Pyridones useful as inhibitors of kinases

• US 20070185125A1
• Filed: 08/25/2006
• Published: 08/09/2007
• Est. Priority Date: 08/29/2005
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Jimenez, Juan-Miguel, Durrant, Steven, Charrier, Jean-Damien, Mortimore, Michael, Ramaya, Sharn, Golec, Julian
• Granted Patent: US 7,786,120 B2
• Time in Patent Office: Days
• US Class Current: 514/252.110
• 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 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• 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 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/08 Antiseborrheics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• 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 27/02 Ophthalmic agents
• 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 31/08 for leprosy
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• 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: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 213/64 : attached in position 2 or 6
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds useful as inhibitors of protein kinase. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders. The invention also provides processes for preparing compounds of the inventions.

Claims

1. A compound of formula I:

2. The compound according to claim 1, wherein V is

5. The compound according to claim 1 or claim 2, wherein n is 1 and T is C_1-3aliphatic optionally interrupted with one occurrence of O, NR⁵, or S.

6. The compound according to claim 1 or claim 2, wherein n is 0.

7. The compound according to claim 6, wherein Q is C_1-10 aryl, C_3-10 cycloaliphatic, 5-14 membered heteroaryl, or 5-14 membered heterocyclyl.

8. The compound according to claim 7, wherein Q is C_6-10 aryl or 5-14 membered heteroaryl.

9. The compound according to claim 8 wherein Q is a 6 membered aryl or a 5-6 membered heteroaryl.

10. The compound according to claim 9, wherein Q is a 6 membered heteroaryl.

11. The compound according to claim 9, wherein Q is phenyl.

12. The compound according to claim 7, wherein

Q is substituted with up to 3 J^Q groups;

wherein each J^Q is independently selected from CN, halo, C_1-6alkyl, C_1-4haloalkyl, —

OR^o, —

N(R^o)₂, —

SR^o, —

(C_1-6alkyl)-OR^o, —

(C_1-6alkyl)-N(R^o)₂, (C_1-6alkyl)-SR^o, —

(U)_m—

(C_6-10aryl), —

(U)_m-(5-12 membered heteroaryl), —

(U)_m-(3-12 membered heterocyclyl), —

(U)_m-(C_3-10cycloaliphatic), —

C(O)OR^o, —

NR^oCOR^o, —

COR^o, —

CON(R^o)₂, —

SO₂R^o, and —

SO₂N(R^o)₂;

U is a C_1-10alkyl, wherein 0-1 methylene units are independently replaced by, —

NR^o—

, —

O—

, or —

S—

;

m is 0 or 1.

13. The compound according to claim 12, wherein each J^Q is CN, halo, C_1-6alkyl, C_1-4haloalkyl, —

OR^o, —

N(R^o)2, —

SR_o, —

NH—

(C_1-6alkyl)(3-8 membered heterocyclyl), —

O—

(C_1-6alkyl)-(3-8 membered heterocyclyl), 3-8 membered heterocyclyl, —

C(O)OR^o, —

NR^oCOR^o, —

COR^o, —

CON(R^o)₂, —

SO²Ro, or —

SO₂N(R^o)₂ wherein each J^Q is optionally and independently substituted with 0-5 R^X.

14. The compound according to claim 13, wherein J^Q is —

N(R^o)₂, OR^o, or a 5-8 membered heterocyclyl optionally substituted with 0-5 R^X.

15. The compound according to claim 14, wherein J^Q is a group selected from piperidinyl, piperazinyl, and pyrrolidinyl, wherein said group is optionally substituted with 0-5 R^X.

16. The compound according to claim 12, wherein R^X is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, t-butyl, halogen, NO₂, CN, NH₂, NH(C_1-4aliphatic), N(C_1-4aliphatic)₂, OH, O(C_1-4aliphatic), CO₂H, OCF₃, CF₃, COCH₃, —

(C_1-4alkyl)_0-1-O(C_1-4alkyl), —

C_1-4alkyl)_0-1-O(C_1-4alkyl)OH, —

(C_1-4alkyl)_0-1-NH(C_1-4alkyl), —

(C_1-4alkyl)_0-1-N(C_1-4alkyl)₂, —

(C_1-4alkyl)_0-1-NH₂, and —

(C_1-4alkyl)_0-1-(3-7 membered heterocyclyl).

17. The compound according to claim 12, wherein R_o is selected from H, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, t-butyl, COCH₃, —

C_1-4alkyl)-O(C_1-4alkyl), —

(C_1-4alky)-O(C_1-4alkyl)OH, —

(C_1-4alkyl)-NH(C_1-4alkyl), —

(C_1-4alkyl)-N(C_1-4alkyl)₂, —

(C_1-4alkyl)-NH₂, and —

(C_1-4alkyl)_0-1-(3-7 membered heterocyclyl).

18. The compound according to claim 1, wherein each R³ and R⁴ is independently H.

19. The compound according to claim 18 wherein R³ and R⁴ are both H.

20. The compound according to claim 1, wherein R² is 5-8 membered monocyclyl optionally substituted with up to five J^R2.

21. The compound according to claim 20, wherein R² is C_3-8cycloaliphatic optionally substituted with up to five J^R2.

22. The compound according to claim 20, wherein R² is a 5-6 membered aryl or heteroaryl ring, wherein said ring is optionally sulbstituted with up to five J^R2.

23. The compound according to claim 22, wherein R² is a 6-membered aryl or 6-membered heteroaryl ring having 0-2 nitrogen atoms, wherein said ring is optionally substituted with up to five J^R2.

24. The compound according to claim 23, wherein R² is a phenyl, pyridyl, pyrazinyl, or pyrimidyl ring, wherein said ring is optionally substituted with up to five J^R2.

25. The compound according to claim 24, wherein each J^R2 is independently oxo or halo.

26. The compound according to claim 24, wherein each J^R2 is independently selected from C_1-6alkyl, phenyl, —

C_1-6alkyl-(phenyl), 5-6 membered heteroaryl, —

C_1-6alkyl-(5-6 membered heteroaryl), 3-8 membered heterocyclyl, —

C_1-6alkyl-(3-8 membered heterocyclyl), C_1-4haloalkyl, —

OR^o, —

N(R^o)₂, —

SR^o, NO₂, CN, —

(C_1-6alkyl)-OR^o, —

(C_1-6alkyl)-N(R^o)₂, —

(C_1-6alkyl)-SR^o, —

C(O)OR^o, —

NR^oCOR^o, —

COR^o, —

CON(R^o)₂, —

SO₂R^o, —

SO₂N(R^o)₂, and a C_1-6 alkylidene chain wherein up to three methylene units of the chain are independently replaced by —

NR^o—

, —

O—

, —

S—

, —

SO—

, SO₂—

, or —

CO—

;

each J_R2 is independently and optionally substituted with 0-5 R^X.

27. The compound according to claim 26, wherein each J^R2 is selected from —

OR^o, —

N(R^o)₂, —

SR^o, —

(C_1-6alkyl)-OR^o, —

(C_1-6alkyl)-N(R^o)₂, or —

(C_1-6alkyl)-SR^o;

wherein each J^R2 is independently and optionally substituted with 0-5 R^X.

28. The compound according to claim 1 selected from the following:

29. The compound according to claim 1 selected from the following:

30. A composition comprising a compound of claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

31. A method of inhibiting protein kinase activity in a patient comprising administering to said patient a compound of claim 1,

32. A method of inhibiting protein kinase activity in a biological sample comprising contacting said biological sample with a compound claim 1,

33. A method of inhibiting Tec family (Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase activity in a patient comprising administering to said patient a compound of claim 1.

34. A method of inhibiting Tee family (Tec, Btk, Itk/Emt/Tsk, Bmx, Txk/Rlk) kinase activity in a biological sample comprising contacting said biological sample with a compound of claim 1.

35. A method of inhibiting Itk kinase activity in a patient comprising administering to said patient a compound of claim 1.

36. A method of inhibiting Itk kinase activity in a biological sample comprising contacting said biological sample with a compound of claim 1.

37. A method of treating an autoimmune, inflammatory, proliferative, or hyperproliferative disease or an immunologically-mediated disease comprising administering to a patient in need thereof a compound of claim 1.

38. The method of claim 37, comprising the further step of administering to said patient an additional therapeutic agent selected from an agent for the treatment of an autoimmnune, inflammatory, proliferative, hyperproliferative disease, an immunologically-mediated disease, rejection of transplanted organs or tissues, and Acquired Immunodeficiency Syndrome (AIDS), wherein:

said additional therapeutic agent is appropriate for the disease being treated; and

said additional therapeutic agent is administered together with said composition as a single dosage form or separately from said composition as part of a multiple dosage form.

39. A method of treating asthma, acute rhinitis, allergic, atrophic rhinitis, chronic rhinitis, membranous rhinitis, seasonal rhinitis, sarcoidosis, farmer'"'"'s lung, fibroid lung, idiopathic interstitial pneumonia, rheumatoid arthritis, seronegative spondyloarthropathis, ankylosing spondylitis, psoriatic arthritis and Reiter'"'"'s disease, Behcet'"'"'s disease, Sjogren'"'"'s syndrome, systemic sclerosis, psoriasis, systemic sclerosis, atopical dermatitis, contact dermatitis and other eczematous dermatitis, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, epidermolysis bullosa, urticaria, angiodemas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia, areata vernal conjunctivitis, Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, pancreatitis, Crohn'"'"'s disease, ulcerative colitis, food-related allergies, multiple sclerosis, artherosclerosis, acquired immunodeficiency syndrome (AIDS), lupus eythematosus, systemic lupus, erythematosus, Hashimoto'"'"'s thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia purpura, restenosis following angioplasty, tumours, artherosclerosis, systemic lupus erythematosus, allograft rejection, acute and chronic allograft rejection following transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea;

or chronic graft versus host disease comprising administering to a patient in need thereof a compound of claim 1.

40. A process for preparing a compound of formula 4:

41. A process for preparing a compound of formula 10 comprising reacting a compound of formula 4 under suitable cyclopropination conditions to form the compound of formula 10;

42. A process for preparing a compound of formula 11 comprising reacting a compound of formula 4 under suitable epoxide-forming conditions to form the compound of formula 11;

43. A process for preparing a compound of formula 12 comprising reacting a compound of formula 4 under suitable dihydroxylation and oxidizing conditions to form the compound of formula 12;

3-4. -4. (canceled)