PYRAZOLOPYRIMIDINE DERIVATIVES AS TYROSINE KINASE INHIBITORS

• US 20140221398A1
• Filed: 05/16/2012
• Published: 08/07/2014
• Est. Priority Date: 05/17/2011
• Status: Active Grant

• Current Assignee: Principia Biopharma Inc. (Sanofi )
• Original Assignee: Principia Biopharma Inc. (Sanofi )
• Inventors: Goldstein, David Michael, Brameld, Kenneth Albert
• Granted Patent: US 9,376,438 B2
• Time in Patent Office: Days
• US Class Current: 514/262.1
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 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: C07D 487/04 Ortho-condensed systems

Abstract

The present disclosure provides compounds and pharmaceutically acceptable salts that are tyrosine kinase inhibitors, in particular BLK, BMX, EGFR, HER2, HER4, ITK, Jak3, TEC, Btk, and TXK and are therefore useful for the treatment of diseases treatable by inhibition of tyrosine kinases such as cancer and inflammatory diseases such as arthritis, and the like. Also provided are pharmaceutical compositions containing such compounds and pharmaceutically acceptable salts and processes for preparing such compounds and pharmaceutically acceptable salts.

Claims

1-22. -22. (canceled)

23. A compound of Formula (I):

24. The compound of claim 23 or a pharmaceutically acceptable salt thereof wherein:

25. The compound of claim 23 or a pharmaceutically acceptable salt thereof wherein:

26. The compound of claim 24 or a pharmaceutically acceptable salt thereof wherein L is O, S, NH, N(methyl), NHCO, CONH, or NHCONH.

27. The compound of claim 25 or a pharmaceutically acceptable salt thereof wherein L is O, S, NH, N(methyl), NHCO, CONH, or NHCONH.

28. The compound of claim 23 or a pharmaceutically acceptable salt thereof wherein R³ and R⁴ are independently hydrogen, methyl, fluoro, methoxy, chloro, trifluoromethyl, or trifluoromethoxy.

29. The compound of claim 26 or a pharmaceutically acceptable salt thereof wherein R³ and R⁴ are independently hydrogen, methyl, fluoro, methoxy, chloro, trifluoromethyl, or trifluoromethoxy.

30. The compound of claim 27 or a pharmaceutically acceptable salt thereof wherein R³ and R⁴ are independently hydrogen, methyl, fluoro, methoxy, chloro, trifluoromethyl, or trifluoromethoxy.

31. The compound of claim 28 or a pharmaceutically acceptable salt thereof wherein R⁶ and R⁷ are independently hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, or cyano.

32. The compound of claim 29 or a pharmaceutically acceptable salt thereof wherein R⁵ is hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy or cyano;

R¹ is formula (a)

33. The compound of claim 30 or a pharmaceutically acceptable salt thereof wherein R⁵ is hydrogen, methyl, methoxy, fluoro, chloro, trifluoromethyl, trifluoromethoxy, or cyano;

R¹ is formula (a)

34. The compound of claim 29 or a pharmaceutically acceptable salt thereof wherein R⁵ is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, or haloalkoxy;

R¹ is formula (b)

35. The compound of claim 30 or a pharmaceutically acceptable salt thereof wherein R⁵ is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, or haloalkoxy;

R¹ is formula (b);

36. The compound of claim 34 or a pharmaceutically acceptable salt thereof wherein X^a is O;

R^c′

is ethyl, propyl, cyclopropyl, or alkyl substituted with hydroxyl, alkoxy, alkylamino or dialkylamino;

P is alkylene; and

Q is a bond.

37. The compound of claim 35 or a pharmaceutically acceptable salt thereof wherein X^a is O;

R^c′

is ethyl, propyl, cyclopropyl, or alkyl substituted with hydroxyl, alkoxy, alkylamino or dialkylamino;

P is alkylene; and

Q is a bond.

38. The compound of claim 31 or a pharmaceutically acceptable salt thereof wherein the

39. The compound of claim 36 or a pharmaceutically acceptable salt thereof wherein the

40. The compound of claim 37 or a pharmaceutically acceptable salt thereof wherein the

41. A pharmaceutical composition comprising a compound of claim 23 or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable excipient.

42. A method of treating an inflammatory, autoimmune or proliferative disease in a patient which method comprises administering to the patient in need thereof, a pharmaceutical composition comprising a compound of claim 23 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable exciplent.

43. The method of claim 47 wherein the disease is inflammatory bowel disease, arthritis, lupus, rheumatoid arthritis, psoriatic arthritis, juvenile arthritis, Sjogren'"'"'s syndrome, multiple sclerosis, ankylosing spondylitisis, idiopathic thrombocytopenic purpura, scleroderma, Wegener'"'"'s granulomatosis, psoriasis, asthma, colitis, conjunctivitis, dermatitis, uveitis, eczema, diffuse large B cell lymphoma, follicular lymphoma, chronic lymphocytic lymphoma, chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplamascytic lymphoma/Waldenstrom macroglobulinemia, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, mantle cell lymphoma, mediastinal (thymic) large B cell lymphoma, non-Hodgkin lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, burkitt lymphoma/leukemia, or lymphomatoid granulomatosis.