Compounds and methods for kinase modulation, and indications therefor

Abstract

Compounds and salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof and uses thereof are described. In certain aspects and embodiments, the described compounds or salts thereof, formulations thereof, conjugates thereof, derivatives thereof, forms thereof are active on each of B-Raf, B-Raf V600E and c-Raf-1 protein kinase. In certain aspects and embodiments, the described compounds are active in inhibiting proliferation of a Ras mutant cell line. Also described are methods of use thereof to treat diseases and conditions, including melanoma, glioma, glioblastoma, pilocytic astrocytoma, liver cancer, biliary tract cancer, cholangiocarcinoma, colorectal cancer, lung cancer, bladder cancer, gallbladder cancer, breast cancer, pancreatic cancer, thyroid cancer, kidney cancer, ovarian cancer, adrenocortical cancer, prostate cancer, gastrointestinal stromal tumors, medullary thyroid cancer, tumor angiogenesis, acute myeloid leukemia, chronic myelomonocytic leukemia, childhood acute lymphoblastic leukemia, plasma cell leukemia, and multiple myeloma.

1 . A compound having the chemical structure of Formula I, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or a tautomer or a stereoisomer thereof,
 wherein:
 R 1  is lower alkyl or aryl substituted with one or two members selected from trifluoromethyl, trifluormethoxy, lower alkyl or halogen; 
 Ar is selected from the group consisting of bicyclic heteroaryl optionally independently substituted with one or more R 2 , thiophenyl optionally independently substituted with one or more R 3 , thiazolyl optionally independently substituted with one or more R 4 , oxazolyl optionally independently substituted with one or more R 5 , pyrazolyl optionally independently substituted with one or more R 6 , pyridyl optionally independently substituted with one or more R 7 , pyrimidinyl optionally independently substituted with one or more R 8 , phenyl substituted with one or more R 9 , and pyrazinyl optionally independently substituted with one or more R 10 ; 
 each R 2  is independently selected from the group consisting of —CN, —NO 2 , —C(O)—R 11 , —S(O) 2 —R 12 , —O—R 13 , —N(R 14 )—R 5 , fluoro, chloro, lower alkyl, lower alkylthio, fluoro substituted lower alkylthio, cycloalkylamino, and heterocycloalkylamino, wherein lower alkyl is optionally independently substituted with one or more fluoro, lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or heterocycloalkylamino; 
 
 each R 3  is independently selected from the group consisting of —CN, —OH, —NH 2 , —NO 2 , —C(O)—R 11 , —S(O) 2 —R 12 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally independently substituted with one or more lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, or fluoro substituted lower alkylthio;
 each R 4  is independently selected from the group consisting of —CN, —OH, —NH 2 , —NO 2 , —C(O)—R 11 , —S(O) 2 —R 12 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkylamino, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally independently substituted with one or more lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, or fluoro substituted lower alkylthio; 
 each R 5  is independently selected from the group consisting of —CN, —OH, —NH 2 , —NO 2 , —C(O)—R 11 , —S(O) 2 —R 12 , fluoro, chloro, lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, fluoro substituted lower alkylthio, mono-alkylamino, di-alkylamino, cycloalkyl, cycloalkylamino, heterocycloalkyl, phenyl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally independently substituted with one or more lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, or fluoro substituted lower alkylthio; 
 each R 6  is independently selected from the group consisting of —CN, —OH, —NH 2 , —NO 2 , —C(O)—R 11 , —S(O) 2 —R 12 , fluoro, chloro, and lower alkyl, wherein lower alkyl is optionally independently substituted with one or more fluoro, lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, heterocycloalkylamino, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl, wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally independently substituted with one or more lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, or fluoro substituted lower alkylthio; 
 each R 7  is independently selected from the group consisting of —C(O)—R 11 , —S(O) 2 —R 12 , —C(O)—N(H)—O—R 16 , —O—R 13 , —N(R 14 )—R 15 , fluoro, chloro, lower alkyl, lower alkylthio, fluoro substituted lower alkylthio, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl, wherein lower alkyl is optionally independently substituted with one or more fluoro, lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, and heterocycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally independently substituted with one or more lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, or fluoro substituted lower alkylthio; 
 each R 8  is independently selected from the group consisting of —C(O)—R 11 , —S(O) 2 —R 12 , —C(O)—N(H)—O—R 16 , —O—R 13 , —N(R 14 )—R 15 , fluoro, chloro, lower alkyl, lower alkylthio, fluoro substituted lower alkylthio, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl, wherein lower alkyl is optionally independently substituted with one or more fluoro, lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or heterocycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally independently substituted with one or more lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, or fluoro substituted lower alkylthio; 
 each R 9  is independently selected from the group consisting of —CN, —NO 2 , —C(O)—R 11 , —S(O) 2 —R 12 , —C(O)—N(H)—O—R 16 , —O—R 13 , —N(R 14 )—R 15 , fluoro, chloro, lower alkyl, lower alkylthio, fluoro substituted lower alkylthio, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl, wherein lower alkyl is optionally independently substituted with one or more fluoro, lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or heterocycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally independently substituted with one or more lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, or fluoro substituted lower alkylthio; 
 each R 10  is independently selected from the group consisting of —CN, —NO 2 , —C(O)—R 11 , —S(O) 2 —R 12 , —C(O)—N(H)—O—R 16 , —O—R 13 , —N(R 14 )—R 15 , fluoro, chloro, lower alkyl, lower alkylthio, fluoro substituted lower alkylthio, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl, wherein lower alkyl is optionally independently substituted with one or more fluoro, lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or heterocycloalkylamino, and wherein cycloalkyl, heterocycloalkyl, phenyl and heteroaryl are optionally independently substituted with one or more lower alkyl, fluoro substituted lower alkyl, lower alkoxy, fluoro substituted lower alkoxy, lower alkylthio, or fluoro substituted lower alkylthio; 
 each R 11  is independently selected from the group consisting of lower alkyl, —OR 13 , —NH 2 , mono-alkylamino, di-alkylamino, cycloalkylamino, and heterocycloalkylamino; 
 each R 12  is independently selected from the group consisting of —NH 2 , lower alkyl, mono-alkylamino, di-alkylamino, cycloalkylamino, heteroaryl, and heterocycloalkylamino; 
 each R 13  is independently hydrogen or lower alkyl, wherein lower alkyl is optionally substituted with one or more fluoro, or, when R 13  is C 2-6 , alkyl, R 13  is optionally independently substituted with lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or heterocycloalkylamino; and 
 each R 14 , R 15  and R 16  is independently hydrogen, lower alkyl, or cycloalkyl, wherein lower alkyl is optionally substituted with one or more fluoro, or, when R 14 , R 15  or R 16  is C 2-6 , R 14 , R 15  and R 16  are independently substituted with lower alkoxy, mono-alkylamino, di-alkylamino, cycloalkylamino, or heterocycloalkylamino. 
 
 
     
     
         2 . The compound of  claim 1 , wherein Ar is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein: 
         W represents the point of attachment to the 5-position of the pyrrolo[2,3-b]pyridine ring of Formula I, wherein W is attached at any available position of the 6-membered phenyl ring portion of Ar; 
         X represents the point of attachment to the 5-position of the pyrrolo[2,3-b]pyridine ring of Formula I, wherein X is attached at any available position of the 6-membered ring portion of Ar; 
         Y represents the point of attachment to the 5-position of the pyrrolo[2,3-b]pyridine ring of Formula I, wherein Y is attached at any available position of the bicyclic ring of Ar; 
         R 24 , R 26 , R 28 , R 30 , R 32 , R 34 , R 36 , R 70  and R 72  are selected from the group consisting of hydrogen, —C(O)—R 45 , —S(O) 2 —R 46 , and lower alkyl, wherein lower alkyl is optionally independently substituted with one or more fluoro, or, when R 24 , R 26 , R 28 , R 30 , R 32 , R 34 , and/or R 36  is C 7-6 , alkyl, R 24 , R 26 , R 28 , R 30 , R 32 , R 34 , and R 36  are each optionally independently substituted with one or more lower alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino; 
         each R 25 , R 27 , R 29 , R 31 , R 33 , R 35 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 , R 44 , R 71  and R 73  are independently selected from the group consisting of —CN, —C(O)—R 45 , —S(O) 2 —R 46 , —O—R 47 , —N(R 48 )—R 49 , fluoro, chloro, lower alkyl, and cycloalkylamino, and are attached at any available position of the bicyclic ring of Ar, wherein lower alkyl is optionally independently substituted with one or more fluoro, lower alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino;each R 45  and R 46  are independently selected from the group consisting of —O—R 47 , —N(R 48 )—R 49 , lower alkyl, mono-alkylamino, di-alkylamino, and cycloalkylamino; 
         each R 47  is independently hydrogen or lower alkyl, wherein lower alkyl is optionally independently substituted with one or more fluoro, or, when R 47  is C 2-6 , alkyl, R 47  is optionally substituted with one or more lower alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino; 
         each R 48  and R 49  are independently selected from the group consisting of hydrogen, lower alkyl, or cycloalkyl, wherein lower alkyl is optionally independently substituted with lower alkoxy, mono-alkylamino, di-alkylamino, or cycloalkylamino; and 
         each p is independently 0, 1, 2 or 3. 
       
     
     
         3 . The compound of  claim 1 , wherein Ar is selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein: 
         Z represents the point of attachment to the 5-position of the pyrrolo[2,3-b]pyridine ring of Formula I; 
         R 50 , R 51  and R 52  are independently selected from hydrogen or the R 3  substituents; 
         R 53  and R 54  are independently selected from hydrogen or the R 4  substituents; 
         R 57  and R 58  are independently selected from hydrogen or the R 5  substituents; 
         R 59 , R 60  and R 62  are independently selected from hydrogen or the R 6  substituents; R 61  is selected from the group consisting of hydrogen, —C(O)—R 45 , —S(O) 2 —R 46 , and lower alkyl optionally substituted with one or more fluoro, or, when one or more of R 59 , R 60  and R 62  is C 2-6 , alkyl, R 59 , R 60  and/or R 62  are optionally independently substituted with one or more lower alkoxy, mono-alkylamino, di-alkylamino or cycloalkylamino; 
         R 65 , R 66 , R 67  and R 68  are independently selected from hydrogen or the R 7  substituents; 
         R 77 , R 78  and R 79  are independently selected from hydrogen or the R 8  substituents; 
         R 80 , R 81  and R 82  are independently selected from hydrogen or the R 9  substituents, and R 83 , R 84  and R 85  are independently selected from hydrogen or the R 10  substituents. 
       
     
     
         4 . The compound of  claim 1 , wherein Ar is: 
       
         
           
           
               
               
           
         
       
     
     
         5 . The compound of  claim 4 , wherein p is 0. 
     
     
         6 . The compound of  claim 4 , wherein R 24  and R 26  are each independently selected from H, lower alkyl, lower alkyl carbamoyl, lower alkyl-C(═O)— or lower alkyl sulfonyl. 
     
     
         7 . The compound of  claim 5 , wherein R 24  and R 26  are each independently selected from H, methyl, ethyl, propyl, acetyl, CH 3 NC(═O)—, methylsulfonyl or ethylsulfonyl. 
     
     
         8 . The compound of  claim 1 , wherein Ar is: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein Ar is: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 1 , wherein Ar is: 
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound of  claim 1 , wherein Ar is: 
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound of  claim 1 , wherein Ar is 
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound of  claim 1 , wherein Ar is 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 1 , wherein Ar is 2-thiazolyl, 4-thiazolyl or 5-thiazolyl, each of which is optionally substituted with from 1 to 2 R 4 . 
     
     
         15 . The compound of  claim 1 , wherein Ar is 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl or 5-pyrazolyl, each of which is optionally substituted with from 1 to 3 R 6 . 
     
     
         16 . The compound of  claim 1 , wherein Ar is 2-thiophenyl or 3-thiophenyl, each of which is optionally substituted with from 1 to 3 R 3 . 
     
     
         17 . The compound of  claim 1 , wherein Ar is 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted with from 1 to 3 R 7 . 
     
     
         18 . The compound of  claim 1 , wherein Ar is 2-pyrimidinyl, 3-pyrimidinyl or 4-pyrimidinyl, each of which is optionally substituted with from 1 to 3 R 8 . 
     
     
         19 . The compound of  claim 1 , wherein Ar is 2-pyrazinyl, optionally substituted with from 1 to 2 R 10 . 
     
     
         20 . The compound of  claim 1 , wherein Ar is 2-oxazolyl, 4-oxazolyl or 5-oxazolyl, each of which is optionally substituted with from 1 to 2 R 5 . 
     
     
         21 . The compound of  claim 1 , wherein Ar is phenyl, optionally substituted with from 1 to 3 R 9 . 
     
     
         22 . The compound of  claim 1 , wherein the substituent R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 10  is selected from —CN, —OH, —NH 2 , —C(O)—R 11 , —S(O) 2 —R 12 , optionally substituted lower alkyl, optionally substituted lower alkoxy, optionally substituted alkylamino, optionally substituted phenyl or optionally substituted heteroaryl. 
     
     
         23 . The compound of  claim 22 , wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9  or R 10  is selected from 4-piperidinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, methyl, ethyl, propyl, isopropyl, 1,2,3,4-tetrazol-1-yl, 1,2,3,4-tetrazol-3-yl, 4-pyrazolylsulfonyl, 3-pyrazolylsulfonyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrazinyl, carbamoyl, alkylcarbamoyl, alkoxycarbonyl, phenoxycarbonyl, 1-imidazolyl, 2-imidazolyl, 4-imidazolyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, dialkylamino, alkylamino, alkoxy, methoxy, 2-oxo-1-pyrrolidinyl, 2-oxo-3-pyrrolidinyl, 2-oxo-4-pyrrolidinyl, 2-oxo-5-pyrrolidinyl, sulfamoyl, alkylsulfamoyl, phenylsulfamoyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, fluoro, chloro, methylsulfonyl, 3-dimethylaminopropoxy, dimethylamino, cyclopropylamino, 2-methoxyethylamino, 2-pyridinyloxy, 3-pyridinyloxy, 4-pyridinyloxy, CF 3 O—, CN, methylamino, 2-dimethylaminoethylamino, 3-methoxypropylamino, isopropylamino, methoxy, amino, alkoxycarbamoyl, methoxycarbamoyl, formyl, 2-methylaminoethyl, 1,2,4,-oxadiazol-3-yl, 1,2,4,-oxadiazol-5-yl, 1-azetidinyl, 2-azetidinyl or 3-azetidinyl, each of which is optionally substituted with a member selected from a lower alkyl, lower alkoxy, dimethylamino, methylamino, CN, CF 3 , F, Cl or CF 3 O. 
     
     
         24 . The compound of  claim 1 , wherein Ar is 1H-4-indazolyl, 1H-5-indazolyl, 1H-6-indazolyl, 1H-7-indazolyl, 1,3-benzothiazol-4yl, 1,3-benzothiazol-5yl, 1,3-benzothiazol-6yl, 1,3-benzothiazol-7yl, imidazo[1,2-a]pyridine-2-yl, imidazo[1,2-a]pyridine-3-yl, imidazo[1,2-a]pyridine-5-yl, imidazo[1,2-a]pyridine-6-yl, imidazo[1,2-a]pyridine-7-yl, imidazo[1,2-a]pyridine-8-yl, imidazo[1,2-a]pyrimidin-5-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-7-yl, imidazo[1,2-a]pyrimidin-8-yl, 1H-indol-5yl, 1H-indol-2yl, 1H-indol-3yl, 1H-indol-4yl, 1H-indol-6yl, 1H-indol-7yl, 3-methyl-1-H-indol-5-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 1-oxo-isoindolin-4-yl, 1-oxo-isoindolin-5-yl, 1-oxo-isoindolin-6-yl, 1-oxo-isoindolin-7-yl, 2-oxo-indolin-4-yl, 2-oxo-indolin-5-yl, 2-oxo-indolin-6-yl or 2-oxo-indolin-7-yl, each of which is optionally substituted with one to two members selected from methyl, amino, CF 3 , CF 3 O, CH 3 O, acetyl, alkoxycarbonyl, t-butoxycarbonyl, dimethylamino, fluoro, chloro or methylaminoethyl. 
     
     
         25 . The compound of  claim 1 , wherein Ar is 1H-4-indazolyl, 1H-5-indazolyl, 1H-6-indazolyl, 1H-7-indazolyl, 1-methyl-4-indazolyl, 1-methyl-5-indazolyl, 1-methyl-6-indazolyl, 1-methyl-7-indazolyl, 1-acetyl-4-indazolyl, 1-acetyl-5-indazolyl, 1-acetyl-6-indazolyl, 1-acetyl-7-indazolyl, 1-methylsulfonyl-4-indazolyl, 1-methylsulfonyl-5-indazolyl, 1-methylsulfonyl-6-indazolyl, 1-methylsulfonyl-7-indazolyl, 1-methyl-3-amino-6-indazolyl, 1,3-benzothiazol-4yl, 1,3-benzothiazol-5yl, 1,3-benzothiazol-6yl, 1,3-benzothiazol-7yl, imidazo[1,2-a]pyridine-2-yl, imidazo[1,2-a]pyridine-3-yl, imidazo[1,2-a]pyridine-5-yl, imidazo[1,2-a]pyridine-6-yl, imidazo[1,2-a]pyridine-7-yl, imidazo[1,2-a]pyridine-8-yl, 7-trifluoromethylimidazo[1,2-a]pyrimidin-2-yl, 7-trifluoromethylimidazo[1,2-a]pyrimidin-3-yl, imidazo[1,2-a]pyrimidin-5-yl, imidazo[1,2-a]pyrimidin-6-yl, imidazo[1,2-a]pyrimidin-7-yl, imidazo[1,2-a]pyrimidin-8-yl, 1H-indol-5yl, 1H-indol-2yl, 1H-indol-3yl, 1H-indol-4yl, 1H-indol-6yl, 1H-indol-7yl, 3-methyl-1-H-indol-5-yl, quinazolin-2-yl, quinazolin-4-yl, quinazolin-5-yl, quinazolin-6-yl, quinazolin-7-yl, quinazolin-8-yl, benzimidazol-2-yl, benzimidazol-4-yl, benzimidazol-5-yl, 1-methyl-2-aminobenzimidazol-5-yl, 1-methyl-2-aminobenzimidazol-4-yl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl, 1-oxo-isoindolin-4-yl, 1-oxo-isoindolin-5-yl, 1-oxo-isoindolin-6-yl, 1-oxo-isoindolin-7-yl, 2-oxo-indolin-4-yl, 2-oxo-indolin-5-yl, 2-oxo-indolin-6-yl or 2-oxo-indolin-7-yl. 
     
     
         26 . The compound of  claim 1 , wherein R 1  is methyl, ethyl, n-propyl, 2-trifluoromethyl-phenyl, 3-trifluoromethyl-phenyl, 4-trifluoromethyl-phenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2,3-difluoro-phenyl, 2,4-difluoro-phenyl, 2,6-difluoro-phenyl, 2,5-difluoro-phenyl, 3,4-difluoro-phenyl, 3,5-difluoro-phenyl or 3,6-difluoro-phenyl. 
     
     
         27 . The compound of  claim 1 , wherein the compound is selected from the group consisting of:
 4-(4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (P-1001),   Propane-1-sulfonic acid{2,4-difluoro-3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1002),   4-(4-{3-[2,6-Difluoro-3-(4-trifluoromethyl-benzenesulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (P-1003),   N-{2,4-Difluoro-3-[5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide (P-1004),   Propane-1-sulfonic acid{2,4-difluoro-3-[5-(1-pyrimidin-2-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1005),   Propane-1-sulfonic acid(3-{5-[3,5-dimethyl-1-(1H-tetrazol-5-yl)-1H-pyrazol-4-yl]-1H-pyrrolo [2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-1006),   Propane-1-sulfonic acid(3-{5-[1-(1,3-dimethyl-1H-pyrazole-4-sulfonyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-1007),   Propane-1-sulfonic acid(2,4-difluoro-3-{5-[1-(1H-tetrazol-5-yl)-1H-pyrazol-4-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-1008),   N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-1009),   N-{3-[5-(2,5-Dimethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide (P-1010),   N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-1011),   Propane-1-sulfonic acid{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1012),   Propane-1-sulfonic acid{2,4-difluoro-3-[5-(1-pyridin-2-yl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1013),   4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-pyrazole-1-carboxylic acid amide (P-1014),   Propane-1-sulfonic acid[2,4-difluoro-3-(5-pyridin-2-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide (P-1401),   N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-1402),   N-[2,4-Difluoro-3-(5-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-1403),   N-{2,4-Difluoro-3-[5-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-1404),   N-{2,4-Difluoro-3-[5-(3-fluoro-pyridin-4-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-1405),   N-{3-[5-(2,6-Dimethoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide (P-1406),   N-{2,4-Difluoro-3-[5-(5-methanesulfonyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-1407),   N-{2,4-Difluoro-3-[5-(6-methyl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-1408),   N-{3-[5-(6-Dimethylamino-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide (P-1409),   N-[2,4-Difluoro-3-(5-pyrimidin-5-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-difluoro-benzenesulfonamide (P-1500),   N-{3-[5-(2,4-Dimethoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide (P-1501),   N-{3-[5-(2-Dimethylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide (P-1502),   N-{2,4-Difluoro-3-[5-(2-methyl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-1503),   Propane-1-sulfonic acid{3-[5-(2-cyclopropylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-1504),   Propane-1-sulfonic acid(2,4-difluoro-3-{5-[2-(2-methoxy-ethylamino)-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-1505),   N-{3-[5-(2-Cyclopropylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-earbonyl]-2,4-difluoro-phenyl}-2,5-difluoro-benzenesulfonamide (P-1506),   N-(2,4-Difluoro-3-{5-[2-(2-methoxy-ethylamino)-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-2,5-difluoro-benzenesulfonamide (P-1507),   Propane-1-sulfonic acid(2,4-difluoro-3-{5-[2-(pyridin-3-yloxy)-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-1508),   Propane-1-sulfonic acid{2,4-difluoro-3-[5-(2-trifluoromethoxy-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1509),   Propane-1-sulfonic acid{3-[5-(2-cyano-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P-1510),   Propane-1-sulfonic acid{2,4-difluoro-3-[5-(2-imidazol-1-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1511),   Propane-1-sulfonic acid{3-[5-(2-azetidin-1-yl-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (P4512),   Propane-1-sulfonic acid{2,4-difluoro-3-[5-(2-isopropylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1513),   Propane-1-sulfonic acid{2,4-difluoro-3-[5-(2-methylamino-pyrimidin-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1514),   Propane-1-sulfonic acid(3-{5-[2-(2-dimethylamino-ethylamino)-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-2,4-difluoro-phenyl)-amide (P-1515),   Propane-1-sulfonic acid(2,4-difluoro-3-{5-[2-(3-methoxy-propylamino)-pyrimidin-5-yl]-1H-pyrrolo[2,3-b]pyridine-3-carbonyl}-phenyl)-amide (P-1516),   2-Chloro-5-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-benzamide (P-1700),   Propane-1-sulfonic acid{2,4-difluoro-3-[5-(1-oxo-2,3-dihydro-1H-isoindol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1701),   Propane-1-sulfonic acid{2,4-difluoro-3-[5-(3-oxo-2,3-dihydro-1H-isoindol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1702),   Propane-1-sulfonic acid{2,4-difluoro-3-[5-(2-oxo-2,3-dihydro-1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-amide (P-1703),   3-{3-[3-(2,5-Difluoro-benzenesulfonylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-methoxy-benzamide (P-1704),   4-{3-[3-(2,5-Difluoro-benzenesulfonylamino)-2,6-difluoro-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-N-methoxy-benzamide (P-1705),   N-{2,4-Difluoro-3-[5-(4-methylsulfamoyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-1706),   N-{2,4-Difluoro-3-[5-(4-sulfamoyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-phenyl}-2,5-difluoro-benzenesulfonamide (P-1707),   N-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-nicotinamide (P-1800),   3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid pyridin-3-ylamide (P-1801) and   5-Methyl-2,3-dihydro-isoxazole-3-carboxylic acid{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyridin-5-yl}-amide (P-1802).   
     
     
         28 . A composition comprising a compound of  claim 1 , and a pharmaceutically acceptable carrier, dilutent or excipient. 
     
     
         29 . A pharmaceutical composition comprising a compound of  claim 1  and another drug. 
     
     
         30 . A kit comprising a compound according to  claim 1 . 
     
     
         31 . A method for treating one or more disease indications selected from the group consisting of melanoma, glioma, glioblastoma multiforme, pilocytic astrocytoma, colorectal cancer, thyroid cancer, lung cancer, ovarian cancer, prostate cancer, liver cancer, gallbladder cancer, gastrointestinal stromal tumors, biliary tract cancer, testicular cancer, and cholangiocarcinoma in a subject in need thereof, said method comprising administering to said subject an effective amount of a compound according to  claim 1 , or a compound listed on Table I. 
     
     
         32 . The method of  claim 31 , wherein the indication is melanoma, glioma, glioblastoma multiforme, colorectal cancer or thyroid cancer. 
     
     
         33 . A method for preparing a compound of Formula I according to  claim 1 , 
       
         
           
           
               
               
           
         
       
       said method comprising:
 contacting a compound of Formula Ia: 
 
       
         
           
           
               
               
           
         
         with a compound of Formula Ib: 
       
       
         
           
           
               
               
           
         
         under conditions sufficient to form the compound of Formula I, wherein 
         X 1  is halogen; 
         P 1  is an amino protecting group; and 
         Q is a boronic acid or ester residue. 
       
     
     
         34 . The method  claim 33 , wherein X 1  is Br and Q is 
       
         
           
           
               
               
           
         
       
     
     
         35 . The method of  claim 33 , wherein the contacting comprises reacting a compound of formula Ia and a compound of formula Ib in the presence of a palladium complex.