PYRIDONES USEFUL AS INHIBITORS OF KINASES

• US 20120190699A1
• Filed: 12/14/2011
• Published: 07/26/2012
• Est. Priority Date: 12/16/2004
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Charrier, Jean-Damien, Durrant, Steven, Ramaya, Sharn, Jimenez, Juan-Miguel, Rutherford, Alistair
• Granted Patent: US 8,338,597 B2
• Time in Patent Office: Days
• US Class Current: 514/274
• 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 17/18 Antioxidants, e.g. antiradicals preparations for protection against sunlight A61Q17/00
• 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 25/06 Antimigraine agents
• 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 31/18 : for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• 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 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• 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: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07D 213/22 : containing two or more pyridine rings directly linked together, e.g. bipyridyl
• CPC Class Codes: C07D 213/75 : Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 213/76 : to which a second hetero atom is attached nitro radicals C07D213/61
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 213/84 : Nitriles
• CPC Class Codes: C07D 213/85 : in position 3
• 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 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/14 : containing three or more hetero rings
• CPC Class Codes: C07D 409/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention relates to compounds useful as inhibitors of protein kinases. 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 the compounds of the invention and intermediate compounds useful in these processes.

Claims

1. A compound of formula I:

2. The compound according to claim 1 wherein T is C_1-3aliphatic optionally interrupted with zero or one G groups wherein G is selected from O, NR⁵, and S.

3. The compound according to claim 1 wherein T is —

C_1-2aliphatic-G- wherein G is O or NR⁵, and G is bound to Q in a chemically stable arrangement.

4. The compound according to claim 1 wherein T is C_1-3aliphatic optionally interrupted with zero G groups.

5. The compound according to claim 1 wherein T is C_1-3aliphatic optionally interrupted with zero or one G′

groups.

6. The compound according to claim 1 wherein T is —

CH₂—

.

7. The compound according to claim 1 wherein T is a bond.

8. The compound according to any one of claims 1-7 wherein each R³ and R⁴ is independently H.

9. The compound according to claim 8 wherein R³ and R⁴ are both H.

23. The compound according to claim 1 wherein R² is a 2-4 pyrimidinyl optionally substituted with up to five J^R groups.

28. The compound according to claim 1 wherein each J^R is selected from oxo or ═

NOH.

29. The compound according to claim 1 wherein each J^R is selected from 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, 3-12 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_1-6alkyl 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^R is independently and optionally substituted with R^o.

30. The compound according to claim 29 wherein each J^R is independently and optionally substituted with R^o and 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.

31. The compound according to claim 29 wherein each J^R is independently selected from optionally substituted 5-8 membered heterocyclyl, optionally substituted —

NR(C_1-4alkyl)N(R^o)₂, optionally substituted —

NR(C_1-4alkyl)OR^o, —

N(R^o)₂, or optionally substituted —

NH(5-6 membered heterocyclyl).

32. The compound according to claim 31 wherein each J^R is independently selected from optionally substituted —

NH(5-6 membered heterocyclyl).

33. The compound according to claim 32 wherein the 5-6 membered heterocyclyl contains 1-2 nitrogen atoms.

34. The compound according to claim 33 wherein the 5-6 membered heterocyclyl is selected from pyrrolidine, piperidine, or piperazine.

35. The compound according to claim 1 wherein each X¹ and X² is independently —

C(O)—

or —

NR—

wherein one of X¹ or X² is —

NR— and

the other of X¹ or X² is —

C(O)—

.

36. The compound according to claim 35 wherein X¹ is C(O) and X₂ is NR.

37. The compound according to claim 35 wherein X¹ is NR and X₂ is C(O).

38. The compound according to claim 1 wherein Q a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring system having 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

39. The compound according to claim 38 wherein Q is C_6-10 aryl, C_3-10 cycloaliphatic, 5-14 membered heteroaryl, or 5-14 membered heterocyclyl.

40. The compound according to claim 39 wherein Q is C_6-10 aryl or 5-14 membered heteroaryl.

41. The compound according to claim 40 wherein Q is a 5-6 membered aryl or heteroaryl.

42. The compound according to claim 41 wherein Q is phenyl.

43. The compound according to claim 1 wherein Q is substituted with up to 3 J^Q groups wherein each J^Q is selected from CN, 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, C_3-10cycloaliphatic, —

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

C_1-6alkyl-(C_3-10heterocyclyl), —

C(O)OR^o, —

NR^oCOR^o, —

COR^o, —

CON(R^o)₂, —

SO₂R^o, —

SO₂N(R^o)₂, or C_1-6alkyl wherein up to three methylene units are optionally and independently replaced by, —

NR^o—

, —

O—

, —

S—

, —

SO—

, SO₂—

, —

CO—

, cyclopropyl, C≡

C, or C═

C in a chemically stable arrangement;

each J^Q is optionally and independently substituted with R^o.

44. The compound according to claim 43 wherein each J^Q is —

SO₂N(R^o)₂, —

SO₂R^o, —

NR^oC(O)OR^o, —

C≡

C—

R^o, —

C═

C—

R^o, phenyl, —

O-Ph, —

O—

CH₂Ph, C_5-6heteroaryl, C_3-7heterocyclyl, or C_3-7cycloaliphatic.

45. The compound according to claim 43 wherein each J^Q is CN, C_1-6alkyl, —

CF₃, —

OCF₃, —

OR^o, —

N(R^o)₂, —

SR^o, —

CH₂-halogen, —

SCF₂, —

(C_1-6alkyl)-N(R^o)₂, C₆aryl, C_5-6heteroaryl, —

C(O)OR^o, —

NR^oCOR^o, —

COR^o, or —

CON(R^o)₂.

46. The compound according to any one of claims 38-45 wherein R^o is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, sec-butyl, n-butyl, t-butyl, OH, halogen, —

CH₂-pyrrolidine, 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, or —

(C_1-4alkyl)_0-1-NH₂.

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

50. A method of inhibiting Tec family kinase activity in:

(a) a patient;

or

(b) a biological sample;

which method comprises administering to said patient, or contacting said biological sample with a compound of claim 1.

51. The method of claim 50, wherein the method comprises inhibiting Itk kinase activity.

52. A method of treating or lessening the severity of a disease or condition selected from an autoimmune, inflammatory, proliferative, or hyperproliferative disease or an immunologically-mediated disease comprising administering to a patient in need thereof a compound according to claim 1.

53. The method of claim 52, wherein the disease or disorder is asthma, acute rhinitis, allergic, atrophic rhinitis, chronic rhinitis, membranous rhinitis, seasonal rhinitis, sarcoidosis, farmer'"'"'s lung, fibroid lung, idiopathic interstitial pneumonia, rheumatoid arthritis, seronegative spondyloarthropathic (including 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, angiodermas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia, greata 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 erythematosus, 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 including, without limitation, acute and chronic allograft rejection following for example transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea;

and chronic graft versus host disease.

10-22. -22. (canceled)

24-27. -27. (canceled)

47. A compound selected from the following:

48. A compound selected from the following I-82 to I-85, II-88, II-89, II-90, II-91, II-92 to II-182, III-11 to III-54, IV-1.

54-55. -55. (canceled)