(Halo-benzo carbonyl)heterocyclo fused phenyl p38 kinase inhibiting agents

• US 6,809,199 B2
• Filed: 12/17/2001
• Issued: 10/26/2004
• Est. Priority Date: 12/20/2000
• Status: Expired due to Fees

• Current Assignee: Merck Sharp & Dohme Corporation (Merck & Co., Inc.)
• Original Assignee: Merck & Co., Inc.
• Inventors: Sinclair, Peter J., Rupprecht, Kathleen M., Chen, Meng-Hsin, Bao, Jianming, Doherty, James B., Miao, Shouwu, Stelmach, John E., Hunt, Julianne A., Wisnoski, David D., Kallashi, Florida, Liu, Luping, Goulet, Joung L., Hong, Xingfang, Natarajan, Swaminathan Ravi, Ruzck, Rowena D.
• Primary Examiner(s): Kifle, Bruck
• Application Number:
  US10/023,231
• Publication Number:
  US 20030092712A1
• Time in Patent Office: 1,044 Days
• Field of Search: 544/256, 546/122
• US Class Current: 544/256
• 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 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/16 Emollients or protectives, e.g. against radiation
• 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 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• 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 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 31/22 for herpes viruses
• CPC Class Codes: A61P 33/06 Antimalarials
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: C07D 215/227 : only one oxygen atom which is attached in position 2
• CPC Class Codes: C07D 221/06 : Ring systems of three rings
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 : with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 239/80 : Oxygen atoms
• CPC Class Codes: C07D 249/08 : 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• 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 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 403/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/14 : containing three or more hetero rings
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 451/02 : containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 487/08 : Bridged systems

Abstract

Compounds described by the chemical formula (I) or a pharmaceutically acceptable salt thereof:

are inhibitors of p38 useful in the treatment of inflammatory diseases such as arthritis.

Claims

1. A compound represented by (I):

or a pharmaceutically acceptable salt thereof, wherein

Non-Ar-Cyc is

A is, O, CH₂, or CH;

B is —

C_1-6alkyl-, —

C_0-3alkyl-O—

C_0-3alkyl-, —

C_0-3alkyl-NH—

C_0-3alkyl-, —

C_0-3alkyl-NH—

C_3-7cycloalkyl-, —

C_0-3alkyl-N(C_0-3alkyl)-C(O)—

C_0-3alkyl-, —

C_0-3alkyl-NH—

SO₂—

C_0-3alkyl-, —

C_0-3alkyl-, —

C_0-3alkyl-S—

C_0-3alkyl-, C_0-3alkyl-SO₂—

C_0-3alkyl-, —

C_0-3alkyl-PH—

C_0-3alkyl-, —

C_0-3alkyl-C(O)—

C_0-3alkyl, or a direct bond;

D is CH, CH₂, N, or NH;

optionally A and D are bridged by —

C_1-4alkyl- to form a fused bicyclo ring with A and D at the bicyclo cusps;

E¹ is CH, N, or CR⁶;

or B and E¹ form —

CH═

C<

;

E² is CH₂, CHR, C(OH)R NH, NR, O, S, —

S(O)—

, or —

S(O)₂—

;

G¹ is N, CH, or C(C_1-3alkyl);

G² is N, CH, or C(C_1-3alkyl)

R, R⁷ and R⁷⁷ each independently is hydrogen, C_1-6alkyl-group, C_2-6alkenyl-group, C_4-6cycloalkyl-C_0-6alkyl-group, N(C_0-4alkyl)(C_0-4alkyl)-C_1-4alkyl-N(C_0-4alkyl)-group, —

N(C_0-4alkyl)(C_0-4alkyl) group, C_1-3alkyl-CO—

C_0-4alkyl-group, C_0-6alkyl-O—

C(O)—

C_0-4alkyl-group, C_0-6alkyl-C(O)—

O—

C_0-4alkyl-group, N(C_0-4alkyl) (C_0-4alkyl)-(C_0-4alkyl)C(O)(C_0-4alkyl)-group, phenyl-C_0-4alkyl-group, pyridyl-C_0-4alkyl-group, pyrimidinyl-C_0-4alkyl-group, pyrazinyl-C_0-4alkyl-group, thiophenyl-C_0-4alkyl-group, pyrazolyl-C_0-4alkyl-group, imidazolyl-C_0-4alkyl-group, triazolyl-C_0-4alkyl-group, azetidinyl-C_0-4alkyl-group, pyrrolidinyl-C_0-4alkyl-group, isoquinolinyl-C_0-4alkyl-group, indanyl-C_0-4alkyl-group, benzothiazolyl-C_0-4alkyl-group, any of the groups optionally substituted with 1-6 substituents, each substituent independently being —

OH, —

N(C_0-4alkyl)(C_0-4alkyl), C_1-4alkyl, C_1-6alkoxyl, C_1-6alkyl-CO—

C_0-4alkyl-, pyrrolidinyl-C_0-4alkyl-, or halogen;

or R⁷ together with a bond from an absent ring hydrogen is ═

O;

n′

+n″

=n;

m′

+m″

=m;

n is 1, 2, 3, or 4;

m is 0, 1, 2, 3, or 4;

n+m is 2, 3, 4, 5, or 6;

p is 0, 1, 2, or 3;

R¹, R², R³, R⁴, and R⁶ are each independently halogen, C_0-4alkyl, —

C(O)—

O(C_0-4alkyl), or —

C(O)—

N(C_0-4alkyl)(C_0-4alkyl),

R⁵ and R⁵⁵ independently is H, CH₃, CH₂CH₃, or absent;

R⁸⁸ and R⁸ each is independently —

CN, —

C_0-4alkyl, —

C(O)—

N(C_0-4alkyl)(C_0-4alkyl), —

C(O)—

O—

C_0-4alkyl or 1,3dioxolan-2-yl-C_0-4alkyl-;

R⁹ is —

C_0-4alkyl, or absent; and

any alkyl optionally substituted with 1-6 independent halogen or —

OH.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

D is CH₂.

3. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein

B is a direct bond.

4. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein

B is C_0-3alkyl-O—

C_0-3alkyl.

5. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein

B is C_0-3alkyl-C(O)—

C_0-3alkyl.

6. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein

B is C_1-6alkyl.

7. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein

B is C_0-3alkyl-NH—

C_0-3alkyl.

8. The compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein

G² is N.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

D is CH.

12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

A is O;

D is CH₂.

13. The compound according to claim 12 described by the chemical formula (IVA):

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

A is CH₂;

D is CH₂.

15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein

B is a direct bond.

16. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein

B is C_0-3alkyl-O—

C_0-3alkyl.

17. The compound according to claim 14 represented by

18. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein

A is CH;

D is CH.

19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein

B is a direct bond.

20. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein

B is C_0-3alkyl-O—

C_0-3alkyl.

21. The compound according to claim 18 comprising

28. The compound according to claim 14 represented by

29. The compound according to claim 18 represented by

30. The compound according to claim 1, wherein

A is CH;

D is CH; and

G¹ is N.

31. The compound according to claim 30 represented by

32. The compound according to claim 1 wherein

A is CH;

D is CH; and

G² is N.

33. The compound according to claim 32 represented by

34. The compound according to claim 1 wherein

A is CH₂;

D is CH₂; and

G² is N.

35. The compound according to claim 34 represented by

36. The compound according to claim 1 wherein

A is CH;

D is CH; and

A and D are bridged by —

C_1-4alkyl- to form a fused bicyclo ring with A and D at the bicyclo cusps.

37. The compound according to claim 36 represented by

or a pharmaceutically acceptable thereof.

38. The compound according to claim 12 represented by

or a pharmaceutically acceptable thereof.

9. A compound represented by

11. A compound described by the chemical formula (IIIA):

or a pharmaceutically acceptable salt thereof.

22. A compound represented by

23. A compound represented by

24. A compound represented by

25. A compound represented by

26. A compound represented by

27. A compound represented by

39. A compound represented by

or a pharmaceutically acceptable salt thereof.

40. A compound represented by

or a pharmaceutically acceptable salt thereof.