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Claims for Patent: 8,470,818

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Claims for Patent: 8,470,818

Title:Compounds and methods for kinase modulation, and indications therefor
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.
Inventor(s): Ibrahim; Prabha N. (Mountain View, CA), Artis; Dean R. (Kensington, CA), Bremer; Ryan (Oakland, CA), Mamo; Shumeye (Oakland, CA), Zhang; Chao (Moraga, CA), Zhang; Jiazhong (Forster City, CA), Tsai; Jianming (Vallejo, CA), Hirth; Klaus-Peter (San Francisco, CA), Bollag; Gideon (Orinda, CA), Spevak; Wayne (Berkeley, CA), Cho; Hanna (Oakland, CA), Gillette; Samuel J. (Oakland, CA), Shi; Shenghua (San Diego, CA)
Assignee: Plexxikon Inc. (Berkeley, CA)
Application Number:12/906,980
Patent Claims: 1. A method for treating a subject suffering from a B-Raf or c-Raf-1 protein kinase mediated disease or condition, said method comprising administering to the subject a compound effective for the treatment of the B-Raf or c-Raf-1 protein kinase mediated disease or condition, said compound having the structure of Formula IIIm: ##STR03474## or a pharmaceutically acceptable salt thereof, R.sup.81 is selected from the group consisting of hydrogen; halogen; C.sub.1-6 alkyl optionally substituted with carboxylic acid; C.sub.2-6 alkenyl optionally substituted with carboxylic acid; C.sub.1-6 alkoxy optionally substituted with methoxy or diethylamine; carboxylic acid; carboxylic acid methyl ester; carboxylic acid ethylamide; 4-methyl-piperidin-1-yl; 4-methyl-piperazin-1-yl; morpholin-4-yl; phenyl-amino; phenyl optionally substituted with halogen, --CN, optionally fluoro substituted C.sub.1-6 alkyl, dimethylamine, methoxy, carboxylic acid, carboxylic acid amide, carboxylic acid-dimethyl amide, morpholine-4-carbonyl, morpholine, morpholine-4-methyl, or 2-methoxy-ethoxy; pyridinyl optionally substituted with methoxy, morpholine, or 4-methyl-piperazin-1-yl; 4-methyl-1H-imidazol-2-yl; and N-methyl-pyrazolyl; R.sup.83 is selected from the group consisting of hydrogen, fluoro and chloro; R.sup.112 is selected from the group consisting of C.sub.2-6 alkyl; phenyl optionally substituted with --CN, --NO.sub.2, acetamide, halogen, optionally fluoro substituted C.sub.1-6 alkyl, optionally fluoro substituted C.sub.1-6 alkoxy, or oxazolyl; 2,3-dihydro-benzo[1,4]dioxin-6-yl; methyl substituted thiazole, methyl substituted imidazole, thiophene optionally substituted with methyl, oxazole, isoxazole, or pyridine; furan substituted with methyl or carboxylic acid methyl ester; benzothiazol-6-yl; benzo[b]thiophen-2-yl; piperidin-1-yl; and dimethylamine wherein said disease or condition is selected from the group consisting of acute myeloid leukemia, melanoma, gliomas, sarcomas, histiocytic lymphoma, neurofibromatosis, myelodysplastic syndrome, tumor angiogenesis, thyroid cancer, liver cancer, colorectal cancer, pancreatic cancer, breast cancer, ovarian cancer, lung cancer, polycystic kidney disease and cardio-faciocutaneous syndrome.

2. The method of claim 1, wherein R.sup.112 of said compound having the structure of Formula IIIm is C.sub.2-6 alkyl.

3. The method of claim 1, wherein R.sup.112 of said compound having the structure of Formula IIIm is piperidin-1-yl or dimethylamine.

4. The method of claim 1, wherein R.sup.112 of said compound having the structure of Formula IIIm is selected from the group consisting of 2,3-dihydro-benzo[1,4]dioxin-6-yl; and phenyl optionally substituted with --CN, --NO.sub.2, acetamide, halogen, optionally fluoro substituted C.sub.1-6 alkyl, optionally fluoro substituted C.sub.1-6 alkoxy, or oxazolyl.

5. The method of claim 1, wherein R.sup.112 of said compound having the structure of Formula IIIm is selected from the group consisting of methyl substituted thiazole; methyl substituted imidazole; thiophene optionally substituted with methyl, oxazole, isoxazole, or pyridine; furan substituted with methyl or carboxylic acid methyl ester; benzothiazol-6-yl; and benzo[b]thiophen-2-yl.

6. The method of claim 1, wherein said compound having the structure of Formula IIIm is selected from the group consisting of: Propane-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phe- nyl]-amide, Propane-1-sulfonic acid [3-(5-ethoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, Propane-1-sulfonic acid [2-fluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amid- e, Propane-1-sulfonic acid {3-[5-(2-diethylamino-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-d- ifluoro-phenyl}-amide, Butane-1-sulfonic acid [2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-- amide, or a pharmaceutically acceptable salt thereof.

7. The method of claim 1, wherein said compound having the structure of Formula IIIm is selected from the group consisting of: Propane-1-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide- , Propane-1-sulfonic acid [2,4-difluoro-3-(5-isopropenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phen- yl]-amide, Propane-1-sulfonic acid [2,4-difluoro-3-(5-isopropyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl- ]-amide, Propane-1-sulfonic acid [2,4-difluoro-3-(5-methyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a- mide, Propane-1-sulfonic acid [4-chloro-2-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide- , Propane-1-sulfonic acid [2-fluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, 3-3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]p- yridin-5-yl-acrylic acid, 3-3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]p- yridin-5-yl-propionic acid, Butane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, Propane-1-sulfonic acid [2,4-difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a- mide, Propane-1-sulfonic acid [4-chloro-3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phen- yl]-amide, or a pharmaceutically acceptable salt thereof.

8. The method of claim 1, wherein said compound having the structure of Formula IIIm is selected from the group consisting of: 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr- idine-5-carboxylic acid methyl ester, 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr- idine-5-carboxylic acid, 3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]pyr- idine-5-carboxylic acid ethylamide, or a pharmaceutically acceptable salt thereof.

9. The method of claim 1, wherein said compound having the structure of Formula IIIm is selected from the group consisting of: Propane-1-sulfonic acid [4-chloro-2-fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)- -phenyl]-amide, Propane-1-sulfonic acid [2,4-difluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-a- mide, Propane-1-sulfonic acid {3-[5-(4-dimethylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-- difluoro-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony- l]-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbony- l]-phenyl}-amide, Propane-1-sulfonic acid {3-[5-(3-dimethylamino-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-- difluoro-phenyl}-amide, Propane-1-sulfonic acid [2-fluoro-3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide- , Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl- ]-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-fluoro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl- ]-phenyl}-amide, Propane-1-sulfonic acid {3-[5-(3-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor- o-phenyl}-amide, 3-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]- pyridin-5-yl}-benzoic acid, 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]- pyridin-5-yl}-benzamide, 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]- pyridin-5-yl}-N,N-dimethyl-benzamide, Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(morpholine-4-carbonyl)-phenyl]-1H-pyrrolo[2,3-b]py- ridine-3-carbonyl}-phenyl)-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-morpholin-4-yl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-- carbonyl]-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(3-morpholin-4-ylmethyl-phenyl)-1H-pyrrolo[2,3-b]pyrid- ine-3-carbonyl]-phenyl}-amide, Propane-1-sulfonic acid {3-[5-(4-cyano-3,5-dimethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]- -2,4-difluoro-phenyl}-amide, 3-{3-[2,6-difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]- pyridin-5-yl}-benzamide, Propane-1-sulfonic acid (2,4-difluoro-3-{5-[4-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyridin- e-3-carbonyl}-phenyl)-amide, 4-{3-[2,6-Difluoro-3-(propane-1-sulfonylamino)-benzoyl]-1H-pyrrolo[2,3-b]- pyridin-5-yl}-2,N,N-trimethyl-benzamide, or a pharmaceutically acceptable salt thereof.

10. The method of claim 1, wherein said compound having the structure of Formula IIIm is selected from the group consisting of: Propane-2-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl- )-phenyl]-amide, Propane-1-sulfonic acid [2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]- -amide, Propane-1-sulfonic acid [2,4-difluoro-3-(5-pyridin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phe- nyl]-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3-c- arbonyl]-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(6-morpholin-4-yl-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyrid- ine-3-carbonyl]-phenyl}-amide, Propane-1-sulfonic acid (2,4-difluoro-3-{5-[6-(4-methyl-piperazin-1-yl)-pyridin-3-yl]-1H-pyrrolo[- 2,3-b]pyridine-3-carbonyl}-phenyl)-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methyl-1H-imidazol-2-yl)-1H-pyrrolo[2,3-b]pyridine-- 3-carbonyl]-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-3- -carbonyl]-phenyl}-amide, or a pharmaceutically acceptable salt thereof.

11. The method of claim 1, wherein said compound having the structure of Formula IIIm is selected from the group consisting of: Propane-1-sulfonic acid [2,4-difluoro-3-(5-phenylamino-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)- -phenyl]-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methyl-piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-- carbonyl]-phenyl}-amide, Propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-methyl-piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine-3-- carbonyl]-phenyl}-amide, or a pharmaceutically acceptable salt thereof.

12. The method of claim 1, wherein said compound having the structure of Formula IIIm is selected from the group consisting of: Dimethylamine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, Dimethylamine-1-sulfonic acid [3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-amide, Dimethylamine-1-sulfonic acid [3-(5-phenyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, Piperidine-1-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Piperidine-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, Dimethylamine-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor- o-phenyl}-amide, or a pharmaceutically acceptable salt thereof.

13. The method of claim 1, wherein said compound having the structure of Formula IIIm is selected from the group consisting of: N-{3-[5-(4-Chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-diflu- oro-phenyl}-4-trifluoromethyl-benzenesulfonamide, N-[3-(5-Ethyl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-- 4-trifluoromethyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -3-fluoro-4-methyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -4-methyl-benzenesulfonamide, N-(2,4-Difluoro-3-{5-[4-(2-methoxy-ethoxy)-phenyl]-1H-pyrrolo[2,3-b]pyrid- ine-3-carbonyl}-phenyl)-4-trifluoromethyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -benzenesulfonamide, N-[2,4-Difluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]- -benzenesulfonamide, N-{2,4-difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbo- nyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -2-methyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -5-fluoro-2-methyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -3-methyl-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2-methyl- -benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-methyl- -benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-isopro- pyl-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-benzenes- ulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-5-fluoro- -2-methyl-benzenesulfonamide, N-[2,4-Difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-p- henyl]-benzenesulfonamide, N-{2,4-Difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine- -3-carbonyl]-phenyl}-4-trifluoromethyl-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]benz- enesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-triflu- oromethyl-benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

14. The method of claim 1, wherein said compound having the structure of Formula IIIm is selected from the group consisting of: N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)phenyl]-3-methoxy- -benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-methox- y-benzenesulfonamide, 4-Butoxy-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]- -benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3,4-dime- thoxy-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -4-methoxy-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -3-methoxy-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -2,4-dimethoxy-benzenesulfonamide, 2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-ph- enyl]-2,5-dimethoxy-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,4-dime- thoxy-benzenesulfonamide, 2,3-Dihydro-benzo[1,4]dioxine-6-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -4-difluoromethoxy-benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

15. The method of claim 1, wherein said compound having the structure of Formula IIIm is selected from the group consisting of: 4-Chloro-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]- -benzenesulfonamide, 3,4-Dichloro-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phe- nyl]-benzenesulfonamide, N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl- ]-3-fluoro-benzenesulfonamide, N-[2,4-Difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl- ]-4-fluoro-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -3-fluoro-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -4-fluoro-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -3,5-difluoro-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-fluoro- -benzenesulfonamide, N-{2,4-Difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbo- nyl]-phenyl}-4-fluoro-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -2-fluoro-benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

16. The method of claim 1, wherein said compound having the structure of Formula IIIm is selected from the group consisting of: N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -4-cyano-benzenesulfonamide, N-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -4-oxazol-5-yl-benzenesulfonamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-4-oxazol- -5-yl-benzenesulfonamide, N-{4-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phen- ylsulfamoyl]-phenyl}-acetamide, N-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-3-nitro-- benzenesulfonamide, N-{4-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfamo- yl]-phenyl}-acetamide, 2-Cyano-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-- benzenesulfonamide, 3-Cyano-N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-- benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

17. The method of claim 1, wherein said compound having the structure of Formula IIIm is selected from the group consisting of: Thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, Benzo[b]thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, 5-Pyridin-2-yl-thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, Thiophene-2-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, 2,5-Dimethyl-thiophene-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, 5-Isoxazol-5-yl-thiophene-2-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, 2,5-Dimethyl-thiophene-3-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, 2,4-Dimethyl-thiazole-5-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, Benzothiazole-6-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, 2,4-Dimethyl-thiazole-5-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, 5-Oxazol-5-yl-thiophene-2-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, 1,2-Dimethyl-1H-imidazole-4-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, 5-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-ph- enylsulfamoyl]-furan-2-carboxylic acid methyl ester, 5-[3-(5-Chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyls- ulfamoyl]-2-methyl-furan-3-carboxylic acid methyl ester, 2,5-Dimethyl-furan-3-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, 5-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfa- moyl]-furan-2-carboxylic acid methyl ester, 5-[2,4-Difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenylsulfamoyl]- -2-methyl-furan-3-carboxylic acid methyl ester, 2,5-Dimethyl-furan-3-sulfonic acid [2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide, or a pharmaceutically acceptable salt thereof.

18. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -2,4-difluoro-benzenesulfonamide or a pharmaceutically acceptable salt thereof.

19. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl- ]-3-trifluoromethyl-benzenesulfonamide or a pharmaceutically acceptable salt thereof.

20. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -3-trifluoromethyl-benzenesulfonamide or a pharmaceutically acceptable salt thereof.

21. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl- ]-4-trifluoromethyl-benzenesulfonamide or a pharmaceutically acceptable salt thereof.

22. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine- -3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide or a pharmaceutically acceptable salt thereof.

23. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -2-cyano-benzenesulfonamide or a pharmaceutically acceptable salt thereof.

24. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-{2,4-difluoro-3-[5-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3- -carbonyl]-phenyl}-3-fluoro-benzenesulfonamide or a pharmaceutically acceptable salt thereof.

25. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -4-trifluoromethyl-benzenesulfonamide or a pharmaceutically acceptable salt thereof.

26. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -3-cyano-benzenesulfonamide or a pharmaceutically acceptable salt thereof.

27. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-{2,4-difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbo- nyl]-phenyl}-3-fluoro-benzenesulfonamide or a pharmaceutically acceptable salt thereof.

28. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -4-isopropyl-benzenesulfonamide or a pharmaceutically acceptable salt thereof.

29. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-[3-(5-chloro-1H-pyrrolo[2, 3-1)]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-4-ethyl-benzenesulfonamide or a pharmaceutically acceptable salt thereof.

30. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-dime- thoxy-benzenesulfonamide or a pharmaceutically acceptable salt thereof.

31. The method of claim 1, wherein said compound having the structure of Formula IIIm is dimethylamine-1-sulfonic acid [3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phe- nyl]-amide or a pharmaceutically acceptable salt thereof.

32. The method of claim 1, wherein said compound having the structure of Formula IIIm is butane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide or a pharmaceutically acceptable salt thereof.

33. The method of claim 1, wherein said compound having the structure of Formula IIIm is N-[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-p- henyl]-ethanesulfonamide or a pharmaceutically acceptable salt thereof.

34. The method of claim 1, wherein said compound having the structure of Formula IIIm is propane-1-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phe- nyl]-amide or a pharmaceutically acceptable salt thereof.

35. The method of claim 1, wherein said compound having the structure of Formula IIIm is propane-1-sulfonic acid [2,4-difluoro-3-(5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-p- henyl]-amide or a pharmaceutically acceptable salt thereof.

36. The method of claim 1, wherein said compound having the structure of Formula IIIm is propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor- o-phenyl}-amide or a pharmaceutically acceptable salt thereof.

37. The method of claim 1, wherein said compound having the structure of Formula IIIm is propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3- -carbonyl]-phenyl}-amide or a pharmaceutically acceptable salt thereof.

38. The method of claim 1, wherein said compound having the structure of Formula IIIm is propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide or a pharmaceutically acceptable salt thereof.

39. The method of claim 1, wherein said compound having the structure of Formula IIIm is propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-ph- enyl}-amide or a pharmaceutically acceptable salt thereof.

40. The method of claim 1, wherein said compound having the structure of Formula IIIm is propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide or a pharmaceutically acceptable salt thereof.

41. The method of claim 1, wherein said compound having the structure of Formula IIIm is propane-1-sulfonic acid [4-chloro-2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl- )-phenyl]-amide or a pharmaceutically acceptable salt thereof.

42. The method of claim 1, wherein said compound having the structure of Formula IIIm is propane-1-sulfonic acid [2-fluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide or a pharmaceutically acceptable salt thereof.

43. The method of claim 1, wherein said compound having the structure of Formula IIIm is propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbony- l]-phenyl}-amide and or any pharmaceutically acceptable salts thereof.

44. The method according to any one of claims 18-43 wherein said protein kinase is a mutant of B-Raf.

45. The method according to claim 44 wherein said protein kinase is a V600E mutant of B-Raf.

46. The method according to claim 44 wherein said disease or condition is melanoma.

47. The method according to claim 44 wherein said disease or condition is thyroid cancer.

48. The method according to claim 44 wherein said disease or condition is colorectal cancer.

49. The method of claim 1, wherein the protein kinase is a mutant of B-Raf.

50. The method of claim 1, wherein the protein kinase is a V600E mutant of B-Raf.

51. A method for inhibiting a B-Raf or c-Raf-1 protein kinase activity in a subject in need thereof, said method comprising: administering to the subject an effective amount of a compound of Formula IIIm: ##STR03475## wherein: R.sup.81 is selected from the group consisting of hydrogen, halogen, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, --OH, --NH.sub.2, --CN, --NO.sub.2, --C(O)OH, --S(O).sub.2NH.sub.2, --C(O)NH.sub.2, --C(S)NH.sub.2, --NHC(O)NH.sub.2, --NHC(S)NH.sub.2, --NHS(O).sub.2NH.sub.2, --OR.sup.68, --SR.sup.68, --NR.sup.69R.sup.68, --C(O)R.sup.68, --C(S)R.sup.68, --C(O)OR.sup.68, --C(O)NR.sup.69R.sup.68, --C(S)NR.sup.69R.sup.68, --S(O).sub.2NR.sup.69R.sup.68, --NR.sup.69C(O)R.sup.68, --NR.sup.69C(S)R.sup.68, --NR.sup.69S(O).sub.2R.sup.68, --NR.sup.69C(O)NH.sub.2, --NR.sup.69C(O)NR.sup.69R.sup.68, --NR.sup.69C(S)NH.sub.2, --NR.sup.69C(S)NR.sup.69R.sup.68, --NR.sup.69S(O).sub.2NH.sub.2, --NR.sup.69S(O).sub.2NR.sup.69R.sup.68, --S(O)R.sup.68, and --S(O).sub.2R.sup.68; R.sup.83 is selected from the group consisting of hydrogen, fluoro and chloro; R.sup.112 is selected from the group consisting of optionally substituted C.sub.2-6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and --NR.sup.79R.sup.80; R.sup.68 is selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, provided, however, that when R.sup.68 is optionally substituted lower alkenyl, no alkene carbon thereof is bound to N, S, O, S(O), S(O).sub.2, C(O) or C(S) of --OR.sup.68, --SR.sup.68, --NR.sup.69R.sup.68, --C(O)R.sup.68, --C(S)R.sup.68, --C(O)OR.sup.68, --C(O)NR.sup.69R.sup.68, --C(S)NR.sup.69R.sup.68, --S(O).sub.2NR.sup.69R.sup.68, --NR.sup.69C(O)R.sup.68, --NR.sup.69C(S)R.sup.68, --NR.sup.69S(O).sub.2R.sup.68, --NR.sup.69C(O)NH.sub.2, --NR.sup.69C(O)NR.sup.69R.sup.68, --NR.sup.69C(S)NH.sub.2, --NR.sup.69C(S)NR.sup.69R.sup.68, --NR.sup.69S(O).sub.2NH.sub.2, --NR.sup.69S(O).sub.2NR.sup.69R.sup.68, --S(O)R.sup.68, or --S(O).sub.2R.sup.68, optionally substituted lower alkynyl, provided, however, that when R.sup.68 is optionally substituted lower alkynyl, no alkyne carbon thereof is bound to N, S, O, S(O), S(O).sub.2, C(O) or C(S) of -OR.sup.68, --SR.sup.68, --NR.sup.69R.sup.68, --C(O)R.sup.68, --C(S)R.sup.68, --C(O)OR.sup.68, --C(O)NR.sup.69R.sup.68, --C(S)NR.sup.69R.sup.68, --S(O).sub.2NR.sup.69R.sup.68, --NR.sup.69C(O)R.sup.68, --NR.sup.69C(S)R.sup.68, --NR.sup.69S(O).sub.2R.sup.68, --NR.sup.69C(O)NH.sub.2, --NR.sup.69C(O)NR.sup.69R.sup.68, --NR.sup.69C(S)NH.sub.2, --NR.sup.69C(S)NR.sup.69R.sup.68, --NR.sup.69S(O).sub.2NH.sub.2, --NR.sup.69S(O).sub.2NR.sup.69R.sup.68, --S(O)R.sup.68, or --S(O).sub.2R.sup.68, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; R.sup.69 is selected from the group consisting of hydrogen and optionally substituted lower alkyl; and R.sup.79 and R.sup.80 are independently hydrogen or optionally substituted lower alkyl, or R.sup.79 and R.sup.80 combine with the nitrogen to which they are attached to form optionally substituted 5-7 membered heterocycloalkyl or a pharmaceutically acceptable salt thereof.

52. The method of claim 51, wherein said protein kinase is a mutant of B-Raf.

53. The method of claim 52, wherein said protein kinase is a V600E mutant of B-Raf.

54. The method of claim 51, wherein R.sup.112 is optionally substituted C.sub.2-6alkyl.

55. The method of claim 51, wherein R.sup.81 is halogen or CN.

56. The method of claim 51, wherein the compound is selected from the group consisting of: N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -2,4-difluoro-benzenesulfonamide, N-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl- ]-3-trifluoromethyl-benzenesulfonamide, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -3-trifluoromethyl-benzenesulfonamide, N-[2,4-difluoro-3-(5-methoxy-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl- ]-4-trifluoromethyl-benzenesulfonamide, N-{2,4-difluoro-3-[5-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine- -3-carbonyl]-phenyl}-3-fluoro-benzenesulfonamide, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -2-cyano-benzenesulfonamide, N-{2,4-difluoro-3-[5-(6-methoxy-pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-3- -carbonyl]-phenyl}-3-fluoro-benzenesulfonamide, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -4-trifluoromethyl-benzenesulfonamide, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -3-cyano-benzenesulfonamide, N-{2,4-difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbo- nyl]-phenyl}-3-fluoro-benzenesulfonamide, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -4-isopropyl-benzenesulfonamide, N-[3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]- -4-ethyl-benzenesulfonamide, N-[2,4-difluoro-3-(1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-2,5-dime- thoxy-benzenesulfonamide, dimethylamine-1-sulfonic acid [3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phe- nyl]-amide, butane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide- , N-[2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-- phenyl]-ethanesulfonamide, propane-1-sulfonic acid [2,4-difluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phe- nyl]-amide, propane-1-sulfonic acid [2,4-difluoro-3-(5-morpholin-4-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-p- henyl]-amide, propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluor- o-phenyl}-amide, propane-1-sulfonic acid {2,4-difluoro-3-[5-(4-trifluoromethyl-phenyl)-1H-pyrrolo[2,3-b]pyridine-3- -carbonyl]-phenyl}-amide, propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluoro-phenyl]-a- mide, propane-1-sulfonic acid {3-[5-(4-chloro-phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2-fluoro-ph- enyl}-amide, propane-1-sulfonic acid [3-(5-chloro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2-fluoro-phenyl]-amide- , propane-1-sulfonic acid [4-chloro-2-fluoro-3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine-3-carbonyl- )-phenyl]-amide, propane-1-sulfonic acid [2-fluoro-3-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-phenyl]-amide and propane-1-sulfonic acid {2,4-difluoro-3-[5-(2-methoxy-ethoxy)-1H-pyrrolo[2,3-b]pyridine-3-carbony- l]-phenyl}-amide or a pharmaceutically acceptable salt thereof.
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