Heteroaryl compounds useful as inhibitors of protein kinases

• US 20040214928A1
• Filed: 02/03/2004
• Published: 10/28/2004
• Est. Priority Date: 02/07/2003
• Status: Active Grant

• Current Assignee: Vertex Pharmaceuticals Incorporated
• Original Assignee: Vertex Pharmaceuticals Incorporated
• Inventors: Maltais, Francois, Aronov, Alex, Tang, Qing, Hale, Michael R.
• Granted Patent: US 7,407,962 B2
• Time in Patent Office: Days
• US Class Current: 524/90
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• 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 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 31/12 Antivirals
• 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 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 9/10 : 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 401/14 : containing three or more hetero rings
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 487/04 : Ortho-condensed systems

Abstract

The present invention provides compounds that are inhibitors of protein kinase, particularly inhibitors of ERK2, GSK3, PKA, CDK2 protein kinases, mammalian protein kinases involved in proliferative and neurodegenerative disorders. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of utilizing those compositions in the treatment of various disorders.

Claims

1. A compound of formula I:

2. The compound according to claim 1, wherein:

U is selected from a valence bond, —

N(R)—

, —

S—

, —

O—

, —

N(R)N(R)—

, —

N(R)—

O—

, —

O—

N(R)—

, a C_1-4 alkylidene chain, —

N(R)CO—

, or —

N(R)CO₂—

, or;

U—

R¹ and R^x are taken together to form an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R¹ is selected from R, Ar, —

(CH₂)_yCH(R⁵)R³, or —

(CH₂)_yCH(R⁵)CH(R³)₂;

Q is a C_1-4 alkylidene chain wherein one methylene unit of Q is replaced by —

C(O)—

, —

CO₂—

, —

C(O)N(R)—

, —

SO₂—

, —

SO₂N(R)—

, —

OC(O)N(R)—

, —

C(O)ON(R)—

, or —

C(O)N(R)N(R)—

; and

R² is —

(CH₂)_yR³, —

(CH₂)_yCH(R³)₂, —

(CH₂)_yCH(R⁵)CH(R³)₂, or —

(CH₂)_yN(R⁶)₂.

3. The compound according to claim 1, wherein said compound is of formula II or II′

;

4. The compound according to claim 3, wherein said compound is of formula III or III′

;

5. The compound according to claim 3, wherein said compound is of formula formula IV or IV′

;

6. The compound according to either of claims 4 or 5 wherein:

U is selected from a valence bond, —

N(R)—

, —

S—

, —

O—

, —

N(R)N(R)—

, —

N(R)—

O—

, —

O—

N(R)—

, a C_1-4 alkylidene chain, —

N(R)CO—

, or —

N(R)CO₂—

, or;

U—

R¹ and R^x are taken together to form an optionally substituted 5-6 membered saturated, partially unsaturated, or fully unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R¹ is selected from R, Ar, —

(CH₂)_yCH(R⁵)R³, or —

(CH₂)_yCH(R⁵)CH(R³)₂; and

each R³ is independently selected from R, OR⁴, Ar, CO₂R⁴, —

(CH₂)N(R⁶)₂, or CN.

7. A compound according to claim 1, wherein said compound is selected from the group consisting of:

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

9. The composition according to claim 8, additionally comprising a therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, 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.

10. A method of inhibiting ERK2, GSK3, PKA, or CDK2 kinase activity in a biological sample comprising the step of contacting said biological sample with:

a) a compound according to claim 1;

or

b) a composition according to claim 8.

11. A method of inhibiting ERK2, GSK3, PKA, or CDK2 kinase activity in a patient comprising the step of administering to said patient:

a) a compound according to claim 1;

or

b) a composition according to claim 8.

12. A method for treating, or lessening the severity of, a disease or condition selected from 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, stroke, or baldness, wherein said method comprises administering to a patient in need thereof an effective amount of the composition according to claim 8.

13. The method according to claim 11, wherein said disease or condition is stroke.

14. A method for treating or lessening the severity of a neurodegenerative or neurological disorder, wherein said method comprises administering to a patient in need thereof an effective amount of the composition according to claim 8.

15. A method for treating or lessening the severity of a proliferative disorder, a cardiac disorder, an inflammatory disorder, an autoimmune disorder, a viral disease, or a bone disorder, wherein said method comprises administering to a patient in need thereof an effective amount of the composition according to claim 8.

16. A method for treating or lessening the severity of cancer, wherein said method comprises administering to a patient in need thereof an effective amount of the composition according to claim 8.

17. The method according to claim 16, wherein said cancer is selected from brain (gliomas), breast, colon, head and neck, kidney, lung, liver, melanoma, ovarian, pancreatic, prostate, sarcoma, or thyroid.

18. The method according to claim 12, comprising the additional step of administering to said patient an additional therapeutic agent selected from an anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory agent, a neurotrophic factor, an agent for treating cardiovascular disease, 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.