Compounds and compositions as protein kinase inhibitors

Patent metadata

Field	Value
Publication number	US-2016263113-A1
Application number	US-201615070905-A
Country	US
Kind code	A1
Filing date	Mar 15, 2016
Priority date	Aug 28, 2009
Publication date	Sep 15, 2016
Grant date	—

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.

First claim

1 . (canceled)

2 . A method of treating cancer in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of 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 or a pharmaceutically acceptable salt thereof.

3 . The method of claim 2 , 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.

4 . The method of claim 3 , wherein the cancer is melanoma.

5 . The method of claim 4 , wherein the cancer is metastatic melanoma.

6 . The method of claim 4 , wherein the cancer is melanoma having a B-RAF V600E mutation.

7 . The method of claim 3 , wherein the cancer is colon carcinoma.

8 . The method of claim 6 , wherein the colon carcinoma is a carcinoma having a B-RAF V600E mutation.

9 . The method of claim 2 further comprising administering to the subject an additional therapeutic agent.

10 . The method of claim 9 , wherein the additional therapeutic agent comprises an anticancer compound.

11 . The method of claim 10 , wherein the additional therapeutic agent is a different 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.

12 . The method of claim 11 , wherein the additional therapeutic agent is a MEK inhibitor.

13 . The method of claim 12 , wherein the MEK inhibitor is selected from: AS703026; MSC1936369B; GSK1120212; AZD6244; PD-0325901; ARRY-438162; RDEA119; GDC0941; GDC0973; TAK-733; RO5126766; and XL-518.

14 . The method of claim 13 , wherein the MEK inhibitor is ARRY-438162.

15 . The method of claim 14 , wherein said 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 or a pharmaceutically acceptable salt thereof and said ARRY-438162 are administered as a fixed combination.

16 . The method of claim 14 , wherein said 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 or a pharmaceutically acceptable salt thereof and said ARRY-438162 are administered as a non-fixed combination.

17 . The method of claim 15 , wherein said 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 or a pharmaceutically acceptable salt thereof and said ARRY-438162 are administered sequentially.

18 . The method of claim 15 , wherein said 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 or a pharmaceutically acceptable salt thereof and said ARRY-438162 are administered concurrently.

19 . The method of claim 14 , wherein said cancer is melanoma.

20 . The method of claim 19 , wherein the cancer is metastatic melanoma.

21 . The method of claim 19 , wherein the cancer is melanoma having a B-RAF V600E mutation.

22 . The method of claim 19 , wherein said 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 or a pharmaceutically acceptable salt thereof and said ARRY-438162 are administered as a non-fixed combination.

23 . The method of claim 22 , wherein said 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 or a pharmaceutically acceptable salt thereof and said ARRY-438162 are administered sequentially.

24 . The method of claim 19 , wherein said 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 or a pharmaceutically acceptable salt thereof and said ARRY-438162 are administered as a fixed combination.

25 . The method of claim 14 , wherein said cancer is colon carcinoma.

26 . The method of claim 25 , herein the carcinoma is a carcinoma having a B-RAF V600E mutation.

27 . The method of claim 26 , wherein said 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 or a pharmaceutically acceptable salt thereof and said ARRY-438162 are administered as a non-fixed combination.

28 . The method of claim 27 , wherein said 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 or a pharmaceutically acceptable salt thereof and said ARRY-438162 are administered sequentially.

29 . The method of claim 26 , wherein said 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 or a pharmaceutically acceptable salt thereof and said ARRY-438162 are administered as a fixed combination.

Assignees

• Novartis Ag

Inventors

• Huang Shenlin
• Jin Xianming
• Liu Zuosheng
• Poon Daniel
• TELLEW John
• Wan Yongqin
• Wang Xing
• Xie Yongping

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P1/08

  for nausea, cinetosis or vertigo; Antiemetics · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title