Claims for Patent: 9,314,464

Summary for Patent: 9,314,464

Title:	Compounds and compositions as protein kinase inhibitors
Abstract:	The invention provides a novel class of compounds, pharmaceutical compositions comprising such compounds and methods of using such compounds to treat or prevent diseases or disorders associated with abnormal or deregulated kinase activity, particularly diseases or disorders that involve abnormal activation of B-Raf.
Inventor(s):	Shenlin Huang, Xianming Jin, Zuosheng Liu, Daniel Poon, John Tellew, Yongqin Wan, Xing Wang, Yongping Xie
Assignee:	Novartis AG, Array Biopharma Inc
Application Number:	US13/931,111
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,314,464
Patent Claims:	1. A method for treating a B-Raf protein kinase mediated cancer, wherein the cancer is selected from the group consisting of lung carcinoma, pancreatic carcinoma, bladder carcinoma, colon carcinoma, myeloid disorders, prostate cancer, thyroid cancer, melanoma, adenomas and carcinomas of the ovary, eye, liver, biliary tract, and nervous system, and wherein the method comprises administering to a subject in need of such treatment an effective amount of a compound of Formula (Ia), or a tautomer, stereoisomer or pharmaceutically acceptable salt thereof; wherein the compound of Formula (Ia) is in which: Y is selected from N and CR6; R2, R3, R5 and R6 are independently selected from hydrogen, halo, cyano, C1-4alkyl, halo-substituted-C1-4alkyl, C1-4alkoxy and halo-substituted-C1-4alkoxy; with the proviso that when R5 is fluoro, R3 and R6 are not both hydrogen; R4 is selected from —R9 and —NR10R11; wherein R9 is selected from C1-6alkyl, C3-8cycloalkyl, C3-8heterocycloalkyl, aryl and heteroaryl; wherein said alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl of R9 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, C1-4alkyl, halo-substituted-C1-4alkyl, C1-4alkoxy and halo-substituted-C1-4alkoxy; and R10 and R11 are independently selected from hydrogen and R9; R7 is selected from hydrogen, C1-4alkyl, C3-5cycloalkyl and C3-5heterocycloalkyl; wherein said alkyl, cycloalkyl or heterocycloalkyl of R7 is optionally substituted with 1 to 3 radicals independently selected from halo, cyano, hydroxyl, C1-4alkyl, halo-substituted-C1-4alkyl, C1-4alkoxy and halo-substituted-C1-4alkoxy. 2. The method of claim 1 in which R4 is —R9; wherein R9 is selected from C1-3alkyl and C3-8cycloalkyl; wherein said alkyl or cycloalkyl of R9 is optionally substituted with 1 to 3 radicals independently selected from halo and halo-substituted-C1-4alkyl. 3. The method of claim 2 in which: R2 is selected from hydrogen and fluoro; R3 is selected from chloro, fluoro and methyl; R5 is selected from hydrogen, chloro and fluoro; Y is selected from N and CR6; and R6 is selected from hydrogen and fluoro. 4. The method of claim 1, wherein the compound of Formula (Ia) is selected from: methyl N-[(2S)-1-({4-[3-(3-chloro-5-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-[(4-{3-[3-chloro-5-(propane-1-sulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(3-chloro-2-methanesulfonamidopyridin-4-yl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(3-fluoro-2-methanesulfonamidopyridin-4-yl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(2-chloro-3-ethanesulfonamido-4,5-difluorophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(2,4-difluoro-3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[1-(propan-2-yl)-3-(2,4,5-trifluoro-3-methanesulfonamidophenyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(3-ethanesulfonamido-2,4-difluorophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-2-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propyl]carbamate; methyl N-[(2S)-1-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-1-(oxan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-[(4-{3-[2,4-difluoro-3-(propane-1-sulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(3-cyclopropanesulfonamido-2,5-difluorophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(5-chloro-3-cyclopropanesulfonamido-2-fluorophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; and methyl N-[(2S)-1-[(4-{3-[5-chloro-2-fluoro-3-(propane-1-sulfonamido)phenyl]-1-(propan-2-yl)-1H-pyrazol-4-yl}pyrimidin-2-yl)amino]propan-2-yl]carbamate. 5. The method of claim 1 wherein the compound of Formula (Ia) is a compound of Formula (Ib): in which: R3 is selected from chloro, fluoro and methyl; R5 is selected from fluoro and chloro; and R7 is selected from ethyl and isopropyl. 6. The method of claim 5 wherein the compound of Formula (Ib) is selected from: methyl N-[(2S)-1-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(2,5-difluoro-3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-1-ethyl-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(2-fluoro-3-methanesulfonamido-5-methylphenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(2-chloro-3-methanesulfonamido-5-methylphenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2S)-1-({4-[3-(2-chloro-5-fluoro-3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; methyl N-[(2R)-1-({4-[3-(5-chloro-2-fluoro-3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate; and methyl N-[(2S)-1-({4-[3-(2,5-dichloro-3-methanesulfonamidophenyl)-1-(propan-2-yl)-1H-pyrazol-4-yl]pyrimidin-2-yl}amino)propan-2-yl]carbamate. 7. The method of claim 1, further comprising administering to the subject an additional therapeutic agent selected from an anticancer drug, a pain medication, an antiemetic, an antidepressant or an anti-inflammatory agent. 8. The method of claim 7, wherein the additional therapeutic agent is administered to the subject simultaneously, concurrently or sequentially with the compound of Formula (Ia). 9. The method of claim 8, wherein the additional therapeutic agent is a Raf kinase inhibitor or an inhibitor of MEK, mTOR, HSP90, AKT, PI3K, CDK9, PAK, Protein Kinase C, a MAP kinase, a MAPK Kinase, or ERK. 10. The method of claim 9, wherein the additional therapeutic agent is an inhibitor of MEK or PI3K. 11. The method of claim 10, wherein the MEK inhibitor is selected from: AS703026; MSC1936369B; GSK1120212; AZD6244; PD-0325901; ARRY-438162; RDEA119; GDC0941; GDC0973; TAK-733; RO5126766; and XL-518. 12. The method of claim 11, wherein the MEK inhibitor is ARRY-438162. 13. The method of claim 11, wherein the MEK inhibitor is ARRY-438162 which is administered to the subject sequentially with the compound of Formula (Ia). 14. The method of claim 5, further comprising administering to the subject an additional therapeutic agent selected from an anticancer drug, a pain medication, an antiemetic, an antidepressant or an anti-inflammatory agent. 15. The method of claim 14, wherein the additional therapeutic agent is administered to the subject simultaneously, concurrently or sequentially with the compound of Formula (Ib). 16. The method of claim 15, wherein the additional therapeutic agent is a Raf kinase inhibitor or an inhibitor of MEK, mTOR, HSP90, AKT, PI3K, CDK9, PAK, Protein Kinase C, a MAP kinase, a MAPK Kinase, or ERK. 17. The method of claim 16, wherein the additional therapeutic agent is an inhibitor of MEK or PI3K. 18. The method of claim 17, wherein the MEK inhibitor is selected from: AS703026; MSC1936369B; GSK1120212; AZD6244; PD-0325901; ARRY-438162; RDEA119; GDC0941; GDC0973; TAK-733; RO5126766; and XL-518. 19. The method of claim 18 wherein the MEK inhibitor is ARRY-438162. 20. The method of claim 18, wherein the MEK inhibitor is ARRY-438162 which is administered to the subject sequentially with the compound of Formula (Ib). 21. The method of claim 6, further comprising administering to the subject an additional therapeutic agent selected from an anticancer drug, a pain medication, an antiemetic, an antidepressant or an anti-inflammatory agent. 22. The method of claim 21, wherein the additional therapeutic agent is administered to the subject simultaneously, concurrently or sequentially with the compound of Formula (Ib). 23. The method of claim 22, wherein the additional therapeutic agent is a Raf kinase inhibitor or an inhibitor of MEK, mTOR, HSP90, AKT, PI3K, CDK9, PAK, Protein Kinase C, a MAP kinase, a MAPK Kinase, or ERK. 24. The method of claim 23, wherein the additional therapeutic agent is an inhibitor of MEK or PI3K. 25. The method of claim 23, wherein the MEK inhibitor is selected from: AS703026; MSC1936369B; GSK1120212; AZD6244; PD-0325901; ARRY-438162; RDEA119; GDC0941; GDC0973; TAK-733; RO5126766; and XL-518. 26. The method of claim 25, wherein the MEK inhibitor is ARRY-438162. 27. The method of claim 25, wherein the MEK inhibitor is ARRY-438162 which is administered to the subject sequentially with the compound of Formula (Ib).