Pyrrolo [3,2-C] pyridines useful as inhibitors of protein kinases

• US 20070213327A1
• Filed: 02/12/2007
• Published: 09/13/2007
• Est. Priority Date: 02/14/2006
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Jimenez, Juan-Miguel, Collier, Philip
• Granted Patent: US 7,659,283 B2
• Time in Patent Office: Days
• US Class Current: 514/227.800
• 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 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• 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 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 : Otologicals
• 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 3/14 : for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 31/08 : for leprosy
• CPC Class Codes: A61P 31/12 : Antivirals
• 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 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/04 : Immunostimulants
• 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 5/00 : Drugs for disorders of the endocrine system
• 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: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• 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 R² is H.

3. The compound according to claim 1 or claim 2, wherein R¹ is Q.

4. The compound according to any one of claims 1-3, wherein Q is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from O, N, and S;

5. The compound according to claim 4, wherein Q is a 3-8-membered saturated monocyclic ring having 0-3 heteroatoms independently selected from O, N, and S.

6. The compound according to claim 5, wherein Q is a 3-8-membered saturated monocyclic ring having 0 heteroatoms.

7. The compound according to claim 6, wherein Q is cyclohexyl or cyclopentyl.

8. The compound according to any one of claims 1-7, wherein J^Q is a 3-8 membered heterocyclyl.

9. The compound according to claim 8, wherein J^Q is a 6-membered heterocyclyl containing 1-2 nitrogen atoms.

10. The compound according to any one of claims 1-9, wherein ring A is fully unsaturated (i.e., aromatic).

11. The compound according to any one of claims 1-9, wherein ring A is partially unsaturated or saturated.

12. The compound according to claim 10 or claim 11, wherein Ring A is a monocyclic ring.

13. The compound according to claim 12, wherein Ring A is a 5-membered ring.

14. The compound according to claim 12, wherein Ring A is a 6-membered ring.

15. The compound according to claim 13 or 14, wherein -T-R⁵ is meta or para substituted.

16. The compound according to anyone of claims 10-15, wherein Ring A is a bicyclic ring.

17. The compound according to anyone of claims 10-16, wherein T is —

C(O)NR—

or —

NRC(O)—

.

18. The compound according to claim 17, wherein R is H.

19. The compound according to claim 12 or claim 16, wherein R⁵ is a 3-8-membered saturated, partially unsaturated, or fully unsaturated monocyclic ring having 0-3 heteroatoms independently selected from O, N, and S;

or an 8-12 membered saturated, partially unsaturated, or fully unsaturated bicyclic ring having 0-5 heteroatoms independently selected from O, N, and S.

20. The compound according to claim 19, wherein R⁵ is fully unsaturated (i.e., aromatic).

21. The compound according to claim 19, wherein R⁵ is partially unsaturated or saturated.

22. The compound according to any one of claims 12-21, wherein R⁴ is H, halo, C_1-6 aliphatic, C_3-6cycloaliphatic, NO₂, CN, —

NH₂, —

NH(C_1-4 aliphatic), —

N(C_1-4 aliphatic)₂, —

OH, —

O(C_1-4 aliphatic), CONH₂, CONH(C_1-4 aliphatic), CON(C_1-4 aliphatic)₂, COH, —

CO(C_1-4 aliphatic), —

CO₂H, —

CO₂(C_1-4 aliphatic), —

O(haloC_1-4 aliphatic), or halo(C_1-4 aliphatic).

24. A composition comprising a compound of any one of claims 1-23, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

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

a) a composition of claim 24;

or

b) a compound of any one of claims 1-23.

26. The method of claim 25, wherein said protein kinase is Lck.

27. A method of treating an autoimmune disease, an inflammatory disease, a bone disease, a metabolic disease, a neurological or neurodegenerative disease, cancer, a cardiovascular disease, allergies, asthma, Alzheimer'"'"'s disease, or a hormone-related disease in a patient, comprising the step of administering to the patient:

a) a composition of claim 24;

or

b) a compound of any one of claims 1-23.

28. The method of claim 27, wherein said disease is an autoimmune disease, an inflammatory disease, a proliferative or hyperproliferative disease, or an immunologically-mediated disease.

29. The method according to claim 27 or claim 28, comprising administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, a treatment for Alzheimer'"'"'s disease, a treatment for Parkinson'"'"'s disease, an agent for treating Multiple Sclerosis (MS), a treatment for asthma, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating destructive bone disorders, an agent for treating liver disease, an anti-viral agent, an agent for treating blood disorders, an agent for treating diabetes, or an agent for treating immunodeficiency disorders, wherein:

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

b) 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.

30. 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 (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, 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 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;

or chronic graft versus host disease comprising administering to a patient in need thereof

a) a composition of claim 24;

or

b) a compound of any one of claims 1-23.

31. A method of treat an autoimmune disease, allergies, rheumatoid arthritis, or leukemia comprising the step of administering to the patient:

a) a composition of claim 24;

or

b) a compound of any one of claims 1-23.

33. A composition for coating an implantable device comprising a compound according to any one of claims 1-23 and a carrier suitable for coating said implantable device.

34. An implantable device coated with a composition according to claim 33.

23. A compound selected from the following:

32. A method of treating hypercalcemia, restenosis, osteoporosis, osteoarthritis, symptomatic treatment of bone metastasis, rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, lupus, graft vs. host disease, T-cell mediated hypersensitivity disease, Hashimoto'"'"'s thyroiditis, Guillain-Barre syndrome, chronic obstructive pulmonary disorder, contact dermatitis, cancer, Paget'"'"'s disease, asthma, ischemic or reperfusion injury, allergic disease, atopic dermatitis, or allergic rhinitis.