Piperidin-4-yl azetidine derivatives as JAK1 inhibitors
The present invention provides piperidin-4-yl azetidine derivatives, as well as their compositions and methods of use, that modulate the activity of Janus kinase 1 (JAK1) and are useful in the treatment of diseases related to the activity of JAK1 including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.
1. A method of inhibiting an activity of JAK1 comprising contacting JAK1 with a compound, which is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.
2. A method according to claim 1 , wherein said compound, or pharmaceutically acceptable salt thereof, is selective for JAK1 over JAK2.
3. A method of treating a disease selected from breast cancer, pancreatic cancer, Castleman's disease, leukemia, lymphoma, multiple myeloma, polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM), myelofibrosis, chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia (CMML), hypereosinophilic syndrome (HES), idiopathic myelofibrosis (IMF), systemic mast cell disease (SMCD), lung cancer, colon cancer, colorectal cancer, and cachexia resulting from or associated with cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound, which is {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile, or a pharmaceutically acceptable salt thereof.
4. A method according to claim 1 , wherein said salt is {1-{1-[3-Fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt.
5. A method according to claim 3 , wherein said salt is {1-{1-[3-Fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile adipic acid salt.
6. A method according to claim 3 , wherein the disease is breast cancer.
7. A method according to claim 3 , wherein the disease is pancreatic cancer.
8. A method according to claim 3 , wherein the disease is Castleman's disease.
9. A method according to claim 3 , wherein the disease is leukemia.
10. A method according to claim 3 , wherein the disease is lymphoma.
11. A method according to claim 3 , wherein the disease is multiple myeloma.
12. A method according to claim 3 , wherein the disease is polycythemia vera (PV).
13. A method according to claim 3 , wherein the disease is essential thrombocythemia (ET).
14. A method according to claim 3 , wherein the disease is myeloid metaplasia with myelofibrosis (MMM).
15. A method according to claim 3 , wherein the disease is myelofibrosis.
16. A method according to claim 15 , wherein the myelofibrosis is primary myelofibrosis (PMF).
17. A method according to claim 15 , wherein the myelofibrosis is post polycythemia vera myelofibrosis (Post-PV MF).
18. A method according to claim 15 , wherein the myelofibrosis is post essential thrombocythemia myelofibrosis (Post-ET MF).
19. A method according to claim 3 , wherein the disease is chronic myelogenous leukemia (CML).
20. A method according to claim 3 , wherein the disease is chronic myelomonocytic leukemia (CMML).
21. A method according to claim 3 , wherein the disease is hypereosinophilic syndrome (HES).
22. A method according to claim 3 , wherein the disease is idiopathic myelofibrosis (IMF).
23. A method according to claim 3 , wherein the disease is systemic mast cell disease (SMCD).
24. A method according to claim 3 , wherein the disease is lung cancer.
25. A method according to claim 3 , wherein the disease is colorectal cancer.
26. A method according to claim 3 , wherein the disease is colon cancer.
27. A method according to claim 3 , wherein the disease is cachexia resulting from or associated with cancer.
28. A method according to claim 5 , wherein the disease is breast cancer.
29. A method according to claim 5 , wherein the disease is pancreatic cancer.
30. A method according to claim 5 , wherein the disease is Castleman's disease.
31. A method according to claim 5 , wherein the disease is leukemia.
32. A method according to claim 5 , wherein the disease is lymphoma.
33. A method according to claim 5 , wherein the disease is multiple myeloma.
34. A method according to claim 5 , wherein the disease is polycythemia vera (PV).
35. A method according to claim 5 , wherein the disease is essential thrombocythemia (ET).
36. A method according to claim 5 , wherein the disease is myeloid metaplasia with myelofibrosis (MMM).
37. A method according to claim 5 , wherein the disease is myelofibrosis.
38. A method according to claim 37 , wherein the myelofibrosis is primary myelofibrosis (PMF).
39. A method according to claim 37 , wherein the myelofibrosis is post polycythemia vera myelofibrosis (Post-PV MF).
40. A method according to claim 37 , wherein the myelofibrosis is post essential thrombocythemia myelofibrosis (Post-ET MF).
41. A method according to claim 5 , wherein the disease is chronic myelogenous leukemia (CML).
42. A method according to claim 5 , wherein the disease is chronic myelomonocytic leukemia (CMML).
43. A method according to claim 5 , wherein the disease is hypereosinophilic syndrome (HES).
44. A method according to claim 5 , wherein the disease is idiopathic myelofibrosis (IMF).
45. A method according to claim 5 , wherein the disease is systemic mast cell disease (SMCD).
46. A method according to claim 5 , wherein the disease is lung cancer.
47. A method according to claim 5 , wherein the disease is colorectal cancer.
48. A method according to claim 5 , wherein the disease is colon cancer.
49. A method according to claim 5 , wherein the disease is cachexia resulting from or associated with cancer.