IP Library › Granted Patent US 7,196,095
Granted Patent B2
US 7,196,095 · App. 10/477,367 · Granted Mar 27, 2007

(Pyrimidinyl) (phenyl) substituted fused heteroaryl p38 inhibiting and PKG kinase inhibiting compounds

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Quick Facts
Patent No.
US 7,196,095
App. No.
10/477,367
Granted
Mar 27, 2007
Kind
B2
Abstract

Compounds of formula (I) and pharmaceutically acceptable salts thereof are useful in the treatment of cytokine mediated diseases such as arthritis and in the treatment and/or prevention of protozoal diseases such as coccidiosis

Claims (384)

1. A compound of the formula (I):

or a pharmaceutically acceptable salt thereof,

wherein FusedHet is

R 1 is H,

—C 1-6 alkyl,

—C(O)(C 1-6 alkyl),

—C(O)—C 1 6 alkyl-aryl,

—C 0-4 alkyl-aryl,

—C 0-4 alkyl-indanyl,

C 0-4 alkyl-imidazolyl,

—C 0-4 alkyl-thiazolyl,

—C 0-4 alkyl-pyrazolyl,

—C 0-4 alkyl-oxadiazolyl,

—C 0 4 alkyl-C 3 6 cycloalkyl,

—C 0-4 alkyl-C 1 4 alkoxy,

—C 1-4 alkyl-N(C 0-4 alkyl)(—C 0-4 alkyl),

—C 1-4 alkyl-N(—C 0-4 alkyl)—CO—C 1-4 alkoxy,

C 1-4 alkyl-piperadinyl,

—C 0-4 alkyl-triazolyl,

—C 1-4 alkyl-imidazothiazolyl,

—C 1 4 alkyl-benzimidazolyl,

—C 1-4 alkyl-benzothiazolyl,

—C 1-4 alkyl-benzotetrahydrofuranyl,

C 1-4 alkyl-benzodioxolyl,

—C 1 4 alkyl-(heterocycloC 4 O 2 alkyl),

—C 1-4 alkyl-(heterocycloC 5 O 1 alkyl),

—C 1-4 alkyl-tetrahydrofuran, or

—C 1-4 alkyl-oxetanyl;

R 11 is H or C 1-6 alkyl;

or R 1 and R 11 , together with the N to which they are attached, form a morpholinyl;

R 2 , R 21 , R 22 each independently is H, halogen, or —C 1-4 alkyl;

R 3 is H,

—C 1-4 alkyl,

—C 3-6 cycloalkyl,

—C 1-4 alkyl-aryl,

—C 1-4 alkyl-azetidinyl,

—C 1-4 alkyl-azetidinyl-CO—C 0-4 alkyl-N(C 0-4 alkyl)(C 0-4 alkyl),

—C 1-4 alkyl-pyrrolidinyl,

—C 1 4 alkyl-piperidinyl,

—C 1-4 alkyl-morpholinyl,

—C 1-4 alkyl-N(C 0-4 alkyl)(C 0-4 alkyl),

—C 0-4 alkyl-N(C 0-4 alkyl)(C 0-4 alkyl-C 1-4 alkoxy),

—C 0-4 alkyl-N(C 0-4 alkyl-C 1-4 alkoxy)(C 0-4 alkyl-C 1-4 alkoxy),

—C 1-4 alkyl-N(C 0-4 alkyl)—(C 1-4 alkyl)-aryl,

—C 1-4 alkyl-N(C 0-4 alkyl)—C 1-4 alkyl-tetrahydrofuranyl,

—C 1-4 alkyl-N(C 0-4 alkyl)—C 1-4 alkyl-azetidinyl,

—C 1-4 alkyl-N(C 0-4 alkyl)—C 1-4 alkyl-N(C 0-4 alkyl)(C 0-4 alkyl),

—C 1-4 alkyl-N(C 0-4 alkyl)—C 1-4 alkyl-N(C 0-4 alkyl)—C 0-4 alkyl-SO 2 C 1-4 alkyl),

—CO—N(C 0-4 alkyl)—C 1-4 alkyl-aryl,

CO N(C 0-4 alkyl)—C 1-4 alkyl-N(C 0-4 alkyl)(C 0-4 alkyl),

—C 0-4 alkyl-CO—C 0-4 alkyl,

—C 0-4 alkyl-CO—C 0-4 alkoxy,

—C 0-4 alkyl-CO—N(C 0-4 alkyl)—C 1-4 alkyl-C 1-4 alkoxy,

—C 0-4 alkyl-CO—N(C 0-4 alkyl)—C 1-4 alkyl-aryl,

—C 0-4 alkyl-CO-piperidinyl,

—C 1-4 alkyl-N(C 0-4 alkyl)—C 0-4 alkyl-CO—C 0-4 alkyl-N(C 0-4 alkyl)(C 0-4 alkyl),

C 0-4 alkyl-CO—C 0-4 alkyl-N(C 0-4 alkyl)(C 0-4 alkyl),

O C 1-4 alkyl-aryl,

C 1-4 alkyl O C 1-4 alkyl,

—C 0-4 alkyl-N(C 0-4 alkyl)—C 0-4 alkyl-CO—C 0-4 alkyl,

—C 0-4 alkyl-N(C 0-4 alkyl)—C 0-4 alkyl-CO—C 0-4 alkoxy,

—C 0-4 alkyl-N(C 0 4 alkyl)—C 0-4 alkyl-CO—C 0-4 alkyl-aryl,

—C 0 4 alkyl-N(C 0-4 alkyl)—C 0-4 alkyl-CO—C 0-4 alkyl(aryl) 2 ,

—C 0-4 alkyl-N(C 0-4 alkyl)—C 0-4 alkyl-CO—C 0-4 alkyl-pyrrolyl,

—C 0-4 alkyl-N(C 0-4 alkyl)—C 0-4 alkyl-CO—C 0-4 alkyl-pyrrolidinyl,

—C 0-4 alkyl-N(C 0-4 alkyl)—C 0-4 alkyl-CO—C 0-4 alkyl-azetidinyl,

—C 0-4 alkyl-N(C 0-4 alkyl) C 0-4 alkyl-CO—C 2-4 alkenyl-pyrrolidinyl,

—C 0-4 alkyl-N(C 0-4 alkyl) C 0-4 alkyl-CO C 0-4 alkyl thiophenyl,

—C 0-4 alkyl-N(C 0-4 alkyl)—C 0-4 alkyl-CO—C 2-4 alkenyl-thiophenyl,

—C 0-4 alkyl-N(C 0-4 alkyl)—C 0-4 alkyl-CO—S—C 1-4 alkyl-aryl,

—C 0-4 alkyl-N(C 0-4 alkyl)—C 0-4 alkyl-CO—C 3-6 cyclolkyl,

—C 0 4 alkyl-N(C 0-4 alkyl)—C 0-4 alkyl-CO—O—C 1-4 alkyl-aryl,

—C 0-4 alkyl-CO—N(C 0-4 alkyl)—C 0-4 alkyl-C 1-4 alkoxy,

—C 1-4 alkyl-N(C 0-4 alkyl)(—SO 2 C 1-4 alkyl),

C 0-4 alkyl-N(C 0-4 alkyl)—C 1-4 alkyl-SO 2 C 1-4 alkyl,

—C 0-4 alkyl-S—C 1-4 alkyl-aryl,

—C 1-4 alkyl-PO(C 1-4 alkoxy)(C 1-4 alkoxy),

—C 1-4 alkyl-azetidinyl-CO—N(C 0-4 alkyl)(C 0-4 alkyl),

—C 1-4 alkyl-(heterocycloC 4 N 1 O 1 alkyl),

—C 0 4 alkyl-CO—(heterocycloC 5 N 1 alkyl),

—C 0-4 alkyl-CO—N(C 0-4 alkyl)-(heterocycloC 5 N 1 alkyl),

—C 1-4 alkyl-(heterocycloC 4 N 2 alkyl)—C 1-4 alkyl,

C 1-4 alkyl-(heterocycloC 4 N 2 alkyl)—CO—C 0-4 alkoxy,

—C 1-4 alkyl-(heterocycloC 4 N 2 alkyl)—C 1-4 alkyl-N(C 0-4 alkyl)(C 0-4 alkyl),

—C 1-4 alkyl-(heterobicycloC 5 N 2 alkyl)—C 1-4 alkyl, or

—C 1-4 alkyl-NH-(heterobicycloC 7 N 1 alkyl); and

R 4 is —C 1-6 alkyl;

wherein any of the above aryl, hetaryl, cycloalkyl, or heterocycloalkyl optionally is substituted with 1–4 substituents, each substituent independently is halogen, NO 2 , —CN, —C 1-4 alkyl, —C 0-4 alkoxy, S C 1-4 alkyl, or C 0-4 alkyl-(CO)—C 0-4 alkoxy: and any of the above alkyl optionally is substituted with 1–4 substituents, each substituent independently is halogen, —N 3 , —CN, —COOH, or —C 0-4 alkoxy.

2. The compound according to claim 1 , wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.

3. The compound according to claim 1 , wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.

4. The compound according to claim 1 , wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.

5. The compound according to claim 1 , wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.

6. The compound according to claim 1 , wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.

7. The compound according to claim 1 , wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.

8. The compound according to claim 1 , wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.

9. The compound according to claim 1 , wherein FusedHet is

or a pharmaceutically acceptable addition salt thereof.

10. The compound according to claim 1 represented by

or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 1 represented by:

wherein Ar, R, and Z are

Ar Group

R Group

Z Group

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 OH

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

CH 2 OH

2,4-Difluorophenyl

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 OCH 3

3-Trifluoromethylphenyl

NHCH 2 C(CH 3 ) 3

3-Trifluoromethylphenyl

NHCH 2 C(CH 3 ) 3

3-Trifluoromethylphenyl

NHCH 2 C(CH 3 ) 3

3-Trifluoromethylphenyl

NHCH 2 C(CH 3 ) 3

CH 2 OH

3-Trifluoromethylphenyl

NHCH 2 C(CH 3 ) 3

CH 2 N(CH 3 ) 2

2-Chloro-4-fluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 OH

2-Chloro-4-fluorophenyl

NHCH 2 C(CH 3 ) 3

CHO

2-Chloro-4-fluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 N(CH 3 ) 2

2-Chlorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 OH

2-Chlorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 N(CH 3 ) 2

4-Chlorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 OH

4-Chlorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 N(CH 3 ) 2

3,4-Dichlorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 OH

3,4-Dichlorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 N(CH 3 ) 2

2,3-Dichlorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 OH

2,3-Dichlorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 N(CH 3 ) 2

4-Fluorophenyl

NHCH 2 C(CH 3 ) 3

H

4-Fluorophenyl

NHCH 2 C(CH 3 ) 2 CH 2 OH

H

4-Fluorophenyl

NHCH 2 C(CH 3 ) 2 CH 2 OH

CH 2 NHCH 3

4-Fluorophenyl

NHCH 2 C(CH 3 ) 2 CH 2 OH

CH 2 N(CH 3 )SO 2 CH 3

4-Fluorophenyl

CH 3

4-Fluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 NHSO 2 CH 3

4-Fluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 N(CH 3 )SO 2 CH 3

4-Fluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 PO(OMe) 2

4-Fluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 SO 2 CH 3

4-Fluorophenyl

NHCH 2 C(CH 3 ) 3

CHO

or a pharmaceutically acceptable salt thereof.

12. The compound according to claim 1 represented by:

wherein Ar and R are:

Ar Group

R Group

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

3-Trifluoromethylphenyl

NHCH 2 C(CH 3 ) 3

3-Trifluoromethylphenyl

3-Trifluoromethylphenyl

NH(CH 2 ) 3 OCH 3

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

NHCH 2 C(CH 3 ) 2 CH 2 OH

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

NH(CH 2 ) 3 OCH 3

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

4-Fluorophenyl

or a pharmaceutically acceptable salt thereof.

13. The compound according to claim 1 represented by:

R Group

Z Group

NHCH 2 C(CH 3 ) 3

CON(OMe)Me

NHCH 2 C(CH 3 ) 3

CHO

NHCH 2 C(CH 3 ) 3

CH 2 OH

NHCH 2 C(CH 3 ) 3

CH 2 N(CH 3 ) 2

CON(OMe)Me

CHO

CH 2 OH

CH 2 N(CH 3 ) 2

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 represented by:

wherein Ar, R, and Z are

Ar Group

R Group

Z Group

4-Fluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 OH

4-Fluorophenyl

NHCH 2 C(CH 3 ) 3

CON(OMe)Me

3-Trifluoromethylphenyl

NHCH 2 C(CH 3 ) 3

CON(OMe)Me

3-Trifluoromethylphenyl

NHCH 2 C(CH 3 ) 3

CH 2 N(CH 3 ) 2

2-Chlorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 N(CH 3 ) 2

2-Chloro-4-fluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 OH

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

CON(OMe)Me

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 NH(CH 2 ) 2 OCH 3

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 3

CH 2 NH(CH 2 ) 2 N(CH 3 ) 2

2,4-Difluorophenyl

NH(CH 2 ) 3 OCH 3

CON(OMe)Me

2,4-Difluorophenyl

CON(OMe)Me

2,4-Difluorophenyl

CON(OMe)Me

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 2 CH 2 OH

CH 2 OH

2,4-Difluorophenyl

CON(OMe)Me

2,4-Difluorophenyl

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

2,4-Difluorophenyl

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 2 CH 2 OH

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

NH(CH 2 ) 3 OCH 3

2,4-Difluorophenyl

NH(CH 2 ) 3 OCH 3

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

NHCH 2 C(CH 3 ) 2 CH 2 OH

CON(OMe)Me

2,4-Difluorophenyl

NH(CH 2 ) 4 OH

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

CH 2 N(CH 3 ) 2

2,4-Difluorophenyl

NH(CH 2 ) 3 CO 2 H

CH 2 N(CH 3 ) 2

or a pharmaceutically acceptable salt thereof.

15. The compound according to claim 1 represented by

wherein R is

R

or a pharmaceutically acceptable salt thereof.

16. The compound according to claim 1 represented by

wherein R is

R

or a pharmaceutically acceptable salt thereof.

17. The compound according to claim 1 represented by

wherein R is

R

or a pharmaceutically acceptable salt thereof.

18. The compound according to claim 1 represented by

wherein R is

R

or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 1 represented by

or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 1 represented by

or a pharmaceutically acceptable salt thereof.

21. The compound according to claim 1 represented by

or a pharmaceutically acceptable salt thereof.

22. A compound represented by

or a pharmaceutically acceptable salt thereof.

23. A compound represented by

or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprised of a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.

25. A method of treating a cytokine mediated disease in a mammal, comprising:

administering to a mammalian patient in need of such treatment a compound as described in claim 1 in an amount which is effective to treat said rheumatoid arthritis.