Piperidin-4-yl azetidine derivatives as JAK1 inhibitors

• US 9,464,088 B2
• Filed: 05/28/2014
• Issued: 10/11/2016
• Est. Priority Date: 03/10/2010
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation, Incyte Holdings Corporation (Incyte Corporation)
• Inventors: Huang, Taisheng, Xue, Chu-Biao, Li, Hui-Yin, Li, Qun
• Primary Examiner(s): Moore, Susanna
• Application Number:
  US14/289,121
• Publication Number:
  US 20140275031A1
• Time in Patent Office: 867 Days
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0048 Eye, e.g. artificial tears
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: C07B 2200/13 Crystalline forms, e.g. polymorphs
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 405/14 containing three or more hetero rings
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

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.

Claims

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.

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.

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.

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.