Pyridones useful as inhibitors of kinases

• US 20070155794A1
• Filed: 08/29/2006
• Published: 07/05/2007
• Est. Priority Date: 08/29/2005
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Durrant, Steven, Charrier, Jean-Damien, Ramaya, Sharn
• Granted Patent: US 7,691,885 B2
• Time in Patent Office: Days
• US Class Current: 514/337
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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 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 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 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links

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 when R² is 2-pyridyl and R³ and R⁴ are H;

Q-Q¹ is not

3. The compound according to claim 1 or claim 2, wherein Q is

4. The compound according to claim 1 or claim 2, wherein Q¹ is phenyl optionally substituted with 0-5 J^Q.

5. The compound according to claim 4, wherein Q-Q¹ is

6. The compound according to claim 5, wherein

Q-Q¹ 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, C_6-10aryl, —

C_1-6alkyl-(C_6-10aryl), 5-12 membered heteroaryl, —

C_1-6alkyl-(5-12 membered heteroaryl), 3-12 membered heterocyclyl, —

C_1-6alkyl-(3-12-membered heterocyclyl), C_3-10cycloaliphatic, —

C_1-6alkyl-(C_3-10cycloaliphatic), —

C(O)OR^o, —

NR^oCOR^o, —

COR^o, —

CON(R^o)₂, —

SO₂R^o, or —

SO₂N(R^o)₂;

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

OR^o, —

N(R^o)₂, —

SR^o, 3-8 membered heterocyclyl, —

C(O)OR^o, —

NR^oCOR^o, —

COR^o, —

CON(R^o), —

SO₂R^o, or —

SO₂N(R^o)₂;

wherein each J^Q is optionally and independently substituted witlh (0-5 R^X.

8. The compound according to claim 7, wherein J^Q is —

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

9. The compound according to claim 8, wherein J^Q is a group selected from piperidinyl, piperazinyl, and pyrrolidinyl wherein said group is optionally substituted with 0-5 R^X.

10. The compound according to claim 1 or claim 2, wherein R^X is selected from H, metlyl, 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).

11. The compound according to claim 1 or claim 2, 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_1-4alkyl)-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).

12. The compound according to claim 1 or claim 2, wherein each R³ and R⁴ is independently H.

13. The compound according to claim 12, wherein R³ and R⁴ are both H.

14. The compound according to claim 1 or claim 2, wherein R² is 5-8 membered monocyclyl optionally substituted with up to five J^R2.

15. The compound according to claim 14, wherein R² is C_3-8cycloaliphatic optionally substituted with up to five J^R2.

16. The compound according to claim 14, wherein R² is a 5-6 membered aryl or heteroaryl ring, wherein said ring is optionally substituted with up to five J^R2.

17. The compound according to claim 16, wherein R² is an optionally substituted 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.

18. The compound according to claim 17, wherein R² is a phenyl, pyridyl, pyrazinyl, or pyrimidyl ring, wherein said ring is optionally substituted with up to five J^R2.

19. The compound according to claim 18, wherein R² is a phenyl, 3-pyridyl, 4-pyridyl, pyrazinyl, 2,4-pyrimidyl, or 3,5-pyrimidyl ring, wherein said ring is optionally substituted with up to five J^R2.

20. The compound according to claim 14, wherein each J^R2 is selected from halo, C_1-6alkyl, C_6-10aryl, —

C_1-6alkyl-C_6-10aryl, C_1-4haloalkyl, —

OR^o, —

N(R^o)₂, —

SR^o, NO₂, CN, 3-10 membered -heterocyclyl, —

(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, or 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—

in a chemically stable arrangement;

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

21. The compound according to claim 20, 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.

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

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

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

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

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

27. A method of inhibiting Tec 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.

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

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

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

31. The method of claim 30, comprising the further step of administering to said patient an additional therapeutic agent selected from an agent for the treatment of an autoimmune, inflammatory, proliferative, hyperproliferative disease, or 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.

32. 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, Reiter'"'"'s disease, Behcet'"'"'s disease, Sjogren'"'"'s syndrome, systetnic sclerosis, psoriasis, systemic sclerosis, atopical dermatitis, contact dermatitis and other eczematous dermatitis, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullotis Pemphigus, epidermolysis bullosa, urticaria, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia, areata vernal conjunctivitis, Coeliaic disease, proctitis, eosinophilic gastroenteritis, mastocytosis, pancreatitis, Crohn'"'"'s disease, ulcerative colitis, food-related allergies, multiple sclerosis, artherosclerosis. acquired immunodeficiency syndrome (AIDS), lupus erythernatosus, 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.

33. A process for preparing a compound of formula I:

34. The process of claim 33, wherein the compound of formula 3 is prepared, comprising

b) coupling a compound of formula 1 with R²-A²;

wherein A¹ and A² are corresponding coupling functional groups;

to form a compound of formula 2;

wherein R² is as defined according to claim 1;

c) iodinating the compound of formula 2 under suitable conditions to form a compound of formula 3;

wherein R² is as defined according to claim 1.

35. A compound of formula I′

36. The compound according to claim 35, 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, —

SO₂R^o, or —

SO₂N(R^o)₂;

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