Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as JAK inhibitors

• US 8,691,807 B2
• Filed: 06/19/2012
• Issued: 04/08/2014
• Est. Priority Date: 06/20/2011
• Status: Active Grant

• Current Assignee: Incyte Holdings Corporation And Incyte Corporation
• Original Assignee: Incyte Corporation
• Inventors: Yao, Wenqing, Burns, David M., Zhuo, Jincong
• Primary Examiner(s): Solola, Taofiq A.
• Assistant Examiner(s): Kenyon, John S
• Application Number:
  US13/526,957
• Publication Number:
  US 20130018034A1
• Time in Patent Office: 658 Days
• Field of Search: None
• US Class Current: 514/210.21
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention provides azetidinyl phenyl, pyridyl, or pyrazinyl carboxamide derivatives, as well as their compositions and methods of use, that modulate the activity of Janus kinase (JAKs) and are useful in the treatment of diseases related to the activity of JAK including, for example, inflammatory disorders, autoimmune disorders, cancer, and other diseases.

Claims

1. A compound, which is 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5-difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

2. A composition comprising a compound according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

4. A method of treating multiple sclerosis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

5. A method of treating type I diabetes in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

6. A method of treating lupus in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

7. A method of treating myasthenia gravis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

8. A method of treating myocarditis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

9. A method of treating contact dermatitis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

10. A method of treating psoriasis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

11. A method of treating osteoporosis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

12. A method of treating bone resorption in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

3. A compound, which is 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5 -difluoro-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide.

13. A composition comprising a compound according to claim 3 and a pharmaceutically acceptable carrier.

14. A method of treating multiple sclerosis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 3.

15. A method of treating type I diabetes in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 3.

16. A method of treating lupus in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 3.

17. A method of treating myasthenia gravis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 3.

18. A method of treating myocarditis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 3.

19. A method of treating contact dermatitis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 3.

20. A method of treating psoriasis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 3.

21. A method of treating osteoporosis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 3.

22. A method of treating bone resorption in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 3.

23. A compound, which is 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5 -difluoro-N-[(1R)-2,2,2-trifluoro-1-methylethyl]benzamide, or a pharmaceutically acceptable salt thereof.

25. A composition comprising a compound according to claim 23, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. A method of treating multiple sclerosis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 23, or a pharmaceutically acceptable salt thereof.

28. A method of treating type I diabetes in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 23, or a pharmaceutically acceptable salt thereof.

29. A method of treating lupus in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 23, or a pharmaceutically acceptable salt thereof.

30. A method of treating myasthenia gravis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 23, or a pharmaceutically acceptable salt thereof.

31. A method of treating myocarditis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 23, or a pharmaceutically acceptable salt thereof.

32. A method of treating contact dermatitis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 23, or a pharmaceutically acceptable salt thereof.

33. A method of treating psoriasis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 23, or a pharmaceutically acceptable salt thereof.

34. A method of treating osteoporosis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 23, or a pharmaceutically acceptable salt thereof.

35. A method of treating bone resorption in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 23, or a pharmaceutically acceptable salt thereof.

24. A compound, which is 4-{3-(cyanomethyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-2,5 -difluoro-N-[(1R)-2,2,2-trifluoro--methylethyl]benzamide.

26. A composition comprising a compound according to claim 24 and a pharmaceutically acceptable carrier.

36. A method of treating multiple sclerosis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 24.

37. A method of treating type I diabetes in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 24.

38. A method of treating lupus in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 24.

39. A method of treating myasthenia gravis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 24.

40. A method of treating myocarditis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 24.

41. A method of treating contact dermatitis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 24.

42. A method of treating psoriasis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 24.

43. A method of treating osteoporosis in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 24.

44. A method of treating bone resorption in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of the compound of claim 24.