HETEROBICYCLIC COMPOUNDS USEFUL AS KINASE INHIBITORS

• US 20110190292A1
• Filed: 04/12/2011
• Published: 08/04/2011
• Est. Priority Date: 11/27/2006
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Wrobleski, Stephen T., Dhar, T. G. Murali
• Granted Patent: US 8,309,571 B2
• Time in Patent Office: Days
• US Class Current: 514/234.2
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• 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 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 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 487/04 Ortho-condensed systems

Abstract

A compound of Formula (I)

and enantiomers, diastereomers and pharmaceutically-acceptable salts thereof. Also disclosed are pharmaceutical compositions containing compounds of Formula I, and methods of treating conditions associated with the activity of p38 kinase.

Claims

1. A compound of Formula (I):

2. A compound according to claim 1 wherein;

R¹ is selected from the group consisting of hydrogen, halo, C1-C6 alkyl, cyano and haloalkyl, wherein the haloalkyls have 1-3 carbons and 1-5 halogens;

R² is selected from the group consisting of hydrogen;

hydroxyl;

halo;

haloalkyl wherein the haloalkyls have 1-3 carbons and 1-5 halogens;

C1-C6 alkoxy;

cyano;

optionally substituted C1-C4 alkyl;

C3-C6 cycloalkyl;

heterocyclo;

aryl selected from phenyl and naphthyl;

heteroaryl selected from pyridyl, thiophene, thiazole, indole, indazole, azaindole, quinoline, thiazole, benzthiazole, benzofuran and benzimidazole; and

—

[C(O)]₂NR⁷R⁸, wherein each of R⁷ and R⁸ is independently selected to be H or an optionally substituted C_1-6 alkyl, or R⁷ and R⁸ can be taken together with the carbons to which they are attached to form an optionally substituted 5-6 membered ring;

R³ is selected from the group consisting of hydrogen and C1-C3 alkyl;

R⁴ is selected from the group consisting of hydrogen;

hydroxyl, halo, haloalkyl wherein the haloalkyls have 1-3 carbons and 1-5 halogens, CO₂R¹¹, CONR¹¹R¹² and NR¹¹R¹² wherein each of R¹¹ and R¹² are independently selected from the group consisting of H, C1-C6 straight or branched chain alkyl, C1-C4 straight or branched chain alkyl amino, C1-C4 straight or branched chain dialkyl amino, C1-C4 straight or branched chain alkyl with an OH group; and

C4-C10 heterocyclo with 1-3 members selected from the group consisting of N, S and O, provided there are no O—

O or S—

S bonds in R⁴ and the heterocyclo group can be optionally substituted with a member selected from the group consisting of C1-C4 alkyl, optionally substituted amino, and alkyl amino;

B is —

(CR⁵R⁶)_q—

wherein R⁵ and R⁶ are each independently selected from the group consisting of H and optionally substituted C1-C4 alkyl;

ring A is a aryl or heteroaryl selected from the group consisting of phenyl, naphthyl, pyridyl, thiophene, indole, indazole, azaindole, quinoline, thiazole, benzthiazole, benzofuran and benzimidazole;

m is 0-2;

n is 0-2; and

q is 0-2.

3. A compound according to claim 2 wherein q is 0.

4. A compound according to claim 1 wherein

Q is a bond when L is —

N— and

M is —

C═

;

ring A is selected from the group consisting of phenyl, indole and pyrrolo[2, 3-b]pyridine;

q is 0;

m is 1 or 2;

n is 1 or 3;

R¹ is selected from the group consisting of halo, halo-C_1-3 alkyl and optionally substituted C_1-3 alkyl;

R² is selected from the group consisting of halo, halo-C_1-3 alkyl, optionally substituted C_1-3 alkyl, C_1-3 alkoxy and —

[C(O)]₂NR⁷R⁸; and

R³ and R⁴ are each hydrogen.

5. A compound according to claim 1 selected from the group consisting of:

6. A compound according to claim 1 wherein:

Q is a bond when L is —

C═ and

M is —

N—

;

q is 0;

R¹ is halo or C_1-3 alkyl;

R² is selected from the group consisting of halo, halo-C_1-3 alkyl, optionally substituted C_1-3 alkyl, optionally substituted C_1-3 alkoxy, and —

[C(O)]₂NR⁷R⁸;

R³ is hydrogen;

R⁴ is hydrogen or —

C(O)NR⁹R¹⁰ wherein —

C(O)NR⁹R¹⁰;

ring A is selected from the group consisting of phenyl, indole, indazole, benzo-imidazole, pyrrolo[2,3-b]pyridine and 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole.

7. A compound according to claim 1 selected from the group consisting of:

8. A compound according to claim 1 wherein:

Q is —

N═

when L and M are both —

C═

;

ring A is an indole;

m is 2;

n is 3;

q is 0;

R¹ is halo;

R² is halo, C_1-3 alkyl or —

[C(O)]₂NR⁷R⁸ wherein each of R⁷ and R⁸ is independently a C_1-3 alkyl; and

R³ and R⁴ are each hydrogen.

9. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

10. A method of treating an inflammatory disorder comprising administering to a patient in need of such treatment a pharmaceutical composition according to claim 1.

11. The method of claim 12, wherein the inflammatory disorder is selected from the group consisting of asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease, chronic pulmonary inflammatory disease, diabetes, inflammatory bowel disease, osteoporosis, psoriasis, graft vs. host rejection, atherosclerosis, multiple myeloma, pain, myocardial ischemia and arthritis including rheumatoid arthritis, psoriatic arthritis, traumatic arthritis, rubella arthritis, gouty arthritis and osteoarthritis.

12. A method of inhibiting p38 kinase in a mammal comprising administering to the mammal in need of such treatment at least one compound according to claim 1.