrrolo [2,3 -b]pyridin-5-yl}-propionic acid methyl ester (P-0033), 3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1 H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid (P-0034), 3- {3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1 H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-propionamide (P-0035) and all salts, prodrugs, tautomers, and isomers thereof.
DLMR 329323.5 7 Atty. Dkt. No.: 039363-3550 [0014] In some embodiments, compounds have the structure according to the following Fortnula 11:

Rl F H~ J!~ R2a N N
H
Forinula II
all salts, prodrugs, tautomers and isomers thercof;
wherein:
Wa is as defined for R2 for Formula I; and R' and R' are as defined for Formula I, provided, however, the compound is not F F F
o N o ~ C \ / O \ ( Br O F
F H S O A F HN- S
~F nA HN-S

N H C N H} C N H O
F O O F
0 o F
O
F H
N-S 'o o v O
N H O F F N, > >
F F
F
0 C \ / `N o CI \ / Q A O ~ N-S N~~ 1 /
F N - f ~ F H ~ F ~ HN F
N N 0 CF3 0 N~ H N N
F or~=o , , H

F F
a o 0 ci F HN-~ \/ C~ F HN-~ Cl ~ \ F "N-S
~~~ ~
' N o o C
N H C- N H N H CN
F F
F

0 _ O _ Q ~ \ F HN-S \ ~ ~\ \ F HN-S
~~ F o ~ " 0 ~
H NOz N H N H CN
or o~' N o ( ~ \ F HN-S ~ F

r N
N
H
DLMR 329323.5 8 Atty. Dkt. No.: 039363-3550 [0015] In some embodiments of compounds of Formula II, R' is selected from the group consisting of hydrogen, -CN, -OR', -SR', -NR'R', -NRsC(O)R', NRSS(O)yR', -C(O)NR'R', -C(O)R', -S(0)2NRgR', -S(O)R', -S(O)2R', halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R' or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -O1I, -NI-h, -CN, -NO2, -S(O)2NHzi -C(O)NHz, -OR', -SR', NR'R4, -NRsC(O)R9, -NR$S(O)zR', -S(O),R', -S(O)2NR'R', -C(O)R9, -C(O)NRaR9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and R-a is selected froin the group consisting of -CN, -OR', -SR', -NR'R', -NRsC(O)R', -NR'S(O)zR', -C(O)NR$R', -C(O)R', -S(O)2NR$R', -S(O)R', -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2, or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NHz, -CN, -NOz, -S(O)2NH2, -C(O)NH2, -OR9, -SRg, -NRSR9, -NRgC(O)R', -NR'S(O)2R9, -S(O)2R9, -S(O)LNR8R9, -C(O)R', -C(O)NRsR9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

[0016] In some embodiments of compounds of Formula II, Ri is hydrogen, -CN, -NRgR', -OR', -S(O)zR', fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wllerein cycloalkyl, heterocycloalkyl, aryl or heteroajyl are optionally substituted with one or more substitucnts selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NReR', -OR' and -S(O)2R7 , and R2a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NRR7, -OR7 or -S(O)2R7 .
[0017] In some embodiments of compounds of Formula 11, Ri is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C-1_5alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and R2' is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower allcyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylan-iino.

DLMR 329323.5 9 Atty. Dkt. No.: 039363-3550 [0018] In one embodiment of compounds of Formula II, the compound is selected from the group consisting of:
3-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfaanoyl]-benzoic acid (P-0004), N-[3-(5-Chloro- I H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-difluoromethoxy-benzenesulfonamide (P-0016), 3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(5-methyl-1 H-imidazol-2-yl)-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamidc (P-0024) and all salts, prodiugs, tautomers, and isomers thereof.

[0019] In some cmbodiments, compounds have the structure according to the following Fonnula III:

O O
~ ~ \1 Rs R' F H-So N N
H
Formula III
all salts, prodrugs, tautomers and isomers thereof, wherein:
R6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, cycloalkyl, hetcrocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)zNHzi -C(O)NHz, -C(S)NH2, -NHC(O)NHv, -NHC(S)NH,, -NHS(O)2NH2, -OR', -SR', -NRgR', -C(O)R', -C(S)R', -C(O)OR', -C(O)NRBR', -C(S)NR'R', -S(O)2NRgR7, -NRsC(O)R', -NRgC(S)R', -NRBS(O)2R', -NRRC(O)NHz, -NRaC(O)NR$R', -NRgC(S)NHz, -NRBC(S)NR'R', -NRgS(O)zNHz, -NRSS(O)zNRBR', -S(O)R', and -S(O),R', wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OR', -NRgR', cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of R 6 or as a substituent of lower alkyl are optionally substituted with one or inore substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)zNHz, -C(O)NH2, -OR', -SR9, -NR'Rc', -NR'C(O)R', -NR'S(O),Rg, -S(O)2R', -S(O)zNR'R', -C(O)R9, -C(O)NR'R', halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylasnino; and DLMR 329323.5 10 Atty. Dkt. No.: 039363-3550 R', R3, R', Rg, and R9 are as defined for Formula I, provided, however, the compound is not F F F
a C S p~/ 0\-~ 0 CI F HN~ CI (~ \ F HN / S Br F HNS / S
N~ N N N 0 H
0 F F ...- F
O
Ct O
~ S O 0 0 O
CI F HN S CI I r HN S ( N CI F HN S~

F

O~Oi O \ 1 O
CI ~ F HN S-~ CI F HN-S ~N CI \ HN-~ / S
N H ~ IN H O N~ N' N 0 H
F F

0 O 0 O g~ 0 O 0 O
CI '~ F HN-S Cl 1 F HN-S---(\ N F HN--S \
N N 0 N' N ~ ll' N N 0 H H H
F F F

I ) ~
~ l o o~ o s o ~v~ Q s o F HN-~~ O N F HN-S F HN S\
N I

H H
F F\ F

\~ S O ~ O
( ` \ F HN ~ -~ F HN S ~O F HN S \ N

or F H
O F N-~ S N
NJ_N 0 H

[0020] In some embodiments of compounds of Formula 111, Ri is selected from the group consisting of hvdrogen, -CN, - R', SR', NRsR', -NR'C(O)R' -NRsS(O)zR', C( )NRgR', -C(O)R7, -S(0)2NR'R7, -S(O)R', -S( )-7R7 , halogcn, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R' or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of DLMR 329323.5 I1 Atty. Dkt. No.: 039363-3550 -OH, -NH2, -CN, -NOz, -S(O)2NH2, -C(0)NH2, -OR9, -SR9, -NRaR9, -NR'C(O)R', -NR$S(0)2R9, -S(O)2R', -S(0)2NRgR9, -C(O)Rg, -C(O)NR'R9, halogen, lower alkyl, tluoro substituted lower alkyl, and cycloalkylamino; and R6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of -CN, -OR', -SR', -NR'R7, -NRsC(O)R', -NR'S(O)aR', -C(O)NR'R', -C(O)R7, -S(O)zNRsR', -S(O)R7, -S('O)2R`, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino;
cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of Rb or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH7, -CN, -NO7, -S(O)2NHZ, -C(O)NH:, -OR', -SR', -NRgR9, -NR'C(O)R', -NRBS(O)zR9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR$R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

[0021] In some embodiments of compounds of Formula III, R' is hydrogen, -CN, -NR$R', -OR', -S(O)zR', fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NRaR', -OR' and -S(O)zR', and R 6 is heteroaryl optionally substituted with one or more of -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NRgR', -OR' or -S(O)zR'.

[0022] In some embodiments of compounds of Formula III, R' is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2_6alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and R6 is heteroaryl optionally substituted with one or more of -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.

[0023] In one embodiment of compounds of Formula III, the compound is selected from the group consisting of:
Benzo[b]thiophene-3-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0001), 5-Methyl-2-trifluoromethyl-furan-3-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0002), 5-Oxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0003), Atty. Dkt. No.: 039363-3550 2-Oxo-2H-chromene-6-sulfonic acid [3-(5-chloro-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0005), 5-Isoxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0006), Benzothiazole-6-sulfonic acid [3-(5-chloro-lH-pyn-olo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0009), 1-Methyl-3-trifluoromethyl-I H-pyrazole-4-sulfonic acid [3-(5-chloro-1l1-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0010), IIenzo[1,2,5]thiadiazoe-5-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0013), 5-Methyl-benzo[b]thiophene-2-sulfonic acid [3-(5-chloro-IH-pyrrolo[2,3-b]pyridine-3-carbonyl) ?,4-difluoro-phenyl)-amide (P-0017), 5-Methyl-thiophene-2-sulfonic acid [3-(5-chloro-IH-pyrrolo[2,3-b]pyridine-3-carbonyt)-2,4-difluoro-phenyl]-amide (P-0028), I-Methyl-lH-pyrazole-3-sulfonic acid [3-(5-chloro-IH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0029), Pyridine-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-IH-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-0036) and all salts, prodrugs, tautomers, and isomers thereof.

100241 In some embodiments of the above compounds, compounds are excluded where N (except where N is a heteroaryl ring atom), 0, or S is bound to a carbon that is also bound to N (except where N is a heteroaryl ring atom), 0, or S, except where the carbon forms a double bond with one of the heteroatoms, such as in an amide, carboxylic acid, and the like; or where N
(except where N is a heteroaryl ring atom), 0, C(S), C(O), or S(O)õ (n is 0-2) is bound to an alkene carbon of an alkenyl group or bound to an alkyne carbon of an alkynyl group; accordingly, in some embodiments compounds which include linkages such as the following are excluded from the compounds provided:
-NR-CH2-NR-, -O-CH2-NR-, -S-CH,-NR-, -NR-CH2-0-, -0-CH2-0-, -S-CH2-0-, -NR-CH,,-S-, -O-CIIz-S-, -S-CH?.-S-, -NR-CH=CH-, -CH=CH-NR-, -NR-C RC-, -C EC-NR-, -0-CH=CH-, -CH=CH-O-, -0-C EG, -C -=C-0-, -S(0)0.2-CH=CH-, -CH=CH-S(O)o_a-, -S(0)0_2-C
_:iC-, -C ~C-S(0)0_2-, -C(O)-CH=CH-, -CH=CH-C(O)-, -C ~C-C(O)-, or -C(O)-C Ec-, -C(S)-CH=CH-, -CH=CH-C(S)-, -C ~C-C(S)-, or -C(S)-C aC-, 100251 In reference to compounds herein, unless clearly indicated to the contrary, specification of a compound or group of compounds includes pharmaeeutically acceptable salts of such compound(s), prodrug(s), and all stereoisomers thereof. In reference to compositions, kits, methods of use, etc. of compounds of Formula I, Formula II, or Formula III described herein, it is understood that a DLMR 329323.5 13 Atty, Dkt, No,: 039363-3550 compound of Formula I includes all sub-embodiments thereof, a compound of Fonnula II includes all sub-ernbodiments thereof, and a compound of Formula III includes all sub-embodiments thereof:
unless indicated otherwise.

100261 In one aspect, methods are provided for treating a protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subject an effective amount of one or more compounds of Formula I, Formula II, or Forniula III. The terms "treat,"
"therapy," and like terrns refer to the administration of material, e.g., one or more compounds of Formula I, Formula II, or Formula III, in an amount effective to prevent, alleviate, or ameliorate one or more symptoms of a disease or condition, i.c., indication, and/or to prolong the survival of the subject being treated. The term "protein kinase mediated disease or condition"
refers to a disease or condition in which the biological function of a protein kinase affects the development, course andr`or symptoms of the disease or condition, and/or in which modulation of the protein kinase alters the developinent, course, and/or symptoms of the disease or condition, A protein kinase mediated disease or condition includes a disease or condition for which modulation provides a therapeutic benefit, e.g.
wherein treatment with protein kinase inhibitors, including compounds described hercin, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition. In one aspect, the method involves administering to the subj ect an effective amount of one or more compounds of Formula 1, Formula II, or Forinula III in combination with one or more other therapies for the disease or condition, [0027] In one aspect, methods are provided for treating a protein kinase mediated disease or condition in an aniinal subject, wherein the method involves administering to the subject an effective amount of a compound of any one or more of Formula I, Formula II, or Formula III.

[0028] In one aspect, the invention provides methods for treating a Raf protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subject an effective amount of one or more compounds of Formula I, Formula II, or Formula III. The terms "Raf protein kinase mediated disease or condition," "Raf mediated disease or condition," and the like refer to a disease or condition in which the biological function of a Raf kinase, including any mutations thereof, affects the development, course and/or symptoms of the disease or condition, andfor in which modulation of the Raf protein kinase alters the development, course, andlor symptoms of the disease or condition. The Raf protein kinase includes, but is not limited to, A-Raf, mutations of A-Raf, B-Raf, mutations of B-Raf, c-Raf-I and mutations of c-Raf-1. In some embodiments, the Raf protein kinase is B-Raf inutation V600E. In some embodiments, the Raf protein kinase is B-Raf mutation V600E,7529L In some embodiinents, the disease or condition is a cancer that is amenable to treatment by an inhibitor of the V600E mutant B-Raf. In some embodiments, the disease or condition is a cancer that is amenable to treatment by an inhibitor of the V600E/T529I
mutant B-Raf. The Raf DLMR 329323.5 14 Atty. Dkt. No.: 039363-3550 protein kinase mediated disease or condition includes a disease or condition for which Raf inhibition provides a therapeutic benefit, e.g. wherein treatmcnt with Raf inhibitors, including compounds described herein, provides a therapeutic benefit to the subject suffering from or at risk of the disease or condition. In one aspect, the method involves administering to the subject an effective amount of one or more compounds of Formula I, Formula II, or Formula III in combination with one or more other therapies for the disease or condition. Similarly, thc terms "A-Raf, B-Raf or c-Raf-1 protein kinase mediated disease or condition," "A-Raf, B-Raf or c-Raf-1 mediated disease or corldition," and the like refer to a disease or condition in which the biological function of an A-Raf, B-Raf or c-Raf-1 kinase, respectively, including any mutations thcreof, affects the development, course and/or symptoms of the disease or condition, and/or in which modulation of the A-Raf, B-Raf or c-Raf-1 protein kinase, respectively, alters the development, course, and/or symptoms of the disease or condition.

[00291 In some embodiments, a compound of Formula I, Formula II, or Formula III is an inhibitor of a Raf kinase and has an ICso of less than 500 nm, less than 100 nIVI, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, or less than I nM as determined in a generally acccpted Raf kinase activity assay. In some embodiments, a compound of Formula I, Formula II, or Formula III
will have an IC50 of less than 500 nm, less than 100 nM, less than 50 nM, less than 20 nM, less than nM, less than 5 nM, or less than 1 nM with respect to A-Raf, B-Raf, c-Raf-1, B-Raf V600F
mutant, or B-Raf V600E/T5291 mutant. In some embodiments, a compound of Formula I, Formula II, or Formula III will selectively inhibit one Raf kinase relative to one or more other Raf kinases. In some embodiments, the compound of Formula I, Formula II, or Formula III will selectively inhibit the effects of a mutation of the Raf kinase relative to the wild type kinase, for example B-Raf V600F
mutant relative to wild type B-Raf.

[0030J Further to any of the above mentioned embodiments, a compound will also inhibit the effects of a mutation of the kinase, including, but not limited to, a mutation that is related to a disease state, such as a cancer. For example, B-Raf V600E mutant is present in a high percentage of some cancers, such as melanoma, and compounds of Formula I, Formula 11, or Formula III will inhibit the kinase activity of this mutant.

[0031) Furthcr to any of the above embodiments, a compound may selectively inhibit one kinase relative to one or more other kinases, where preferably inhibition is selective with respect to any other kinases, whether a kinase discussed herein, or othcr kinases. In soine embodiments, the compound may selectively inhibit the effects of a mutation of the kinase relative to the wild type kinase, for example B-Raf V600E mutant relative to wild type B-Raf. In some embodiments, the compound may selectively inhibit Fms relative to Kit. Sclective inhibition of one kinase relative to another is such that the IC50 for the one kinase may be at least about 2-fold, also 5-fold, also 10-fold, also 20-fold, DLMR 329323.5 15 Atty. Dkt. No.: 039363-3550 also 50-fold, or at least about 100-fold less than the ICto for any of the other kinases as determined in a generally accepted kinase activity assay.

[0032] In another aspect, compositions are provided that include a therapeutically effective amount of one or more compounds of Formula 1, Fonnula 11, or Formula III and at least one pharmaceutically acceptable carrier, excipient, and/or diluent, including combinations of any two or more compounds of Formula I, Formula 11 or Formula III. The composition can further include a plurality of different phannacologically active compounds, which can include a plurality of compounds of Formula 1, Forinula II, and/or Formula III. In another aspect, the composition can include one or more compounds of Formula I, Formula II, or Formula III along with one or more compounds that are therapeutically effective for the same disease indication. In one aspect, the composition includes one or more compounds of Formula I, Formula II, or Formula III along with one or more compounds that are therapeutically effective for the same disease indication, wherein the compounds have a synergistic effect on the disease indication. In one aspect, the composition includes one or more compounds of Formula I, Formula II, or Formula III effective in treating a cancer and one or more other compounds that are effective in treating the cancer, further wherein the compounds are synergistically effective in treating the cancer.

100331 In another aspect, methods are provided for treating a protein kinase mediated disease or condition in an animal subject, wherein the method involves administering to the subject an effective amount of a composition including one or more compounds of Formula I, Formula II, or Formula III.
[0034] In one aspect, the invention provides methods for treating a disease or condition mediated by A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, or B-Raf V600F/"1`529I mutant by administering to the subject an effective amount of a composition including one or more compounds of Formula I, Formula II or Formula III. In one aspect, the invention provides methods for treating a disease or condition mediated by A-Raf, B-Raf, c-Raf-1, B-Raf V600E mutant, or B-Raf V600E/T5291 mutant by administering to the subject an effective amount of a composition including one or more compounds of Formula I, Formula II, or Formula III in combination with one or more other suitable therapies for treating the disease. In one aspect, the invention provides methods for treating a cancer mediated by B-Raf V600F mutant or B-Raf V600E/T5291 mutant by adniinistering to the subject an effective amount of a composition including one or more of Formula I, Formula II, or Forinula III in combination with one or more suitable anticancer therapies, such as one or more chemotherapeutic drugs.

[0035] In one aspect, the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including one or more compounds of Formula I, Fonnula II, or Formula III, in combination with one or more other therapies or medical procedures DLMR 329323.5 16 Atty. Dkt. No.: 039363-3550 cftectivc in treating the cancer. Other therapies or medical procedures include suitable anticancer therapy (e.g. drug therapy, vaccine therapy, gene therapy, photodynamic therapy) or medical procedure (e.g. surgery, radiation treatment, hyperthermia heating, bone marrow or stem cell transplant). In one aspect, the one or more suitable anticancer therapies or medical procedures is selected from treatment with a chemotherapcutic agent (e.g. chemotherapeutic drug), radiation treatment (e.g. x-ray, y-ray, or electron, proton, neutron, or a. particle beam), hyperthermia heating (e.g. microwave, ultrasound, radiofrequencv ablation), Vaccine therapy (e.g.
AFP gene hepatocellular carcinoma vaccine, AFP adenoviral vector vaccine, AG-858, allogeneic GM-CSF-secretion breast cancer vaccine, dendritic cell peptide vaccines), gene therapy (e.g. Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (c.g.
aminolevulinic acid, motexafin lutetium), surgery, and bone marrow and stem cell transplantation.
10036] In a preferred embodiment, the invention provides a method of treating a cancer by administering to the subject an effective amount of a composition including one or more compounds of Formula I, Formula II, or Formula III, in combination with one or more suitable chemotherapeutic agents. In one aspect, the one or more suitable chemotherapeutic agents is selected from an alkylating agent, including, but not limited to, adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and treosulfan; an antibiotic, including, but not limited to, bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; an antimetabolite, including, but not limited to, azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; an immunotherapy, including, but not limited to, alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, panitumumab, pertuzumab, rituximab, tositumomab, trastuzumab, and ibritumomab tiuxetan; a hormone or hormone antagonist, including, but not limited to, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, magestrol, raloxifene, tamoxifen, and toremifene; a taxane, including, but not limited to, DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; a retinoid, including, but not limited to, alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; an alkaloid, including, but not limited to, etoposide, homoharringtoninc, tcniposide, vinblastine, vincristine, vindesine, and vinorelbine; an antiangiogenic agent, including, but not limited to, AE-941 (GW786034, Neovastat), A13T-510, 2-methoxyestradiol, lenalidomide, and thalidomide; a topoisomerase inhibitor, including, but not limited to, amsacrine, edotecarin, exatecan, irinotecan (also active metabolite SN-38 (7-ethyl-10-hydroxy-camptothecin)), rubitecan, topotecan, and 9-aminocamptothecin; a kinase inhibitor, DLMR_329323.5 Atty. Dkt. No.: 039363-3550 including, but not limited to, erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AVIN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine), and vatalanib; a targeted signal transduction inhibitor including, but not limited to bortezomib, geldanamycin, and rapamycin; a biological response modifier, including, but not limited to, imiquimod, interfcron-a, and interleukin-2; and other chemotherapeutics, including, but not limited to 3-AP (3-amino-2-carboxyaldehyde thiosemicarbazone), aminoglutethimide, asparaginase, brtiostatin-l, cilengitide, E7389, ixabepilone, procarbazine, sulindac, temsirolimus, tipifarnib. Preferably, the method of treating a cancer involves administering to the subject an effective amount of a composition including one or more of Formula I, Formula II, or Formula III in combination with a chemotherapeutic agent selected from 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, vinblastinc, bevacizumab, cetuximab, or erlotinib.

[0037] In another aspect, the invention provides a method of treating or prophylaxis of a disease or condition in a mammal, by administering to the mammal a therapeutically effective amount of one or more compounds of Formula I, Formula II, or Formula III, a prodrug of such compound, or a pharmaceutically acceptable salt of such compound or prodrug. The compound can be alone or can be part of a composition. In another aspect, the invention provides a method of treating or prophylaxis of a disease or condition in a mammal, by administering to the mammal a therapeutically effective amount of onc or more compounds of Formula I, Formula II, or Formula III, a prodrug of such compound, or a pharmaceutically acceptable salt of such compound or prodrug in combination with one or more other suitable therapies for the disease or condition.

[0038] In a related aspect, the invention provides kits that include a composition as described herein. In some embodiments, the composition is packaged, e.g., in a vial, bottle, flask, which may be further packaged, e.g., within a box, envelope, or bag; the composition is approved by the U.S. Food and Drug Administration or similar regulatory agency for administration to a mammal, e.g., a human;
the composition is approved for administration to a mammal, e.g., a human, for a protein kinase mediated disease or condition; the invention kit includes written instructions for use and/or other indication that the composition is suitable or approved for administration to a mammal, e.g., a human, for a protein kinase-mediated disease or condition; and the composition is packaged in unit dose or single dose form, e.g., single dose pills, capsules, or the like.

f 00391 In aspects involving treatment or prophylaxis of a disease or condition with onc or more compounds of Formula I, Formula II, or Formula III, the disease or condition is, for example without limitation, neurologic diseases, including, but not limited to, cerebrovascular ischemia, multi-infaret dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease, amyotrophic lateral sclerosis, dementia, senile chorca, and Iduntnigton's disease;
neoplastic diseases and associated DLMR 329323.5 18 Atty. Dkt. No.: 039363-3550 complications, including, but not limited to, chemotherapy-induced hypoxia, gastrointestinal stromal tumors (GISTs), prostate tumors, mast cell tumors (including canine mast cell tumors), acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, gliomas, glioblastoma, astrocytoma, neuroblastoma, sarcomas (e.g. sarconlas of neuroectodermal origin, leiomyosarcoma), carcinomas (e.g. lung, breast, pancreatic, colon, hepatocellular, renal, female genital tract, squamous cell, carcinoma in situ), lymphoma (e.g. histiocytic lymphoma, non-Hodgkin's lymphoma), MEN2 syndromes, neurofibromatosis (including Schwann cell neoplasia), myelodysplastic syndrome, leukemia, tumor angiogenesis, cancers of the thyroid, liver, bone, skin, brain, central nervous system, panereas, lung (e.g. small cell lung cancer, non small cell lung cancer), breast, colon, bladder, prostate, gastrointestinal tract, endometrium, fallopian tube, testes and ovary, and metastasis of tumors to other tissues; pain of neuropathic or inflammatory origin, including, but not limited to, acute pain, chronic pain, bone pain, cancer-related pain and migraine; cardiovascular diseases, including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g.
thrombotic microangiopathy syndromes), atherosclerosis, reperfusion injury and ischemia (e.g.
cerebrovascular ischcmia, liver ischemia); inflammation including, but not limited to, age-related macular degeneration, rheumatoid arthritis, allergic rhinitis, inflammatory bowel disease (IBD), ulecrative colitis, Crohn's disease, systemic lupus erythematosis, Sjogren's Syndrome, Wegener's granulomatosis, psoriasis, scleroderma, chronic thyroiditis, Grave's disease, myasthenia gravis, multiple sclerosis, ostcoarthritis, cndometriosis, scarring (e.g. dermal, tissue), vascular restcnosis, fibrotic disorders, hypereosinophilia, CNS inflammation, pancreatitis, nephritis, atopic dermatitis, and hepatitis;
immunodeficiency diseases ,including, but not limited to, severe combined immunodeficiency (SCID), organ transplant rejection, and graft versus host disease; renal or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, interstitial nephritis, Lupus nephritis, prostate hyperplasia, chronic renal failure, tubular necrosis, diabetes-associated renal complications, and hypertrophy; metabolic diseases, including, but not limited to, type I diabetes, type 2 diabetes, metabolic syndrome, obesity, hepatic steatosis, insulin resistance, hyperglycemia, lipolysis and obesity; infection, including, but not limited to, Helicobacterpylori, Hepatitis and Influenza viruses, fever, and sepsis; pulmonary diseases, including, but not limited to, chronic obstnictive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), asthma, allergy, bronchitis, emphysema, and pulmonary fibrosis; genetic developmental diseases, including, but not limited to, Noonan's syndrome, Crouzon syndrome, acrocephalo-syndactyly type I, Pfeiffer's syndrome, Jackson-Weiss syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faeiocutaneous syndrome (CFC) and neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases; disorders of bone structure, mineralization and bone reformation and resorption, including, but not limited to, osteoporosis, increased risk of fracture, Paget's disease, hypercalcemia, and metastatis of cancer to DLMR 329323.5 19 Atty. Dkt. No.: 039363-3550 bone; Grave's disease; Hirschsprang's discase; lvmphoedema; selective T-cell defect {STI?); X-linked aL,~)i:iwaglobulinemia; diabetic retinopathy; alopecia; erectile dysfunction;
and tuberous sclrosis.
10040J In aspects involving treaiment or prophylaxis of a disease or condition with one or more compounds of Formula 1, Formula 11, or Formula III, the invention provides methods for treating an A-Raf-mediated, B-Raf-mediated or c-Kaf-l-mediated disease or condition in an animnl subject (cõg.
a mammal such as a human, other primates, sports animals, animals of commercial ii3terest such as caitlc, farrn aniinals such as Iiorses, or pets such as dogs and cats), e.g., a disease or condition characterized by abnormal A-Raf, B-Raf, andlor c-Raf- 1 activity (e.g. kinase activity). Invention mcihods involve administering to the subject suffering from or at risk of an A-Raf-mediated, B-Raf-mediated, and/or c-Raf-I-mediated diseasc or condition an effective amount of one or more compounds of Formula I, Formula II or Formula III. In one embodiment, the A-Raf-meditated,l3-Raf-mediated, and/or C-Raf mediated disease is selected from the group consisting of neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g. histiocytic lymphoma) neurofibromatosis, acute mveloid leukemia, myclodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma; pain of neuropathic or inflammatory origin, including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine; cardiovascular diseases, including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathy syndromes), atherosclerosis, and reperfusion injury; inflammation including, but not limitcd to, psoriasis, arthritis and autoimmune diseases and conditions, ostcoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBl3); immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease; renal or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephzitis, prostate hyperplasia; metabolic disorders, including, but not liinited to, obesitv;
infection, including, but not limited to, Helicvhacterpylori, flcprrritis and Influenza viruses, fever, and sepsis; pulmonary diseases, including, but not limited to, chronic ubstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases, including, but not limited to, Noonan's syndrome, Costello syndrome, (faciocufaowuskulcial syndrome), LROPARU syndrome, cardio-faciocutancous syndrome (CFC), and neural crest syndi m.e abni,rmalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrinc di,ca cs: and dise<j=es {issociated ",ith n usclc regeneration or degeneration, including, but not lirn.itcd to, sarcupcitia. muscular dystrophies (including, but not Iinaited to, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic, (Jculopharyngeal, Distal and Congenital Muscular QLMR 329323.5 20 Atty. Dkt. No.: 039363-3550 Dystrophies), motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atropliy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocrine abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy) diseases of peripheral nerve (including, but not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, and periodic paralysis), and metabolic diseases of muscle (including, but not limited to, phosphotylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency).

10041] In a related aspect, one or more compounds of Formula I, Formula II, or Formula III, can be used in the preparation of a mcdicament for the treatment of an A-Raf-mediated, B-Raf-mediated or c-Raf- l -mediated disease or condition selected from the group consisting of neurologic diseases, including, but not limited to, multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lyrnphoma (e.g. histiocytic lymphoma) neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma; pain of neuropathic or inflammatory origin, including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine;
cardiovascular diseases, including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathy syndromes), atherosclerosis, and reperfusion injury; inflammation including, but not limited to, psoriasis, arthritis and autoimmune diseases and conditions, osteoarthritis, endoinetriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease; renal or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia; metabolic disorders, including, but not limited to, obesity;
infection, including, but not limited to, Helicobacter pylori, Hepatitis and Influenza viruses, fever, and sepsis; pulmonary diseases, including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmentat diseases, inctuding, DLMR_329323.5 Atty. Dkt. No.: 039363-3550 but not Iiinited to, Noonan's syndrome, Costello syndrome, (faciocutancoskeletal syndrome), LE I'AI.tD syndroine, cardio-faciocutaneous syndrome (CFC), and neural crest syndrome abnormalities causing cardiovascular, sketetal, intestinal, skin, hair and endocrine diseases; and diseases associated with muscle regeneration or degeneration, including, but not limited to, sarcopenia, muscular dystrophies {including, but not limited to, Duchenne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohum.eral,MN~i}tonic. C3cuiopharyyngeal, Distal and Congenital Muscular Dystrophies), motor neuron diseases (inc'nding, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate pi ria; muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult ipinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocri.ne abnorm.alities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy) diseases of peripheral nerve (including, but not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, and periodic paralysis), and metabol.ic diseases of muscle (including, but not limited to, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency).

[0042] The compounds of Formula I, Formula II, or Formula IIr with kinase activity IC50 less than M as determined in a standard assay described herein can be used to treat the following exemplary protein kinase mediated diseases and conditions related to protein kinases A-Raf, B-Raf andlctr c-Raf-1, including any mutations thereof; for example without limitation.
modulation ofA-Raf, which is related to neurologic diseases such as multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinsfln's disease;
neoplastic diseases incluLhng, but not limited to, melanoma, glioma, sarcoma, carcinoma (e,g.
colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g. histiocytic lymphoma), neurcChroruatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis;
pain ef neurol.~s,chic or inflammatory origin, including acute pain, chronic pain, cancer-.-(2latccl pain and migriine; and diseases associated with muscle regeneration or c3 c~en,~ration, inc hIdi ng.
but not l'rm,tcd to, vascular restenosis, sarcopenia. muscular dystropl)ics (including, but r<>t limited tu, 1)uchenne, Becker, Emery-Dreifuss, LAm.b-Girdle, F'aciosrapuJuhumeral, Ivfyoz(xnic, (}culopharyngeal, Distal and Congenital Muscular Dystrophies), motor neuron disease~ (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive QLMR 329323.5 22 Atty. Dkt. No.: 039363-3550 spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocrine abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopatby) diseases of peripheral nerve (including, but not limited to, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, parainyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, and periodic paralysis), and metabolic diseases of muscle (including, but not limited to, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, camitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency);
inodulation of B-Raf and/or c-Raf-1, which is related to neurologic diseases, including, but not limited to, lnulti-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, gliorna, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g. histiocytic lymphoma) neurofibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogencsis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma; pain of neuropathic or inflammatory origin, including, but not limited to, acute pain, chronic pain, cancer-related pain, and migraine; cardiovascular diseases, including, but not limited to, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic inicroangiopathy syndromes), atherosclerosis, and reperfiision injury; inflammation including, but not limited to, psoriasis, arthritis and autoimmune diseases and conditions, osteoarthritis, endometriosis, scan-ing, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (IBD); immunodeficiency diseases, including, but not limited to, organ transplant rejection, graft versus host disease; renal or prostatic diseases, including, but not limited to, diabetic nephropathy, polycystic kidney disease, nephrosclerosi.s, glomerulonephritis, prostate hyperplasia; metabolic disorders, including, but not limited to, obesity;
infection, including, but not limited to, Helicobacter pyloYi, Hepatitis and Influenza viruses, fever, and sepsis;
pulmonary diseases, including, but not limited to, chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS); genetic developmental diseases, including, but not limited to, Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARD syndroine, cardio-faciocutaneous syndrome (CFC), and neural crest DLMR 329323.5 23 Atty. Dkt. No.: 039363-3550 syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases.

100431 Additional aspects and embodiments will be apparent from the following Detailed Description and from the claims.

DE1'AILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0044] As used herein the following definitions apply unless clearly indicated otherwise:
[0045] "Halogen" refer to all halogens, that is, chtoro (CI), fluoro (F), bromo (Br), or iodo (I).
100461 "Hydroxyl" or "hydroxy" refer to the group -OH.

[0047] "Thiol" refers to the group -SII.

[0048] "Lower alkyl" alone or in combination means an alkane-derived radical containing from 1 to 6 carbon atorns (unless specifically defined) that includes a straight chain alkyl or branched alkyl.
The straight chain or branched alkyl group is attached at any available point to produce a stable compound, In many embodiments, a lower alkyl is a straight or branched alkyl group containing from 1-6, 1-4, or 1-2, carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, t-butyl, and the like. A
"substituted lower alkyl" denotes lower alkyl that is independently substituted, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound. For example "fluoro substituted lower alkyl" denotes a lower alkyl group substituted with one or more fluoro atoms, such as perfluoroalkyl, where preferably the lower alkyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions are attached at any available atom to produce a stable compound, when optionally substituted alkyl is an R group of a moiety such as -OR, -NHR, -C(O)NIIR, and the like, substitution of the alkyl R group is such that substitution of the alkyl carbon bound to any -0-, -S-, or -N- of the moiety (except where -N- is a heteroaryl ring atom) excludes substituents that would result in any -0-, -S-, or -N- of the substituent (except where -N- is a heteroaryl ring atom) being bound to the alkyl carbon bound to any -0-, -S-, or -N- of the moiety.
.
[0049] "Lower alkenyl" alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically defined) and at least one, preferably 1-3, more preferably 1-2, most preferably one, carbon to carbon double bond. Carbon to carbon double bonds may be either contained within a straight chain or branched portion, Examples of lower alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, and the like. A
"substituted lower alkenyl"
denotes lower alkenyl that is indcpendently substituted, with one or more, preferably 1, 2, 3, 4 or 5, DLMR 329323.5 Atty Dkt. No,: 039363-3550 71so 1, 2, or 3 substituents, attached at any available atom to produce a stable compound. For example "ilucvo substituted lom,er alkenyl" denotes a lower alkenyl group substituted with one or more fluora stotns, where pre"erabl\ the lower alkenyl is substituted with 1, 2, 3,4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. Wliiic; it is understood that substitutions are attached at any available atom to prodr;cc a stable compound, substitutioii of alkenyl groups are such that -b`, -C(O)-, -C(S)-, -C(NH)-, -S(O)-.
-S(Q)z _, -0-, -S-, or N(excePt w?,ere N is a heteroaryl ring atom), are not bound to an alkene carbon thereof; Further, where alkenyl is a substituent of another moiety or an R
group of a moiety such as -OR, -NHR, -C(O)R, and the like, substitution of the moiety is such that any -C(O)-, -C(S)-, -S(C))-, -S(0)_-, -0-, -S-, or N therefll'(except where N is a heteroaryl ring atom) are not bflund to an alkene carbon of the alkenyl substituent or R group, Further, where alkenyl is a substituent of another moiety or an R group of a moiety such as -OR, -NHR, -C(O)NHR, and the like, substitution of the alkenyl R
group is such that substitution of the alkenyl carbon bound to any 0, S, or N
of the moiety (except where N is a heteroaryl ring atom) excludes substituents that would result in any 0, S, or N of the substituent (except where N is a heteroaryl ring atom) being bound to the alkenyl carbon bound to any 0, S, or N of the moiety. An "alkenyl carbon" rcfers to any carbon within an alkenyl group, whether saturated or part of the carbon to carbon double bond. An "alkene carbon"
refers to a carbon within an alkenyl group that is part of a carbon to carbon double bond.

[(1l150] "Lower alkynyl" alone or in combination means a straight or branched hydrocarbon containing 2-6 carbon atoms (unless specifically dcfined) containing at least one, preferably one, carbon to carbon triple bond. Examples of alkynyl groups include ethynyl, propynyl, butynyl, and the like. A "substituted lower alkynyl" denotes lower alkynyl that is independently substituted, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound, For example "fluoro substituted lower alkynyl"
denotes a lower alkynyl group substituted with one or more fluoro atoms, where preferably the lower alkynyl is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atons. While it is understood that substitutions are attached at any available atom to produce a stable compound, substitution of alkynyl groups are such that -F, -C(O)-, -C(S)-, -C(NH)-, -S(O)-, -S(O)2-, -0-, -S-, or N (except whc,-e N is a heteroaryl ring atom) are not bound to an alkyne carbon thereof, Further, where alkynyl is a substitucnt of r,riothei- rnoiety or an R group of a moiety such as -OR, -NHR, -C(O)R, and the like, substitut ion of the , oiety is such that any -C(Q)-, -C(S)-,-S((.?)-, -S(0)2-, -0-, -S-, or N
thereof (except \\ ltere N is a heterflaryl ring atom) are not bound to an alkyne carbon of the alkynyl substitti ent or R group.
Furtlier, nhtre, ulkynyl is a substituc t of anothcr nioic[y or an Rgrc,uh of anuiot\such as -OR, -'.11III:, -C(O jNHR, and the like, s,Jistitut ion o#'the alkynyl R group is such t11,3,t substitutioa o;the alkynyl carbon bounkl to any 0, S, or N of the moiety (except where N is a bct~~:oar.l rim~ ,11tom) excludes substitucnts tluit would result in any 0, S, flr N of the substituent (cxccp< hcre N is a heteroaryl rin g nt~~~n} being bound to the alkynyl carbon bound to any 0, S, or N of thc, moiety. 'An (3uMR 329323.5 25 Atty. Dkt. No.: 039363-3550 "alkynyl carbon" refers to any carbon within an alkynyl group, whether saturated or part of the carbon to carbon triple bond, An "alkyne carbon" refers to a carbon within an alkynyl group that is part of a carbon to carbon triple bond.

100511 "Cycloalkyl" refers to saturated or unsaturated, non-aromatic monocyclic, bicyclic or tricyclic carbon ring systems of 3-10, also 3-8, more preferably 3-6, ring members per ring, such as cyclopropyl, cyclopentyl, cyclohexyl, adamantyl, and the like, A "substituted cycloalkyl" is a cycloalkyl that is independently substituted, unless indicated othenvise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attacl-ied at any available atom to produce a stable compound.

100521 "Heterocycloalkyl" refers to a saturated or unsaturated non-aromatic cycloalkyl group having froin 5 to 10 atoms in which from I to 3 carbon atoms in the ring are replaced by heteroatoms of 0, S
or N, and are optionally fused with benzo or heteroaryl of 5-6 ring members.
Heterocycloalkyl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen.
Heterocycloalkyl is also intended to include compounds in which a ring carbon may be oxo substituted, i.e. the ring carbon is a carbonyl group, such as lactones and lactams. The point of attachment of the hetcrocycloalkyl ring is at a carbon or nitrogen atom such that a stable ring is retained. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, pyrrolidonyl, piperazinyl, dihydrobenzofury l, and dihydroindolyl. A "substituted heterocycloalkyl" is a heterocycloalkyl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound.

[0053] "Aryl" alone or in combination refers to a monocyclic or bicyclic ring system containing aromatic hydrocarbons such as phenyl or naphthyl, which may be optionally fused with a cycloalkyl of preferably 5-7, more preferably 5-6, ring members. A "substituted aryl" is an aryl that is independently substituted, unless indicated othenvise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any availabte atom to produce a stable compound.

100541 "Heteroaryl" alonc or in combination refers to a monocyclic aromatic ring structure containing 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing one or more, preferably 1-4, more preferably 1-3, even more preferably 1-2, heteroatoms independently selected from the group consisting of 0, S, and N. Heteroaryl is also intended to include oxidized S
or N, such as sulfinyl, sulfonyl and N-oxide of a tertiary ring nitrogen. A
carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced, Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinaoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, DLMR_329323.5 Atty. Dkt. No.: 039363-3550 pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl. tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl. "Nitrogen eontaining heteroaryl" refers to heteroaryl wherein any heteroatoms are N. A"substitutsd heteroaryl" is a heteroarvl that is independently substituted, unless indicated otherwise, with one or more, preferably 1, 2, 3, 4 or 5, also 1, 2, or 3 substituents, attached at any available atom to produce a stable compound.

[00551 "Lower alkoxy" denotes the group -OR', where R' is lower alkyl. A
"substituted lower alkoxy" denotes lower alkoxy in which R' is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, Forinula II, or Formula III, including descriptions of substituted cycloalkyl, heterocycloalkyl, aryl and heteroaryl, attached at any available atom to produce a stable compound. Preferably, substitution of lower alkoxy is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents, For example "fluoro substituted lower alkoxy"
denotes lower alkoxy in which the lower alkyl is substituted with one or more fluoro atoins, where preferably the lower alkoxy is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions on alkoxy are attached at any available atom to produce a stable compound, substitution of alkoxy is such that 0, S, or N
(except where N is a heteroaryl ring atom), are not bound to the alkyl carbon bound to the alkoxy O, Further, wliere alkoxy is described as a substituent of another moiety, the alkoxy oxygen is not bound to a carbon atom that is bound to an 0, S, or N of the other moiety (except where N is a heteroaryl ring atom), or to an alkene or alkyne carbon of the other moiety.

[00561 "Lower alkylthio" denotes the group -SRaa, where R88 is lower alkyl. A
"substituted lower alkylthio" denotes lower alkylthio in which R" is lower alkyl substituted with one or more substituents as indicated herein, for example, in the description of compounds of Formula I, Formula II, or Formula III, including descriptions of substituted cycloalkyl, hcterocycloalkyl, aryl and heteroaryl, attached at any available atom to produce a stable compound.
Preferably, substitution of lower alkylthio is with 1, 2, 3, 4, or 5 substituents, also 1, 2, or 3 substituents, For example "fluoro substituted lower alkylthio" denotes lower alkylthio in which the lower alkyl is substituted with one or more fluoro atoms, where preferably the lower alkylthio is substituted with 1, 2, 3, 4 or 5 fluoro atoms, also 1, 2, or 3 fluoro atoms. While it is understood that substitutions on alkylthio arc attached at any available atom to produce a stable compound, substitution of alkylthio is such that 0, S, or N
(except where N is a heteroaryl ring atom), are not bound to the alkyl carbon bound to the alkylthio S.
Further, where alkyltliio is described as a substituent of another moiety, the alkylthio sulfur is not bound to a carbon atom that is bound to an 0, S, or N of the other moiety (except where N is a heteroaryl ring atom), or to an alkene or alkyne carbon of the other moiety.

[00571 "Arnino" or "amine" denotes the group -NH2. "Mono-alkylamino" denotes the group -NHRb1 where Ree is lower alkyl. "Di-alkylamino" denotes the group NRebR~, whcrc Rer' and R" are ^LMR 329323.5 27 Atty. Dkt. No.: 039363-3550 independently lower alkyl. "Cycloalkylamino" denotes the group -NRd R", where R`'d and R"
combine with the nitrogen to form a 5-7 membered heterocycloalkyl, where the heterocycloalkyl may contain an additional heteroatom within the ring, such as 0, N, or S, and may also be further substituted with lower alkyl. Examples of 5-7 membered heterocycloalkyl include, but are not limited to, piperidine, piperazine, 4-methylpiperazine, morpholinc, and thiomorpholine. While it is understood that when mono-alkylamino, di-alkylamino, or cycloalkylamino are substituents on other moieties that are attached at any available atom to produce a stable compound, the nitrogcn of mono-alkylamino, di-alkylamino, or cycloalkylamino as substituents is not bound to a carbon atom that is bound to an 0, S, or N of the other moiety.

[0058] As used hercin, the term "composition" refers to a formulation suitablc for administration to an intended animal subject for therapeutic purposes that contains at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient.

[0059] The term "pharmaceutically acceptable" indicates that the indicated material does not have properties that would cause a reasonably prudent medical practitioner to avoid administration of the material to a patient, taking into consideration the disease or conditions to be treated and the respective route of administration. For example, it is commonly required that such a material be essentially sterilc, e.g., for injectibles.

[0060J In the present context, the term "therapeutically effective" or "effective amount" indicates that the materials or amount of material is effectivc to prevent, alleviate, or ameliorate one or more symptoms of a disease or medical condition, and/or to prolong the survival of the subject being treated.

10061J In the present context, the terms "synergistically effective" or "synergistic effect" indicate that two or more compounds that are therapeutically effectivc, when used in combination, provide improved therapeutic effects greater than the additive effect that would be expected based on the effect of each compound used by itself.

[0062] As used herein, the terms "ligand" and "modulator" are used equivalently to refer to a compound that changes (i.e., increases or decreases) the activity of a target biomolecule, e.g., an enzyme such as a kinase. Generally a ligand or modulator will be a small molecule, where "small molecule refers to a compound with a molecular weight of 1500 daltons or less, or preferably 1000 daltons or less, 800 daltons or less, or 600 daltons or less. Thus, an "improved ligand" is one that possesses better pharmacological andlor pharmacokinetic properties than a reference compound, where "better" can be defined by one skilled in the relevant art for a particular biological system or therapeutic use.

DLMR 329323.5 28 Atty. Dkt. No.: 039363-3550 [00631 In the context of compounds binding to a target, the terms "greater affinity" and "selcctive"
indicates that the compound binds more tightly than a reference compound, or than the same compound in a reference condition, i.e., with a lower dissociation constant.
In some embodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000-fold greater affinity, 100641 As used herein in connection with compounds of the invention, the term "synthesizing" and like terms means chemical synthesis from one or more precursor materials.

[00651 By "assaying" is meant the crcation of experimental conditions and the gathering of data regarding a particular result of the experimental conditions. For example, enzymes can be assayed based on their ability to act upon a detectable substrate. A compound or ligand can be assayed based on its ability to bind to a particular target molecule or molecules.

[00661 As used herein, the term "modulating" or "modulate" refers to an effect of altering a biological activity, especially a biological activity associated with a particular biomolecule such as a protein kinase. For example, an agonist or antagonist of a particular biomolecule modulates the activity of that biomolecule, e.g., an enzyme, by either increasing (e.g.
agonist, activator), or decreasing (e.g. antagonist, inhibitor) the activity of the biornolecule, such as an enzyme. Such activity is typically indicated in terms of an inhibitory concentration (ICSU) or excitation concentration (EC50) of the compound for an inhibitor or activator, respectively, with respect to, for example, an enzyme.

[00671 The present invention concerns compounds of Formula I, and all sub-generic formulae, compounds of Formula II and all sub-generic formulae, and compounds of Formula III and all sub-generic formulae that are modulators of protein kinases, for example without limitation, the compounds are modulators of at least one of the kinases selected from the group consisting of A-Raf, B-Raf, c-Raf-1, and and any mutants thereof, and the use of such compounds in the treatment of diseases or conditions.

Kinase targets and indications of the invention [00681 Protein kinases play key roles in propagating biochemical signals in diverse biological pathways. More than 500 kinases have been described, and specific kinases have been implicated in a wide range of diseascs or conditions (i.e., indications), including for example without limitation, cancer, cardiovascular disease, inflammatory disease, neurological disease, and other diseases. As such, kinases represent important control points for small molecule therapeutic intert-=ention.
Description of specific target protein kinases contemplated by the present invention follow:

DLMR 329323.5 Atty. Dkt. No.: 039363-3550 [0069] A-Raf: Target kinase B-Raf (i.e., v-raf murine sarcoma 3611 viral oncogcnc homolog 1) is a 67.6 kDa serinelthreonine kinase encoded by chromosome Xp11.4-p11.2 (symbol:
ARAF). The mature protein comprises RBD (i.e., Ras binding domain) and phorbol-ester/DAG-type zinc finger domain and is involved in the transduction of mitogenic signals from the cell membrane to the nucleus. A-Raf inhibitors may be useful in treating neurologic diseases such as multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (AD), Parkinson's disease; neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g. colorectal, lung, breast, pancreatic, thyroid, renal, ovarian), lymphoma (e.g. histiocytic lymphoma), neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis; pain of neuropathic or inflammatory origin, including acute pain, chronic pain, cancer-related pain and migraine;
and diseases associated with muscle regeneration or degeneration, including, but not limited to, vascular restenosis, sarcopenia, muscular dystrophics (including, but not limited to, Duchcnne, Becker, Emery-Dreifuss, Limb-Girdle, Facioscapulohumeral, Myotonic, Oculopharyngeal, Distal and Congenital Muscular Dystrophies), motor neuron diseases (including, but not limited to, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal lnuscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, and adult spinal muscular atrophy), inflammatory myopathies (including, but not limited to, dermatomyositis, polymyositis, and inclusion body myositis), diseases of the neuromuscular junction (including, but not limited to, myasthenia gravis, Lambert-Eaton syndrome, and congenital myasthenic syndrome), myopathies due to endocrine abnormalities (including, but not limited to, hyperthyroid myopathy and hypothyroid myopathy) diseases of peripheral nerve (including, but not limited to, Charcot-Marie-Tooth disease, Dejerine-Soltas disease, and Friedreich's ataxia), other myopathies (including, but not limited to, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, and periodic paralysis), and metabolic diseases of muscle (including, but not limited to, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine pahnatyl transferase deficiency, phosphoglyccratc kinase dcticiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency).

[0070] B-Raf: Target kinase B-Raf (i.e., v-raf murine sarcoma viral oncogene homolog BI) is a S4.4 kDa serine/threonine kinase encoded by chromosome 7q34 (symbol: BItAF).
The mature protein comprises RBD (i.e., Ras binding domain), Cl (i.e., protein kinase C
conserved region 1) and STK (i.e., serine(threonine kinase) domains.

[0071] Target kinase B-Raf is involved in the transduction of mitogenic signals from the cell membrane to the nucleus and may play a role in the postsynaptic responses of hippocampal ncurons.
As such, genes of the R,`W family encode kinases that are regulated by Ras and mediate cellular DLN7R 329323.5 30 Atty. Dkt. No.; 039363-3550 responses to growth signals. Indeed, B-Raf kinase is a key component of the RAS->Raf->MEK->ERKnVIAP kinase signaling pathway, which plays a fundamental role in the regulatiori of cell growth, division and proliferation, and, when constitutively activated, causes tumorigenesis. Among several isoforms of Raf kinase, the B-type, or B-Raf, is the strongest activator of the downstream MAP kinase signaling.

100721 The BRAF gene is frequently mutated in a varicty of human tumors, especially in malignant melanoma and colon carcinoma. The most common reported mutation was a missense thymine (T) to adenine (A) transversion at nucleotide 1796 (T1796A; amino acid change in the B-Raf protein is Val<600> to Glu<600> ) observed in 80% of malignant melanoina tumors.
Funetional analysis reveals that this transversion is the only detected mutation that causes constitutivc activation of B-Raf kinase activity, independent of RAS activation, by converting B-Raf into a dominant transforming protein. Based on precedents, human tumors develop resistance to kinase inhibitors by mutating a specific amino acid in the catalytic domain as the "gatekeeper". (Balak, et.
al., Clin Cancer Res. 2006, 12:6494-501). Mutation of Thr-529 in BRAF to Ile is thus anticipated as a mechanism of resistance to BRAF inhibitors, and this can be envisioned as a transition in codon 529 from ACC to ATC.

100731 Niihori et al., report that in 43 individuals with cardio-facio-cutaneous (CFC) syndroine, ttiey identified two heterozygous KRAS mutations in tliree individuals and eight BRAF mutations in 16 individuals, suggesting that dysregulation of the RAS-RAF-ERK pathway is a common molecular basis for the tliree related disorders (Niihori et al., Nat Genet. 2006, 38(3):294-6).

[00741 c-Raf-1: Target kinase c-Raf 1(i.e., v-raf murine sarcoma viral oncogene homolog 1) is a 73.0 kDa STK encoded by chromosome 3p25 (symbol: RAF1). c-Raf-1 can be targeted to to the mitochondria by BCL2 (i.e., oncogene B-cell leukemia 2) which is a regulator of apoptotic cell death.
Active c-Raf-1 improves BCI_2-mediated resistance to apoptosis, and c-Raf-1 phosphorylates BAD
(i.e., BCL2-binding protein), c-Raf-1 is implicated in carcinomas, including colorectal, ovarian, lung and renal cell carcinoma. C-Raf-1 is also implicated as an important mediator of tumor angiogenesis (Hood, J.D. et al., 2002, Science 296, 2404). C-Raf-I inhibitors may also be useful for the treatment of acute myeloid leukemia and myclodysplastic syndroines (Cruinp, Cun Pharm Des 2002, 8(25):2243-8). Raf-1 activators may be uscful as treatment for neuroendocrine tumors, such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma (Kunnimalaiyaan et al., Anticancer Drugs 2006, 17(2):139-42).

[0075] B-Raf andror C-Raf 1 inhibitors may be useful in treating neurologic diseases such as multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease (A-D), Parkinson's diseasc;
neoplastic diseases including, but not limited to, melanoma, glioma, sarcoma, carcinoma (e.g.
colorectal, lung, bi-east, pancreatic, thyroid, renal, ovarian), lymphoma (e.g. histiocytic lymphoma) DLMR_329323.5 Atty. Dkt. No.: 039363-3550 ncurotibromatosis, acute myeloid leukemia, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuroendocrine tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma; pain of neuropathic or inflammatory origin, including acute pain, chronic pain, cancer-related pain, and migraine; cardiovascular diseases including heart failure, ischemic stroke, cardiac hypertrophy, thrombosis (e.g. thrombotic microangiopathy syndromes), atherosclerosis, reperfusion inlury; inflamination including, but not limited to, psoriasis, arthritis and autoimmune diseases and conditions, ostcoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease (1BD);
immunodeficiency diseases, organ transplant relection, graft versus host disease; renal or prostatic diseases including diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia; metabolic disorders, obesity; infection, including, but not limited to HelieobacteY pylori, Hepatitis and Influenza viruses, fever, sepsis; pulmonary diseases including chronic obstructive pulmonary disease (COPD) and acute respiratory distress syndrome (ARDS);
genetic developmental diseases such as Noonan's syndrome, Costello syndrome, (faciocutaneoskeletal syndrome), LEOPARD syndrome, cardio-faciocutaneous syndrome (CFC), and neural crest syndrome abnonnalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine discases.

Kinase Activity Assays [0076] A number of different assays for kinasc activity can be utilized for assaying for active modulators and/or detennining specificity of a modulator for a particular kinase or group or kinases.
In addition to the assay mentioned in the Examples below, one of ordinary skill in the art will know of other assays that can be utilized and can modify an assay for a particular application. For example, numerous papers concerning kinases describe assays that can be used.

100771 Additional alternative assays can employ binding detenninations. For example, this sort of assay can be fonnatted either in a fluorescence resonance energy transfer (FRE'T) fonnat, or using an AlphaScreen (amplified luminescentproximity homogeneous assay) format by varying the donor and acceptor reagents that are attached to streptavidin or the phosphor-specific antibody.

Organic Synthetic Techniques [00781 A wide array of organic synthetic techniques exist in the art to facilitate constructing potential modulators. Many of these organic synthctic methods are described in detail in standard reference sources utilized by those skilled in the art. One example of such a reference is March, 1994, Advanced Orvanic Chemistry; Reactions, Mechanisms and Structure, New York, McGraw Hill.
Thus, the techniques useful to synthesi7e a potential modulator of kinase function are readily available to those skilled in the art of organic chemical synthesis.

DLMR 329323.5 32 Atty. Dkt. No.: 039363-3550 Alternative Compound Forms or Derivatives [00791 Compounds contemplated herein arc described with reference to both generic formulae and specific comporands. In addition. inveiition compounds may exist in a number of different forms or derivatives, all within the scope of the present invention. Alternative forms or derivatives, such as (a) Isoi;)ers, I'rociru,-,s. and Actit e ibletabolites (b) Tautomers, Stereoisomers, Regioisomers, and Solvated poams (c) .Frodruzs and ivletabo;itcs (d) Pharmaceuticaily acceptable salts and (e) Polymorphic forms, are described. for example, in US Patent Applieation Serial number 11/473,347 (see also, PCT
publication W020I17002433), the disclosure of which is hereby incorporated by reference in its entirety.

Administration 100$01 The methods and compounds will typically be used in therapy for human subjects.
However, they may also be used to treat similar or identical indications in other animal subjects. In this context, the terms "subject," "animal subject," and the like refer to human and non-human vertebrates, e.g. mammals, such as non-human primates, sports and commercial animals, e.g., equines, bovines, porcines, ovines, rodents, and pets, e.g., canines and felines. A description of possible methods and routes of administration may be found, for example, in US
Patent Application Serial number 11/473,347 (see also, PCT publication W02007002433), the disclosurc of which is hereby incorporated by reference in its entirety.

EXAMPLES
[0081] A number of examplcs illustrative of the present invention are described below. In most cases, alternative techniques could also be used. The examples are intended to be illustrative and are not limiting or restrictive to the scope of the invention. Unless specifically noted to the contrary, in cases where a compound number is not preceeded by a(e.g., "I'-0001 ") in the Examples section, compound naming and/or enumeration is not related to naming and/dr enumeration employed in other sections of this application. Similarly, structure and substituent naming and enumeration within the Examples z,re independent of structure and substituent naming and enumeration in above sections of this api;licati,:,n unless clearly uidicated otherwise, 100821 In the fo1Jo inLr 1~xnmp]e-s, it is understood 11iat the solvents and ret gcnts 1.1scd or su~~>~~~tcd are not limitinrr,,inr] c~in be suhstituteti appropriately wilh solvents and reabcnts known to those of skill in the art Re~ictWr 1>roducts way be isolated by m.cans known in the art, such as c:~ar~retion with a suitablc sokcw, ha-cJpilsttion fresm a suitable solvent, clu-ornatoLrahhy using a suitable solvent system, including silica gel column chromatography, H.PLC, preparative TLC, and the like.
Exemplary methods for synthesis of compounds of the present invention may be found in US Patent DLMR_329323.5 Atty. Dkt. No.: 039363-3550 Application Serial number 11/473,347 (see also, PCT publication W02007002433), the disclosure of which is hereby incorporated by refei-ence. The 1H-pyrrolo[2,3-b]pyridine core of compounds described in the examples may also be referred to as 7-azaindole in the examples.

Example 1. Synthesis of compounds of Forniula X

HQ O
R ~ A+ pStep 1 R' Step 2 R' N N H N N N
H N H
Xa Xb H
X
Xc Step I - Prepaf-ation of cornpounds of Formula Xc andXd [0083] To a compound of Formula Xa (RI is as defined in paragraph [0009]) and a compound of Formula Xb (Y is consistent with compounds of Formula 1, Formula II, or Formula III, e.g. Y is:

~
~ J R2 1 \ / ~ 6 N-S \~ N-S \~ 2 S R
F H p F H O R or F H O, where R' and R3 are as defined in paragraph [0009], and R6 is as defined in paragraph [0017], where indicates the attachment point to the carbonyl carbon) is added an appropriate solvent (e.g.
methanol) followed by an appropriate base (e.g. potassium hydroxide, sodium methoxide). The reaction is typically allowed to stir at room temperature overnight. Isolation by conventional means (e.g. extraction, washing and filtering) affords a mixture containing compound of Formula Xc, which may be isolated by silica gel chromatography if desired.

Step 2 - Pr'epar=ation of compounds of Formula X
[0084] To a compound of Formula Xc in an appropriate solvent (e.g.
tetrahydrofuran) is added an oxidizing agent (e.g.Dess-Martin periodane, TEMPO, DDQ). Typically, the reaction is allowed to stir at i-oom temperature for 20 minutes. Isolation by conventional means (e.g.
extraction and silica gel column chromatography) affords compounds of Formula X.

Example 2. Synthesis of Compounds of Formula X

C?
Y
+ '~--Y Step 1 N H Ci H
Xa Xd X

DLMR_329323.5 Atty. Dkt. No.: 039363-3550 Step -1- Synthesis of compound of Forrnasla X
[00851 Compound of Formula X is synthesized by reacting a compound of Formula Xa (see Example 1) with a compound of Formula Xd (Y is as defined in Example 1), e.g.
benzoyl chloride, in the presence of a Lewis acid (e.g. aluminuin trichloride) in an inert solvent (e.g. dichloromethane) under an inert atmosphere (e.g. argon) at room temperature or with heating up to reflux for 1-18 hours. The desired compound X is isolated by extraction and silica gel column chromatography, ExAmple 3. Synthesis of Compounds of Formula X

RI Ri R' ~
~ Step 1 Step 2 I + \~
~ ~Y' H N ~ N F
NXa H N Xf P O;O
Xe Xg HO O
RI ~Y' 1. Step 4 i Yi Step 3 F ,5 R
~ O 2. Step 5 1 O O
N N Xh N H X
P
Step - 1- Synthesis of cornpor.rnd Xe [00861 Compound of Formula Xe can be synthesized by reacting a compound of Formula Xa (see Example 1) with hexamethyltetramine and acetic acid in water with heating to reflux for two hours, After cooling, the desired compound precipitates and may be collected by filtration.

Step - 2 - Synthesis of compound of ForrnuZa Xf [00871 Compound of Formula Xf, where P is a nitrogen protecting group, is synthesized by reacting a compound Xe with an appropriate reagent to introduce a protecting group (e.g.
triisopropylsilylchloride) and a base (e.g. sodium hydride) in a solvent (e.g.
tetrahydrofuran) typically at room temperature for 8-12 hours. The desired compound is isolated by conventional means (e.g.
extraction).

Step - 3 - Synthesis of'cotnpound of'Formit(a Xh [00881 Coinpound of Forulula Xh is synthesized by reacting a compound of Formula Xf in a solvent (e.g. tetrahydrofuran) with an organolithium reagent (e,g. phenyl lithium) in a solvent (e.g, tetrahydrofuran) under an inert atmosphere, cooled to -78 C. An appropriate organolithium reagent '/ R2 z can also be prepared by reacting compounds of Formula Xg, where Yi is ~~ R
DLMR_329323.5 Atty. Dkt. No.: 039363-3550 or -R6 indicates attachment point to the sulfone), where W, Wand Rb are as defined in Eznmpl4 1, with an organolithium reagent (e.g. butyllithium) in a solvent (e.g.
tetrahydrofuran) under an inert atmosphere, cooled to -78 C. The reaction is typically allowed to w<irm to room temperature and stirred for 30 minutes. The desired compound is isolated by eom,cnticmal means (e.g. extraction).

St, /, -4 - Synthesis of an intermediate of compouttd o, f Formulca X
[00891 An intermediate of compound of Forniula X is synthesized by reacting aco >p~nunc of Formula Xh with an appropriate reagent to remove the protecting group,l', (e.g. tetra-n-butyl ammonium fluoride) in an appropriate solvent (e.g. tetrahydrofuran). The final product is isolated by standard procedures (e.g. extraction).

Step - 5 - Synthesis of canipound of Formula X
100901 Compound of Formula X is synthesized by reacting the intermediate from Step 4 with an oxidizing agent (e.g. Dess-Martin periodane, TEMPO) in an aprotic solvent (e.g. tetrahydrofuran) typically at rooM temperature for 20 minutes. The desired c- mpouiid is isolated by conventional means (e.g. extraction and silica gel chromatography).

Example 4: Synthesis of 5-pyridin-3-yl-lH-pyrr l [2,3-b]pyridine 22.

[0091] 5-Pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine 22 was synthesized in one step from 5-bromo-lH-pyrraio[2,3-b]pyridine 1 as described in Scheme 7.

Scheme 7 Br B(m-I)z N
~ Step 1 N H N N

Step 1-Prepatation bf5-pyritlira-3 yZ-IH-pyrrolc)[2,3-b]pyri, li) ze (22):
[00921 To 5-bromo-7-azaindole (1, 1.00 g, 5.M' mniol) in water (13.0 znL) and acetonitrile (36 mL) were added pyridine-3-boronic acid (21, 1.0 g, 8.1 minol), pot;issium carbonate (1.79 g, 0.0130 mol) and Tetraki.s(ti-it)henylphosp?tiiue)hallt,dium(O) (5(1,0 mg, 0,043 mmol) under an atmosphere of nitrogen. The re~iction an.isttture was Iieated to 170 C overn.ight. The reaction mixture was poured into water and eN"tnictecl.~itl; t:thyl acetate. The organic layer wa;
w.nslled with brine, dried over sodium sulfate, and conce,its-.lted. The residue was purified with silica ~;el column chrcinatourapay-eluting with 25% ethyl acetate in hexarlc to pre>vide a light yellow solid (22, $20 mg, 82%).
N1S(1_5Ip1 -H'] - 196.1.

QLMR_329323.9 Atty. Dkt, No.: 039363-3550 [0093] Additional compounds were prepared following the protocol of Scheme 7, either b_y substituting pyridine-3-boronic acid with an appropriate boronic acid or by substituting the 5-bromo-7-azaindole with 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine and reacting with a suitable aryl or heteroaryl halide (i,e. coupling with the boronic acid ester on the azaindole, and the halide on the group to be coupled to the 5-position of the azaindole). The following compounds were prepared by this procedure:
5-(5-Methyl-lH-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (34), 5-(1-Methyl-lH-iinidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (35), and 5-(1,5-Dimethyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (59).
The following table indicates either 5-bromo-7-azaindole or 5-(4,4,5,5-Tetramethyl-[1,3,2]
dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine starting material (column 1) and the appropriate reagent to be coupled to the 5 position of the azaindole (column 2) to afford the resulting compound (column 3), with the observed mass given in column 4.

Reagent coupled to MS(ESI) Starting azaindole 5 position Compound [M+H ]-observed ~N
oB N~Br H 199.2 N H H N N
H
B
~ N ~
//-NBt N ( ~ \ 199.2 N H N H
N
B 0 Br I 213.2 N H N N
H
Example 5: Synthesis of 5-(1-methyl-lH-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 46.

100941 5-(1-Methyl-lH-pyrazol-4-yl)-1fl-pyrrolo[2,3-b]pyridine 46 was synthesized in one step from 5-bromo-IH-pyrrolo[2,3-b]pyridine 1 as shown in Schcme 12, DLMR_329323.5 Atty. Dkt. No.: 039363-3550 Scheme 12 Br o~~
l B 'O NN

N Step 1 \ \ ( \~
N H N_N N H

Step 1 -Preparativn of5-(1-?tiethyl-IH-pyra-~ol-4-yl)-1H-pyrrolof2,3-6]pyridirre (46):
[0095] To 5-bromo-7-azaindole (1, 1.04 g, 5.28 mmol) in 1.00 M potassium carbonate in water (15.8 mL) and tetrahydrofuran (50.0 mL) were added 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (45, 1.65 g, 7.92 mmol), Tetrakis(triphenylphosphinc)-palladium(0) (0.305 mg, 0.26 inmol) and tetra-n-butylammonium iodide (0.20 g, 0.53 mmol). The reaction mixture was stirred at 70 C overnight. The reaction mixture was poured into water and the organic layer was washed with brine, dried over sodium sulfate, and concentrated. The residue was purified with silica gel column chromatography eluting with 25% ethyl acetate in hexane to provide a light yellow solid (46, 670 mg, 64.0%). MS(ESI)[M+H+]+ = 199.4.

Example 6: Preparation of propane-2-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-IH-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyll-amide 51.

100961 Propane-2-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide 51 was synthesized in four steps from 2,4-difluorophenylamine 47 as shown in Scheme 13.

Scheme 13 F O F , F
~ Step 1 Step 2 H + N"~ Step 3 ~. ( ~ f F ( F
F NH HN~ ~ HN- S ~ 22 N H
47 2 48 s 49 F F
N~ HO O
O Step 4 F HN^ N~ F HN-O\

Step 1-Preparatior: ofpropane-2-sidfonic acid (2,4-diluaro phenyl)-amide (48):
[0097] To 2,4-difluoro-phenylamine (47, 4.0 mL, 40.0 ininol) in dichloromethane (50 mL) were added pyridine (3.37 mL, 42.3 mmol), propane-2-sulfonyl chloride (6.00 g, 42.3 mmol) and DLMR_329323.5 Atty. Dkt. No.: 039363-3550 dimethylarninopyridine (0.20 g, 1.64 mmol) under an atmosphere of nitrogen.
The rcaction was stirred at 45 C overni0ht. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gcl column chromatography 3% methanol in methylene chloride to give a white solid (48, 8.0 g, 85%). MS(ESI) [M-H+]' = 234Ø

Step 2- Preparation of propane-2-sulfonic aeid (2, 4-difluoro-3-forrmyl -pheny!)-arnide (49):
[0098] 'I'o propanc-2-sulfonic acid (2,4-difluoro-phenyl)-amide (48, 2.35 g, 9.95 mmol) in tetrahydrofuran (70 mL) under an atmosphere of nitrogen cooled with a dry ice;
acetone bath was added 1.60 M of n-butyllithium (1.60 M in hexane, 6.53 mL, 10.45 mmol). The reaction was stirred for 40 minutes, and then another portion of n-butyllithium (1.60 M in hexane, 6.S4 mL, 10.94 mmol).
The reaction was stirred for 1 hour and N,N-dimethylfonnatnide (0.92 mL, 11.9 mmol) was added.
The reaction was allowed to warm to room temperature ovcrnight. The reaction was poured into water extracted with ethyl acetate. The organic layer was washed with brine, dried ovcr anhydrous sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography (dichloromethane/methanol 5%) to give the compound (49, 1.4 g, 53.4%). MS(ESI) [M - H-]' = 263 .4.

Step 3- Preparation of propane-2-sulf nic acid {Z, 4-dif uoro-3-[hydroxy-(S -pyridin-3-yl-I FI-pyrrolo[2,3-bJpyridu7-3 yl)-naetlrylJ phenyl}-arnide (50):
[0099] To propane-2-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (49, 220.0 mg, 0.83 mm(il) in methanol (15 mL) was added 5-pyridin-3-yl-IH-pyrrolo[2,3-b]pyridine (22, 150.0 ing, 0.77 mmol, prepared as described in Example 4) and potassium hydroxide (537.0 mg, 9.6 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% methanol in dichloromethane to give the compound (50, 160 mg, 45.3%). In this step, minor compound propane-2-sulfonic acid {2,4-difluoro-3-[methoxy-(5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyli-amide was also fonned and isolated. MS(ESI) [M+H+]- =460.1.

Step 4-- Preparation ofpr parte-2-sulfonic acid [2,4-difluoro-3-(S pyridin-3 yl-IHpyrr lof2,3-bJpyridine-3-carbonyl) phenylJ-ar?iide (51):
[0100] To propane-2-sulfonic acid {2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1 H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenyl)-amide (50, 40.0 mg, 0.087 mmol) in tetrahydrofuran (10 mL) was added Dess-Martin periodane (48.0 mg, 0.11 mmol). The reaction was stirred at room temperature for minutes. The reaction was poured into sodium thiosulfatc and potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhvdrous sodium DLMR_329323.5 Atty. Dkt. No.: 039363-3550 sulfate and filtrated. The filtrate was concentrated and purified by silica gel column chromatography cluting with 5% methanol in methylene chloride to give the compound (51, 13.4 mg, 33.5%).
MS(ESI) [M + H+]~ = 45 S.1.

[0101] N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl~-4-isopropyl-benzenesulfonamide P-0018 L-'j 0 4 F H-O
N N
H
was prepared following the protocol of Scheme 13, substituting pi-opane-2-sulfonyl chloride with 4-isopropyl-phenyl sulfonyl chloride in step 1 and 5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine 22 with 5-(2-rnethoxy-ethoxy)- I H-pyrrolo[2,3-b]pyridine 19 in step 3. MS(ESI) [M -H+]'= 530.

101021 N-{2,4-Difluoro-3-[5-(4-methyl-IH-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyll-4-isopropyl-benzenesulfonamide P-0019 F NH O ~'N ~ cyr~

N F H`~
N N
H
was prepared following the protocol of Scheme 13, substituting propane-2-sulfonyl chloride with 4-isopropyl-phenyl sulfonyl chloride in Step 1 and 5-pyridin-3-yl-IH-pyrrolo[2,3-b]pyridine 22 with 5-(5-methyl-lH-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine 34 (see Example 4) in step 3. MS(ESI) [M-H+]`=536.

[0103] N-{2,4-Difluoro-3-[5-(1-methyl-lH-pyrazol-4-yl)-IH-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl r -4-isopropyl-benzenesulfonamide P-0022 F
--N~

F HN '`O
NJ N d H
was prepared following the protocol of Scheme 13, substituting propane-2-sulfonyl chloride with 4-isopropyl-phenyl sulfonyl chloride in Step 1 and 5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine 22 with 5-(1-methyl-lH-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine 46 (see Example 5) in step 3. MS(ES1) [M -FI#]` = 536.

[0104] N-{2,4-Difluoro-3-[5-(5-methyl-lH-imidazol-2-yl)-IH-pyrrolo[2,3-b]pyridine-3-carbony1]-phenyl } -4-trifluoromethyl-benzenesulfonamide P-0025 DLMR_329323.5 Atty. Dkt. No.: 039363-3550 O

N{ r ~ F HN-S-~
~ p p was prepared following the protocol of Scheme 13, substituting propane-2-sulfonyl chloridc with 4-trifluoromethyl-phenyl sulfonyl chloride in Step 1 and 5-pyridin-3-y1-1H-pyrrolo[2,3-blpyridine 22 with 5-(5-methyl-lH-imidazol-2-yl)-1H-pyiTolo[2,3-b]pyridine 34 (see Example 4).
MS(ESI) [M - H-] = 562.

[01051 N-{2,4-Difluoro-3-[5-(1-methyl-lH-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl )-4-propyl-benzenesulfonamide P-0026 F

N F H" ~
N N
H
was prepared following the protocol of Scheme 13, substituting propane-2-sulfonyl chloride with propane sulfonyl chloride in Step 1 and 5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine 22 with 5-(5-methyl-lH-imidazol-2-yl)-lH-pyrrolo[2,3-b]pyridine 35 (see Example 4).
MS(ESI) [M - H+]" -536.2.

[01061 N-{3-[5-(1,5-Dimcthyl-lH-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl} -4-propyl-benzenesulfonamide P-0027 F
`N o N ~ ~ ,~ F ~- ~
Ny N
H
was prcparcd following the protocol of Scheme 13, substituting propane-2-sulfonyl chloride with propane sulfonyl chloride in Step 1 and 5-pyridin-3-yl-lH-pyrrolo[2,3-b]pyridine 22 with 5-(1,5-dimethyl-lH-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine (59) (see Example 4).
MS(ESI) [M - H`]
550.1.

Example 7: Synthesis of N-[3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3,5-difluorobenzenesulfonamidc 58 [01071 Compound P-1841 was synthesized in six steps from 2,4-difluoroaniline 47 as shown in Scheme 14.

DLMR_329323.5 Atty. Dkt. No.: 039363-3550 Scheme 14 F
F O F HO ~
/
F H Cl Step 3 CI NH p 4 ~~ Step F I~ Step 2 +~ F Ste F~ HN H N N Cbz 47 NH2 52 `Cbz 53 Cbz 6 H 54 F F F F
O O.
CI Step 5 O' + S02CI F
F NH CI F NH (~ Step 6 Cl F H;5 N N Cbz N F ~ F N H 58 O

Step 1- Preparation of (2, 4-difluoro -phenyl)-car6ami.c acid benzyyl ester (52):
[0108] To 2,4-difluoroaniline (47, 7.0 mL, 0.070 mol) in 100 mL of dichloromethane was added pyridine (11 mL, 0.14 mol) and benzyl chloroformate (11.9 mL, 0.0834 mol). The reaction mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and KHSO4 solution. The organic layer was dried (MgSO4), concentrated and crystallized from hexanes to give compound 52 (15.6 g, 85%).

Step 2 - Preparation of (2,4-difluoro-3 formyl-phenyl)-carbamic acid benzyl ester (53):
[0109] Into a round bottom flask was added (2,4-difluoro-phenyl)-carbamic acid benzyl ester (52, 3.83 g, 14.5 mmol) in tetrahydrofuran (148 mL, 1.82 mol). The solution was chilled to - 78 C and n-butyllithium (1.60 M in hexane, 19.1 mL, 30.0 mmol) was added over 30 minutes followed by the addition of, N,N-dimethylformamide (1.12 mL, 14.5 mol). The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and crystallized from ether to give compound 53 (3.0 g, 71%).

Step 3 - Preparation of (2,4-difluoro-3-[hydroxy-(1H-pyrrolo[2,3-bJpyridin-3 yl)-met/rylJ yhenylt-carbaniic acid benzyl ester (54):
[0110] Into a round bottom flask was added 5-chloro-1 H-pyrrolo[2,3-b]pyridine (6, 0.524 g, 3.43 mmol) in methanol (5.00 mL, 0.123 mol). Potassium hydroxide (0.800 g, 14?
mmol) and (2,4-difluoro-3-formyl-phenyl)-carbamic acid benzyl ester (53, 1.02 g, 3.5 mmol) were added and the reaction mixture was stirred overnight. The reaction mixture was poured into 1N HG1 and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and crystallized from ethyl acetate to give compound 54 (710 mg, 46%).
MS(ESI)[M+I-i']' -- 444.
DLMR 329323.5 42 Atty, Dkt. No.: 039363-3550 Step 4-Preparatiotl of[2,4-difluoro-3-(IH-pyrrolo[2,3-bJpyridine-3-carbonyl) plzenylJ-carbanlic acid benzyl ester (55):
[0111] Into a round bottom flask was added {2,4-difluoro-3-[hydroxy-(1H-pyiTolo[2,3-b]pyridin-3-yl)-methyl]-phenyl] -carbamic acid benzyl ester (54, 1.01 g, 2.28 mmol) in tetrahydrofuran (5.00 mL, 0.0616 mol). Dess-Martin periodinane (1.20 g, 2.89 mmol) was added in portions. The reaction mixture was stirred at ambient temperature for 10 minutes, then poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated and purified by silica gel chromatography to give compound 55 (914 mg, 91 lo).
MS(ESI)[M4-W]' = 442.
Step 5 - Preparation of (3-Amino-2,6-d~fuoro -pItenyl)-(i-chloro-IH-pyrrolo[2,3-b]pyridin-3-yl) -rnethanone (56):
101121 [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phcnyl]-carbamic acid benzyl ester (55, 800 mg, 1.81 mmol) was added to 10 M NaOH (15.00 mL) and warmed to reflux overnight. The reaction mixture was diluted with 30 mL of water and was extracted with ethyl acetate to give compound 56 (450 mg, 81 % ).

Step 6 -Preparation of~'V-[3-(5-chloro-IH-pyrrolo[2,3-bJpyridine-3-carbonylJ-2,4-difluoro -phenvlJ-3,5-difluorobenaenesulfonainide (58):
[01131 Into a microwave reaction vessel were combined (3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl) -methanone (56, 50 mg, 0.16 mmol), 3,5-difluorobenzenesulfonyl chloride (57, 103 mg, 0.49 mmol), pyridine (0.5 mL, 6.1820 mol) and tetrahydrofuran (3.0 mL,). '1'he reaction was warmed in the CEM microwave at 300 watts, 130 C for 10 minutes.
The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was collected, dried over Na7SO4, filtered and concentrated. "l'he compound (58) was isolated using column chromatography (silica, hexane:ethyl acetate 70:30) to obtain 36 mg (46%) compound. MS =
482Ø

[0114] Additional compounds were prepared following the protocol of Scheme 14, optionally substituting 5-chloro-lH-pyrrolo[2,3-b]pyri dine 6 with an appropriate azaindole in Step 3 and/or 3,5-difluorobenzenesulfonyl chloride 57 with an appropriate sulfonyt chloride in Step 6. The following compounds were prepared by this procedure:
Benzo[b]thiophene-3-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0001), 5-Methyl-2-trifluoromethyl-furan-3-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0002), 5-Oxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-ditluoro-phenyl]-amide (P-0003), 3-[3-(5-Chloro-1 H-pyrrolo [2,3-b]pyridine-3 -carbonyl)-2,4-difluoro-phenylsulfamoyl]-benzoic acid (P-0004), DLMR_329323.5 Atty. Dkt. No.: 039363-3550 2-Oxo-2H-chromene-6-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0005), 5-Isoxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-IH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0006), 4-Butoxy-N-[3-(5-chloro-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2 ,4-difluoro-phenyl]-benzenesulfonamide (P-0007), N-[3-(5-Chloro-l H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-pyrazol-l-yl-benzenesulfonamide (P-0008), Benzothiazole-6-sulfonic acid [3-(5-chloro-1 H-pyrrolo[2,3-b]pyridine-3-carbonvl)-2,4-difluoro-phenyl]-amide (P-0009), 1-Methyl-3-trifluoromethyl-lH-pyrazole-4-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0010), N-[3-(5-Chloro-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropoxy-bcnzenesulfonamide (P-0011), Benzo[1,2,5]thiadiazoe-5-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0013), 4-tert-Butyl-N-[3-(5-chloro-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide (P-0014), N-[3-(5-Chloro-1 H-pyrrolo [2,3-b]pyridine- 3 -carbonyl)-2,4-di fluoro-phenyl]-4-propyl-benzenesulfonamide (P-0015),N-[3-(5-Chloro-lH-pyrrolo[2,3-b]pyridinc-3-carbonyl)-2,4-difluoro-phenyl]-3-difluoromethoxy-benzenesulfonamide (P-0016), 5-Methyl-benzo[b]thiophene-2-sulfonic acid [3-(5-chloro-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0017), 3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(1-methyl-1 H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phcnyl}-benzenesulfonamide (P-0020), N- {2,4-Difluoro-3-[5-(1-methyl-1 H-pyrazol-4-yl)-I H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide (P-0021), N- {2, 4-Di fluoro-3 -[ 5-(5-methyl-1 II-imidazo l-2-yl)-1 H-pyrrolo [2,3-b]pyridine-3-earbonyl]-phenyl}-4-propyl-benzenesulfonamide (P-0023), 3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(5-methyl-1 H-imidazol-2-yl)-1 H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl} -benzenesulfonamide (P-0024), 5-Methyl-thiophene-2-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0028),1-Methyl-lH-pyrazole-3-sulfonic acid [3-(5-chloro-lH-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide (P-0029),N-[2,4-Difluoro-3-(5-methyl-1 H-pyrrolo[2,3-b]pyridine-3-ca.rbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-0030),N-[3-(5-Cyano-l II-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-DLMR 329323.5 44 Atty. Dkt. No.: 039363-3550 trifluoromethyl-beizenesulfonamide (P-0031), (E)-3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylainino)-benzoyl]-1 H-pyrrolo[2.3-b]pyridin-5-yl}-acrylic acid methyl ester (P-0032), and Pyridine-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-IH-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-0036).
The following table indicates the azaindole used in step 3(column 2) and the sulfonyl chloride used in step 6(column 3) to afford the target compound (column 4). The compound number is provided in colunzn 1, with the observed mass given in column 5.
MS(ESI) Azaindole Sulfonyl chloride Compound [M+Ht]
observed Cl CI F
_ _ O
P-0001 7 ~ ~~5~~ ci 0 H-S 503.96 N N ~ \ 4 \ F H~~
H N H p~
ci F
ci 0 O=S:
P-0002 F C ci N H N 3 / N F H O CF3 H H
ci F
C! O~S= 0 P-0003 N ~ S ci F ~-S 5 ~ C 520.3 ~ N N
N
H"p H
Cl F
cl p~S=O 0 P-0004 c Nf N CI F N' q 491.9 H p OH
H D~ N NN
OH H
F
CI ~CI fl ., I \
S
N ~~ ~ ci \ F H S 515.9 H ' ( N
H
ci F
C~ O-S`O p '/

P-0006 ~ S V ci , \ H ~ O 521.1 N H f,\ F H S 1 N~
NO N H
F
ci Cl 0-g =0 O
P-0007 Ti C1 N ~S 519.9 N/ H I I ~

DLMR329323.5 Atty. Dkt. No.: 039363-3550 MS(ESI) Azaindole Sulfonyl chloride Compound [M+1I ]' obser-ved p F -- - --~
CI \\ -CI C ~F: p P 0008 ~ N N~ S~ CI N~S ~ ~J N S14.3 H N N N H p H
F

,- "C p\/ N
P-0004 S S\ CI ,S 505.1 N N ~ O ~ F N~~
H N N~ N' H O
H
F
CI \ FC OSCI O p~
P-0010 N N' ~ O CI F N- O CF 52 0 3 N H N' H 3 N H
F
CI 0 ~CI P~H OP-0011 N N CI N505.9 H O N N O
H
F ---O N
P-0013 Ci 7\\ N1 ~S~CI CI O S ~ 505.9 N F H/p N~ SN~O
H
F
Cf O 'CI O
N \ f 503.9 P-0014 ~ O CI F N O
H fy N H p H
--- F

P-0015 CI" ( ~\ O; CI CI p ~/, OS 490.3 ~p ~ \ F H ~p N H

cl 0~ CI O al p F
P-0016 N N FYO , ~ S O CI F N'S p~lF 514.3 H F~ N N H O
H
F
CI O p P 0017 11 N N 1 ~ S-CI CI F N S~ 517.}
H O N N H O
H
F
-------N_ p p 0020 -N ~ F~ C~ I SCI N I. F HN~S F F 560 P
N ~ N N
H

DLMR 329323.5 Atty. Dkt. No.: 039363-3550 MS(ESI) Azaindole Sulfonyl chl ride Compound [N4+H']' observed F
N_ ---N~ OO N O
P-0021 ; \ = 'N 536 N N ~ i C1 F HN-S, H Nl H O
F
P 0023 ' S"CIN'~ F N,g 536 1flNN
H H N N HO
H
F
~
Ci O
~
N q P-0024 H F O S=0 N' F HSO\ O 560 N H F~O H N FF

F.
P-0028 tN N f~~-~CI Ci ov F HN-~ 469 H
0 /C' O F
CI S, \ o P-0029 N N / N O Ci N F HN-s " 453 H N' N N o H
F
CI
O
P-0030 ( N N CC~ F HN-s /\ CF3 496 H F3C ~N N o H
_--i N p p 0 ~ \ S\ N ~~ 507 P-0031 i N~ N F\( CI ~ F HN-S ~ ~ CF

Ns N
H

p P-0032 C N N So i 4 f ~ HN-S,` / 566 H F3C a ~ F ~ O
3 N ' N
H
F
/ O O C
P-0036 o N~ S, CI 'o F HN- 445 N
H
N N
H

DLMR_329323.5 Atty. Dkt. No.: 039363-3550 Example 8: Synthesis of 3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzovl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-propionamidc P-0035.

[01151 3-t3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-propionamide P-0035 was synthesized in three steps from (E)-3-{3-[2,6-Difluoro-3-(4-tri fluoromethyl-benzenesulfony lamino)-benzoyl]-1 H-pyrrolo [2, 3-b] pyridin- 5-yl }-acrylic acid methyl ester P-0032 as shown in Scheme 15.

Scheme 15 J ~

0 0 ~ ~ Ste 1 - o ~ ~ Step 2 p O ~ I ti F HN ~S~O
O I \ F HN ~S~O ; ~ N O
N H O N H

o ~~ (~-( o Step 3 s OC
H O ~ F FiNOS~O -~r H ~ I F HNOS~O
N N
H H

Step 1 Preparation of3-{3-{2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylarnino)-henzoylJ-1H-pyrrrolo{2, 3-bJpyridin-5 yl)-propionic acid methyl ester (P-0033):
[0116] To (E)-3-{3-[2,,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acrylic acid methyl ester (P-0032, 229 mg , 0.41 mmol, prepared as described in Example 7) was added methanol (15 mL) and tetrahydrofuran (5 mL).
The solution was degassed with nitrogen for 5 minutes, followed by the addition of PdIC (10%
weight, 30 mg). The reaction mixture was allowcd to stir under an atmosphere of hydrogen at room temperature for 18 hrs.
After removing Pd/C and volatiles, the residue was purified through a quick silica plug eluted with ethyl acetate. Solvent was removed to provide an off-white solid (P-0033, 222 mg, 96%). MS (ES1) [M+H+] -568.3.

Step 2- Preparatioir of 3-{3-[2, 6-dif uaro-3-(4-trifluoromethyl-benzenesu fonylamino)-benzoylJ-]H-pyrrolo[Z,3-b]pyridin-S-yl} propionic acid (P-0034).' [0117] To 3-{3-[2,6-difluoro-3-(4-trilluoromethyl-henzeuesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid methyl ester (P-0033, 215 mg, 0.38 mmol) dissolved in tetrahydrofuran (30 mL) was added 1 N lithium hydroxide solution (15 rnL). The mixture was heated at 50 C for 2 hrs, then acidified to pH-l-2 with 6 N HC1 and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and DLMR 329323.5 48 Atty. Dkt. No.: 039363-3550 concentrated to provide an off-white solid (P-0034, 202 ing, 96%). MS (ESI) [M+H']`-554Ø

Step 3-Prepcrration of3-{3-(2,6-difuoro-3-(4-trifluot'on7et{ty/-benzenesulfonylarnino)-benzovlJ-1H-pyrrolo(2,3-blpyridin-5 ylf-N-ethyl propionamide (R-0035):
[0118] To 3-{3-[2,6-difluoro-3-(4-trifluoromethyl-benzenesulfonylaminQ)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid (P-0034, 42 mg, 0.076 mmol) dissolved in tetrahydrofuran (3 mL) was added a 2.0 M solution of ethylamine in tetrahydrofuran (110 L, 0.23 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (29 mg, 0.15 mmol).
The reaction mixture was stirred at room temperature for 16 hrs, then extracted with ethyl acetate and water. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The desired compound was isolated by silica gel column chromatography (methanolldichlorocnethane), with the eluting solvcnts removed via lyophilizing to provide a white fluffy solid (P-0035, 13 mg, 30%). MS (ESI) [M+W]`= 581Ø

Example 9: Kinase Activity Assays [0119] Assays for the activity of B-Raf, B-Raf V600E, B-Raf V600E/T5291 or c-Raf-1 are known in the art, for example as described in US Patent Application Serial number 11/473,347 (see also, PCT
publication W02007002433), the disclosure of which is hereby incorporated by reference in its entirety.

101201 Representative compounds screened by at least one of the methods described in US Patent Application Serial numbcr 11/473,347, or by similar methods, having IC50 of less than 10 M under the test conditions employed are shown in tables la (B-Raf), lb (B-Raf V600E), lc (B-Raf V600EiT5291), and ld (c-Raf-1).

Table 1 a. Representative compounds with activity toward kinase B-Raf with ICsa < 10 M under the test conditions employed.
B-Raf P-0001, P-0002, P-0003, P-0005, P-0006, P-0007, P-0009, P-0011, P-0013, P-0014, P-0015, P-0016, P-0017, P-0018, P-0019, P-0020, P-0021, P-0022, P-0023, P-0024, P-0025, P-0026, P-0027, P-0028, P-0030, P-0031, P-0032, P-0033, P-0034, P-0035, Table 1 b. Representative compounds with activity toward kinase B-Raf V600E
with 1C;, < 10 h1 under the test conditions employed.
B-Raf P-0001, P-0002, P-0003, P-0005, P-0006, P-0007, P-0009, P-0013, P-0014, P-0015, V600E P-0016, P-0017, P-0019, P-0020, P-0021, P-0022, P-0023, P-0024, P-0025, P-002S, P-0029, P-0030, P-0031, P-0032, P-0033, P-0034, P-0035 DLMR 329323.5 49 Atty. Dkt. No.: 039363-3550 Table I c. Representative compounds with activity toward kinase B-Raf V600E/T5291 with IC5 1) < 10 M under the test conditions employed.
{ 33-Raf V600E I P-0003, P-0005, P-0006 Table 1 d. Representative compounds with activity toward kinase c-Raf-1 with ICso < 10 M under the test conditions employed.

c-Raf-1: P-0001, P-0002, P-0003, P-0005, P-0006, P-0007, P-0008, P-0009, P-0011, P-00131 P-0014, P-0015, P-0016, P-0017, P-0018, P-0019, P-0020, P-0021, P-0022, P-0023, P-0025, P-0030, P-0031 Example 10: Efficacy of Compounds in Combination with Standard-of-Care Chemotherapeutic agents in four human cancer cell lines.

[0121] Compounds of the invention, such as compounds of Formula 1, Formula II, or Formuta III, in combination with a standard chemotherapeutic agent, such as 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, or vinblastine, can be assessed for their effectiveness in killing human tumnr cells. Human tumor cell lines, such as A-375 (malignant melanoma), SK-MEL-2 (malignant melanoma, skin metastasis), COLO 205 (colorectal adenocarcinoma, ascites metastasis) or SW-620 (colorectal adenocarcinoma, lymph node metastasis) can be treated with a compound of Formula 1, Formula II, or Formula III alone, or in combulation with one of the above-mentioned chemotherapeutic agents.

101221 Tumor cells are grown as a monotayer at 37 C in a humidified atmosphere (5% COzi 95%
air). Cells are grown in a suitable culture medium, e.g. RPMI 1640 (Ref BE12-702F, Cambrex, Verviers, Belgium) containing 2 mM L-glutainine and supplemented with 10%
fetal bovine sei-um (Ref DE14-801E, Cambrex). For experimental use, the tumor cells are detachcd from the culture flask by a 5-minute treatment with trypsin-versene (Ref 02-007E, Cambrex), diluted in Hanks' medium without calcium or magnesium (Ref BE10-543F, Cambrex). Trypsin treatment is neutralized by culture mediuin addition. The cells are counted in a hemocytometer and their viability assessed by 0.25% trypan blue exclusion.

101231 The celt lines are checked for mycoplasma contamination with the Mycotect assay kit (Ref 15672-017, Invitrogen, Cergy-Pontoise, France) in accordance with the manufacturer's instructions. The mycoplasma test is assayed from the culture supernatants of the cell lines and compared to negative and positive controls.

DLMR 329323.5 Atty. Dkt. No.: 039363-3550 [01241 The tumor cells (10,000 per well) are plated in 96-well flat-bottom microtitration plates (Ref 055260, Nunc, Dutscher, Brumath, France) and incubated at 37 C for 24 hours before treatment in 100 l of drug-free culture medium supplemented with 10% FBS. In order to assess the IC5 of each compound to be used for each cell line, the tumor cells are incubated in a 200 l final volume of RPMI 1640 supplemented with 10% FBS and containing either a compound of Fonnula 1, Fonnula 11, or Formula III, or one of 5-tluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, or vinblastine. The compounds are tested in a suitable concentration range, such as 10"1 to 10-' M for a compound of Formula I, Formula II, or Fonnula III, 5-fluorouracil, dacarbazine or gefitinib, 10"9 to 10"4 M for carboplatin, oxatiplatin, or temozolomide, 10-1' to 10-6 M
for paclitaxel or SN-38, and 10"15 to 10-10 M for vinblastine. Compounds of Fonnula I, Formula II, or Fonnula III are dissolved in DMSO and diluted with culture medium to the desired concentrations. 5-fluorouracil (50 mg/ml, Dakota Pharm, LePlessis Robinson, France), carboplatin (10 mg/ml, Aeuettant, Lyon, France), and paclitaxel (6 mg/ml, Bristol-Myers Squibb SpA, Rueil Malmaison, France), are diluted with culture medium to the desired concentrations.
Dacarbazine (Sigma, Saint Quentin Fallavier, France) and vinblastine (Lilly France S.A., Saint Cloud, France) are dissolved in NaC1 0.9% and diluted with culture medium to the desired concentrations.
Gefitinib is dissolved in a mixed solution of RPMI 1640 and DMSO and diluted with culture medium to the desired concentrations (maximum final DMSO of 0.1 % v%v). SN-38 (LKT Laboratories, Inc., St. Paul, Minnesota) is dissolved in DMSO and diluted with culture medium to the desired concentrations (maximum final DMSO of 0.1% v/v). Temozolomide (LK.1' Laboratories, Inc., St.
Paul, Minnesota) is dissolved in water for injection and diluted with culture medium to the desired concentrations.
Cells are incubated for 96 hours in the presence of test substances at 37 C
under 5% COz. At the end of treatments, the cytotoxic activity is evaluated by an MTT assay.

[01251 For the MTT assay, at the end of the cells treatment, 20 l of a 5 mg/mi solution 0.22 m filtered tetrazolium reagent (MTT, Ref M2128, Sigma) in Phosphate Buffered Saline (PBS, Ref BE17-517Q, Cambrex), is added in each well. Cultiue plates are incubated for 2 h at 37 C. The resulting supernatant is removed and formazan crystals dissolved with 200 l of DMSO per well.
Absorbency (OD) is measured at 570 nm in each well using VICTOR"" 1420 multilabeled counter (Wallac, PerkinElmer, Courtaboeuf, France).

[01261 The IC50 for each compound on each cell line is determined from the OD
measurements of each sample. 'Itie dose response inhibition of cell proliferation is expressed as:

IC = (OD of drug exposed cells I OD of drug free wells) x 100.

The mean of multiple measurements for each concentration is plotted vs. the drug concentration. The dose-response cun=es are plotted using XLFit 3(IDBS, United Kingdom). The IC50 (drug concentration to obtain 50% inhibition of cell proliferation) determination values are calculated using DLMR_329323.5 Atty. Dkt. No.: 039363-3550 the XLFit 3 from semi-log curves. The ICso value determined for each compound in each cell line is used to determine the concentration of a compound of Formula I, Formula 11, or Formula III, and of the standard chemotherapeutic to be used in combination.

101271 The cells are treated with a combination of five concentrations of a compound of Formula 1, Formula II, or Forrnula III and five concentrations of one of 5-fluorouracil, carboplatin, dacarbazine, gefitinib, oxaliplatin, paclitaxel, SN-38, temozolomide, or vinblastine, based on the IC30 results. The compounds and cells are treated per the IC50 determination described above and assayed by the MTT
assay.

101281 The results are assessed to determine whether the combination is synergistic or antagonistic.
The compound interactions are calculated by multiple drug effect analysis and are performed by the median equation principle according to the methodology described by Chou and Talalay (Adv.
Enzyme Regul. 1984, 22: 27-55).

101291 The combination index (CI) will be calculated by the Chou et al.
equation (Adv. Enzyme Regul. 19S4, 22: 27-55 ; Encyclopaedia of human biology, Academic Press, 1991, 2: 371-9;
Synergism and Antagonism in Chemotherapy, Academic Press, 1991, 61-102) which takes into account both the potency (D,, or ICso) and the shape of the dose-effect curve (thc m value). The general equation for the CI of the two compounds is given by:

(D), (D)2 (D), (D)z CI = + --_._ _- +
(Djj (DC), (Dz)I (Ds) 2 where:
(Dx)j and (DJz in the denominators are the doses (or concentrations) for compound I and compound 2 alone which demonstrate x% of inhibition, whereas (D), and (D)2 in the numerators are doses of both compounds (1 and 2) in combination that also inhibit x% (iso-effective). CI<1, = 1, and >1 indicate synergism, additive effect and antagonism, respectively.

[0130] The (D,); and (D,), can be calculated from the median-effect equation of Chou et al. (J. Natl.
Cancer lnst. 1994, 86: 1517-24):

DLMR_329323.5 Atty. Dkt. No.: 039363-3550 ~ ~1?m i DK _ D
where:
D,n is the median-effect dose that is obtained from the anti-log of x-intercept of the median-effect plot, x = log(D) versiis y log{f~ (1 ~a)}, or D,, = 1Wy-`nCercepO/m; and m is the slope of the median-effect plot and fa is the fraction of cells affected by the treatment.
Each Cl will be calculated with CalcuSyn software (Biosoft, UK) from the mean affected fraction at each drue ratio concentration.

[0131] Additional examples of certain methods contemplated by the present invention may be found in the following applications: U.S. Patent Publ. No. 2006/058339, App. Ser.
No. 11/154,287; U.S.
Patent Publ. No. 2006/058340, App. Ser. No. 11/154,988; U.S. Prov. App. No.
60/682,076, filed May 17, 2005; U.S. Prov. App. No. 60/682,058, filed May 17, 2005; U.S. Prov. App.
No. 60/682,063, filed May 17, 2005; U.S. Prov. App. No. 60/682,051, filed May 17, 2005; U.S. Prov.
App. No. 60/682,042, filed May 17, 2005; U.S. Prov. App. No. 60/692,750, filed June 22, 2005; and U.S. Prov. App. No.
60/692,960, filed June 22, 2005; U.S. Prov. App. No. 60/731,528, filed October 28, 2005, U.S. Patent App. No. 11/435,381, filed May 16, 2006, and U.S. Patent App. No. 11/473,347, filed June 21, 2006, each of which are hereby incorporated by reference herein in their entireties including all specifications, figures, and tables, and for all purposes.

[0132] All patents and other references cited in the specification are indicative of the level of skill of those skilled in the art to which the invention pertains, and are incorporated by reference in their entireties, including any tables and figures, to the same extent as if each reference had been incorporated by reference in its entirety individually.

[01331 One skilled in the art would readily appreciate that the present invention is well adapted to obtain the ends and advantages mentioned, as well as those inherent therein.
The methods, variances, and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention.
Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.

101341 It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. For example, variations can be made to crystallization or co-crystallization conditions for Ret and Ret surrogate proteins andlor various kinase domain sequences can be used.
DLMR 329323.5 53 Atty. Dkt. No.: 039363-3550 Thus, such additional embodiments are within the scope of the present invention and the following claims, [01351 The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. Thus, for example, in each instance herein any of the terms "comprising", "consisting essentially of' and consisting of' may be replaced with either of the other two terms_ Thus, for an embodiment of the invention using one of the terms, the invention also includes another embodiment wherein one of these terms is replaced with another of these ternis. In each embodiment, the terms have their established meaning. Thus, for example, one embodiment may encompass a method "comprising" a series of steps, another embodiment would encompass a method "consisting essentially of' the same steps, and a third embodiment would encompass a method "consisting of' the samc steps. The tenns and expressions which have been employed arc used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

101361 In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of inembcrs of the Markush group or other group.

101371 Also, unless indicated to the contrary, where various numerical values are provided for embodiments, additional embodiments are described by taking any 2 different values as the endpoints of a range. Such ranges are also within the scope of the described invention, 107381 Thus, additional embodiments are within the scope of the invention and within the following claims.

DLMR 329323.5 54

Claims (21)

1. A compound having the chemical structure of Formula I, all salts, prodrugs, tautomers and isomers thereof, wherein:
R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH,, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, -OH, -NH2, C(O)OH, -C(O)NH2, -OR7, -NR8R7, -C(O)OR7, -C(O)NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R2 is selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R7, -NR8C(S)NH2, NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, -OR7, -NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R3 is selected from the group consisting of hydrogen, fluoro and chloro;
R7 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R7 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R8 at each occurrence is independently hydrogen or lower alkyl; and R9 at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy, provided, however, the compound is not

2. The compound of Claim 1, wherein:
R7 is selected from the group consisting of hydrogen, -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R7 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and R2 is selected from the group consisting of -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alk-yl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2 or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

3. The compound of Claim 2, wherein:
R1 is hydrogen, -CN, -NR8R7, -OR7, -S(O)2R7, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 and -S(O)2R7, and R2 is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 or -S(O)2R7.

4. The compound of Claim 3, wherein:
R1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2-6alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and R2 is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.

5. The compound of Claim 1, wherein the compound is selected from the group consisting of:
4-Butoxy-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-pyrazol-1-yl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-isopropoxy-benzenesulfonamide, 4-tert-Butyl-N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-benzenesulfonamide, N-[3-(S-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-propyl-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]phenyl}-4-isopropyl-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(4-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide, 4-Difluoromethoxy-N-{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-isopropyl-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(1-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-propyl-benzenesulfonamide, N-{3-[5-(1,5-Dimethyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-4-propyl-benzenesulfonamide, N-[2,4-Difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-trifluoromethyl-benzenesulfonamide, N-[3-(5-Cyano-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide, (E)-3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-acrylic acid methyl ester, 3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid methyl ester, 3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-propionic acid, 3-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-ethyl-propionamide; and all salts, prodrugs, tautomers, and isomers thereof.

6. A compound having the chemical structure of Formula II, all salts, prodrugs, tautomers and isomers thereof, wherein:
R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, -OH, -NH2, C(O)OH, -C(O)NH2, -OR7, -NR8R7, -C(O)OR7, -C(O)NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R2a, is selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C-(S)R7, -NR8S(O)2R7, -NR8C(O)NH2, -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl is optionally substituted with one or more substituents selected from fluoro, -OR7, NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R21 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R3 is selected from the group consisting of hydrogen, fluoro and chloro;

R7 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R7 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R8 at each occurrence is independently hydrogen or lower alkyl; and R9 at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and wherein heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy, provided, however, the compound is

7. The compound of Claim 6, wherein:
R1 is selected from the group consisting of hydrogen, -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7 , halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and R2a, is selected from the group consisting of -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R2a or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino,

8. The compound of Claim 7, wherein:
R1 is hydrogen, -CN, -NR8R7, -OR7, -S(O)2R7, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 and -S(O)2R7, and R2a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 or -S(O)2R7,

9. The compound of Claim 8, wherein:
R1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2-6alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and R2a is -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino,

10. The compound of Claim 6, wherein the compound is selected from the group consisting of:
3-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenylsulfamoyl]-benzoic acid, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-3-difluoromethoxy-benzenesulfonamide.
3-Difluoromethoxy-N-{2,4-difluoro-3-[5-(5-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-benzenesulfonamide; and all salts, prodrugs, tautomers, and isomers thereof.

11. A compound having the chemical structure of Formula III, all salts, prodrugs. tautomers and isomers thereof, R1 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO3, -C(O)OH.

-S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7 -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NH2, NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from fluoro, -OH, -NH2, C(O)OH, -C(O)NH2, -OR7, -NR8R7, -C(O)OR7, -C(O)NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl, lower alkenyl or lower alkynyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R3 is selected from the group consisting of hydrogen, fluoro and chloro;
R6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -OH, -NH2, -CN, -NO2, -C(O)OH, -S(O)2NH2, -C(O)NH2, -C(S)NH2, -NHC(O)NH2, -NHC(S)NH2, -NHS(O)2NH2, -OR7, -SR7, -NR8R7, -C(O)R7, -C(S)R7, -C(O)OR7, -C(O)NR8R7, -C(S)NR8R7, -S(O)2NR8R7, -NR8C(O)R7, -NR8C(S)R7, -NR8S(O)2R7, -NR8C(O)NH, -NR8C(O)NR8R7, -NR8C(S)NH2, -NR8C(S)NR8R7, -NR8S(O)2NH2, -NR8S(O)2NR8R7, -S(O)R7, and -S(O)2R7, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, -OR7, -NR8R7, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of R6 or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R7 is selected from the group consisting of lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R7 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R7, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino;
R8 at each occurrence is independently hydrogen or lower alkyl; and R9 at each occurrence is independently selected from the group consisting of lower alkyl, heterocycloalkyl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, and cycloalkylamino, and heterocycloalkyl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, -CN, lower alkyl, fluoro substituted lower alkyl, lower alkoxy and fluoro substituted lower alkoxy, provided, however, the compound is not

12. The compound of Claim 11, wherein:
R1 is selected from the group consisting of hydrogen, -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as R1 or as substituents of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and R6 is heteroaryl optionally substituted with one or more substituents selected from the group consisting of -CN, -OR7, -SR7, -NR8R7, -NR8C(O)R7, -NR8S(O)2R7, -C(O)NR8R7, -C(O)R7, -S(O)2NR8R7, -S(O)R7, -S(O)2R7, halogen, lower alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein lower alkyl is optionally substituted with one or more substituents selected from the group consisting of fluoro, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, and wherein cycloalkyl, heterocycloalkyl, aryl, and heteroaryl as a substituent of R6 or as a substituent of lower alkyl are optionally substituted with one or more substituents selected from the group consisting of -OH, -NH2, -CN, -NO2, -S(O)2NH2, -C(O)NH2, -OR9, -SR9, -NR8R9, -NR8C(O)R9, -NR8S(O)2R9, -S(O)2R9, -S(O)2NR8R9, -C(O)R9, -C(O)NR8R9, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

13. The compound of Claim 12, wherein:
R1 is hydrogen, -CN, -NR8R7, -OR7, -S(O)2R7, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of halogen, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 and -S(O)2R7, and R6 is heteroaryl optionally substituted with one or more of -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, -NR8R7, -OR7 or -S(O)2R7.

14. The compound of Claim 13, wherein:
R1 is hydrogen, -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkoxy substituted C2-6alkoxy, aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, and cycloalkylamino, and R6 is heteroaryl optionally substituted with one or more of -CN, fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino.

15. The compound of Claim 11, wherein the compound is selected from the group consisting of:
Benzo[b]thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 5-Methyl-2-trifluoromethyl-furan-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 5-Oxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 2-Oxo-2H-chromene-6-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 5-Isoxazol-5-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl]-amide, Benzothiazole-6-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 1-Methyl-3-trifluoromethyl-1H-pyrazole-4-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Benzo[1,2,5]thiadiazoe-5-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 5-Methyl-benzo[b]thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, 5-Methyl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-aimide, 1-Methyl-1H-pyrazole-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyrridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Pyridine-2-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide; and all salts, prodrugs, tautomers, and isomers thereof.

16. A composition comprising: a pharmaceutically acceptable carrier; and a compound according to any of Claims 1-15.

17. A method for treating a subject suffering from or at risk of an A-Raf-mediated, B-Raf-mediated and/or c-Raf-1-mediated disease or condition, comprising administering to the subject an effective amount of a compound of any of Claims 1-15 or a composition of Claim 16.

18. The method of Claim 17, wherein the compound or composition is approved for administration to a human.

19. The method of Claim 18, wherein the disease or condition is selected from the group consisting of multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, melanoma, glioma, sarcoma, cancer of the colon, lung, breast, pancreas, thyroid, ovary, liver, or kidney, medullary thyroid cancer, carcinoid, small cell lung cancer, pheochromocytoma, lymphoma, neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuropathic pain, inflammatory pain, acute pain, chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, psoriasis, arthritis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease, immunodeficiency diseases, organ transplant rejection, graft versus host disease, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, prostate hyperplasia, obesity, Helicobacter-pylori infection, Hepatitis infection, Influenza virus infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, Noonan's syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, sarcopenia, muscular dystrophy, motor neuron diseases, inflammatory myopathies, diseases of the neuromuscular junction, myopathies due to endocrine abnormalities, diseases of peripheral nerve, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis and metabolic diseases of muscle.

20. A kit comprising a compound according to any of Claims 1-15 or a composition according to Claim 16.

21. The kit of Claim 20, wherein the compound or composition is approved for a medical indication selected from the group consisting of multi-infarct dementia, head injury, spinal cord injury, Alzheimer's disease, Parkinson's disease, melanoma, glioma, sarcoma, cancer of the colon, lung, breast, pancreas, thyroid, ovary, liver, or kidney, medullary thyroid cancer, carcinoid, small cell lung cancer, pheochromocytoma, lymphoma, neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis, neuropathic pain, inflammatory pain, acute pain, chronic pain, cancer-related pain, migraine, heart failure, ischemic stroke, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, psoriasis, arthritis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, rheumatoid arthritis, inflammatory bowel disease, immunodeficiency diseases, organ transplant rejection, graft versus host disease, diabetic nephropathy, polycystic kidney disease nephrosclerosis, glomerulonephritis, prostate hyperplasia, obesity, Helicobacter pylori infection, Hepatitis infection, Influenza virus infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, Noonan's syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair and endocrine diseases, sarcopenia, muscular dystrophy, motor neuron diseases, inflammatory myopathies, diseases of the neuromuscular junction, myopathies due to endocrine abnormalities, diseases of peripheral nerve, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis and metabolic diseases of muscle.