Compositions useful as inhibitors of rock and other protein kinases

• US 20060019956A1
• Filed: 04/27/2005
• Published: 01/26/2006
• Est. Priority Date: 04/28/2004
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Green, Jeremy
• Granted Patent: US 7,531,556 B2
• Time in Patent Office: Days
• US Class Current: 514/241
• 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 11/06 Antiasthmatics
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 15/10 for impotence
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 27/14 Decongestants or antiallergics
• 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 31/14 for RNA viruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• 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 9/00 : 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 9/12 : Antihypertensives
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07F 9/65583 : each of the hetero rings containing nitrogen as ring hetero atom

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.

Claims

1. A compound of formula I:

2. The compound according to claim 1, wherein Ring B is a 5-membered heteroaryl ring selected from pyrazole, imidazole, triazole, tetrazole, furan, oxazole, isoxazole, or oxadiazole, wherein Ring B is optionally substituted with 0-2 R⁴ groups.

3. The compound according to claim 2, wherein Ring B is selected from any of the following:

4. The compound according to claim 1, wherein said compound is of formula II:

5. The compound according to claim 1, wherein said compound is of formula III:

6. The compound according to either of claims 4 or 5, wherein Ar¹ is selected from:

7. The compound according to claim 1, wherein said compound is of formula IV:

8. The compound according to claim 1, wherein said compound is of formula V:

9. The compound according to claim 8, wherein said compound is selected from the following formulae V-A′

, V-B′

, V-C′

, V-D′

, or V-E′

;

10. The compound according to claim 1, wherein said compound is selected from the following formulae VI-A, VI-B, VI-C, VI-D, or VI-E:

11. The compound according to claim 1, wherein G is —

NR²-Q¹- and R² and Q¹-R³, taken together with the nitrogen atom, form the cyclic group;

12. The compound according to claim 10, wherein said compound is selected from the following formulae VII-A, VII-B, VII-C, VII-D, or VII-E:

13. The compound according to claim 10, wherein said compound is selected from the following formulae VII-A′

, VII-B′

, VII-C′

, VII-D′

, or VII-E′

;

14. The compound according to claim 10, wherein R² and Q¹-R³, taken together with the nitrogen atom, form a cyclic group:

15. The compound according to claim 10, wherein R² and Q¹-R³, taken together with the nitrogen atom, form a cyclic group:

16. The compound according to claim 1, wherein:

each occurrence of R¹ is optionally substituted C₁-C₄aliphatic, OH, OR, SR, or N(R)₂.

each R is independently hydrogen, or is U_(n)R′

, where n is 1, and U is —

CH₂—

, —

CH₂CH₂—

, —

CH₂CH₂CH₂—

, —

CH₂CH₂CH₂CH₂—

, —

CH₂O—

, —

CH₂S—

, —

CH₂NR—

, —

CH₂CH₂O—

, —

CH₂CH₂S—

, —

CH₂CH₂NR—

, —

CH₂CH₂CH₂O—

, —

CH₂CH₂CH₂S—

, —

CH₂CH₂CH₂NR—

, —

CH₂CH₂CH₂CH₂O—

, —

CH₂CH₂CH₂CH₂S—

, —

CH₂CH₂CH₂CH₂NR—

, —

CH₂CH₂OCH₂CH₂—

, —

(CH₂)₄NHCH₂—

, —

(CH₂)₃NHCH₂CH₂—

, or —

CH₂CH₂NHCH₂CH₂—

,

each R′

is independently hydrogen, C₁-C₄alkyl, an optionally substituted group selected from tetrahydropyranyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, pyridinyl, imidazolyl, phenyl, or cyclohexyl, or;

R and R′

, taken together with the nitrogen atom to which they are bound, form an optionally substituted 5- or 6-membered saturated, partially unsaturated, or unsaturated heterocyclyl ring;

each occurrence of R⁴ is independently hydrogen, C_1-6aliphatic, CN, C(O)R, C(O)OR, C(O)N(R)₂, or halogen;

each q is independently 1, 2, or 3; and

each R⁶ is independently R′

, —

N(R)(R′

), —

(CH₂)_1-4N(R)(R′

), —

(CH₂)_1-4C(CH₃)₂N(R)(R′

), —

OR′

, —

(CH₂)_1-4OR′

, —

NR(CH₂)_1-4N(R)(R′

), —

NR(CH₂)_1-4SO₂R′

, —

NR(CH₂)_1-4C(O)OR′

, or —

NR(CH₂)_1-4COR′

, or;

two occurrences of R⁶, taken together with the atoms to which they are bound, form an optionally substituted 3-6-membered saturated, partially unsaturated, or fully unsaturated ring;

17. The compound according to claim 16, wherein:

Q¹ is —

C(O)—

, —

C(O)NR²—

, —

NR²—

, —

SO₂—

, or —

SO₂NR²—

;

Q² is a direct bond, or is —

(CHR⁶)_q—

, (CHR⁶)_qO—

, —

(CHR⁶)_qS—

, —

(CHR⁶)_qS(O)₂—

, —

(CHR⁶)_qS(O)—

, —

(CHR⁶)_qNR—

, or —

(CHR⁶)_qC(O)—

, wherein each q is independently 0, 1, 2, or 3; and

Ar¹ is selected from;

wherein each t is independently 0, 1, 2, 3, 4, or 5, and wherein any Ar¹ is bonded to Q² through any substitutable nitrogen or carbon atom.

18. The compound according to claim 3, wherein R³ is selected from any of the following:

20. A composition comprising an effective amount of compound of claim 1, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

21. The composition of claim 20, additionally comprising a therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, 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.

22. A method of inhibiting ROCK, ERK, GSK, or AGC 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 or a composition of claim 20.

23. The method of claim 22, wherein the method comprises inhibiting ROCK activity.

24. A method of treating or lessening the severity of a disease condition or disorder selected from a proliferative disorder, a cardiac disorder, a neurodegenerative disorder, a psychotic disorder, an autoimmune disorder, a condition associated with organ transplant, an inflammatory disorder, an immunologically mediated disorder, a viral disease, or a bone disorder, comprising the step of administering to said patient a compound of claim 1 or a composition of claim 20.

25. The method of claim 24, comprising the additional step of administering to said patient an additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an anti-psychotic agent, 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:

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.

26. The method of claim 24, wherein disease, condition, or disorder is allergy, asthma, diabetes, Alzheimer'"'"'s disease, Huntington'"'"'s disease, Parkinson'"'"'s disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML, Lou Gehrig'"'"'s disease), multiple sclerosis (MS), schizophrenia, cardiomyocyte hypertrophy, reperfusion/ischemia (e.g., stroke), baldness, cancer, hepatomegaly, cardiovascular disease including cardiomegaly, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, inflammation, hypertension, angina pectoris, cerebrovascular contraction, peripheral circulation disorder, premature birth, arteriosclerosis, vasospasm (cerebral vasospasm, coronary vasospasm), retinopathy, erectile dysfunction (ED), AIDS, osteoporosis, Crohn'"'"'s Disease and colitis, neurite outgrowth, or Raynaud'"'"'s Disease.

27. The method of claim 24, wherein disease, condition, or disorder is atherosclerosis, hypertension, erectile dysfunction (ED), reperfusion/ischemia (e.g., stroke), or vasospasm (cerebral vasospasm and coronary vasospasm).

19. A compound selected from the group consisting of: