Compounds and compositions as protein kinase inhibitors
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.
1. A method of treating melanoma in a subject in need thereof, the method comprising:
(a) detecting a mutant BRAF kinase in the melanoma; and
(b) orally administering to said subject a therapeutically effective amount of:
(i) a pharmaceutical composition comprising 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
(ii) a pharmaceutical composition comprising a MEK inhibitor.
2. The method of claim 1 , wherein said pharmaceutical composition comprising methyl N-[(2 S)-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 pharmaceutical composition comprising said MEK inhibitor are administered as a non-fixed combination.
3. The method of claim 2 , wherein said pharmaceutical composition comprising methyl N-[(2 S)-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 pharmaceutical composition comprising said MEK inhibitor are administered sequentially.
4. The method of claim 3 , wherein the melanoma is melanoma having a B-Raf V600E mutation.
5. The method of claim 4 , wherein the MEK inhibitor is selected from: AS703026; MSC1936369B; GSK1120212; AZD6244; PD-0325901; ARRY-438162; RDEA119; GDC0941; GDC0973; TAK-733; RO5126766; and XL-518.
6. The method of claim 5 , wherein the MEK inhibitor is ARRY-438162.
7. The method of claim 3 , wherein said pharmaceutical composition comprising methyl N-[(2 S)-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 is formulated as a capsule.
8. The method of claim 6 , wherein said pharmaceutical composition comprising methyl N-[(2 S)-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 is formulated as a capsule.
9. The method of claim 2 , wherein said pharmaceutical composition comprising methyl N-[(2 S)-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 pharmaceutical composition comprising said MEK inhibitor are administered concurrently.
10. The method of claim 9 , wherein the melanoma is melanoma having a B-Raf V600E mutation.
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 9 , wherein said pharmaceutical composition comprising methyl N-[(2 S)-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 is formulated as a capsule.
14. The method of claim 12 , wherein said pharmaceutical composition comprising methyl N-[(2 S)-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 is formulated as a capsule.
15. The method of claim 4 , wherein said melanoma is metastatic melanoma.
16. The method of claim 15 , wherein the MEK inhibitor is selected from: AS703026; MSC1936369B; GSK1120212; AZD6244; PD-0325901; ARRY-438162; RDEA119; GDC0941; GDC0973; TAK-733; RO5126766; and XL-518.
17. The method of claim 16 , wherein the MEK inhibitor is ARRY-438162.
18. The method of claim 10 , wherein said melanoma is metastatic melanoma.
19. The method of claim 18 , wherein the MEK inhibitor is selected from: AS703026; MSC1936369B; GSK1120212; AZD6244; PD-0325901; ARRY-438162; RDEA119; GDC0941; GDC0973; TAK-733; RO5126766; and XL-518.
20. The method of claim 19 , wherein the MEK inhibitor is ARRY-438162.