IP Library › Granted Patent US 7,482,370

Granted Patent B2

US 7,482,370 · App. 11/180,863 · Granted Jan 27, 2009

Compounds for the treatment of inflammatory disorders

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Quick Facts

Patent No.: US 7,482,370
App. No.: 11/180,863
Granted: Jan 27, 2009
Kind: B2

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Abstract

This invention relates to compounds of the Formula (I): or a pharmaceutically acceptable salt, solvate or isomer thereof, which can be useful for the treatment of diseases or conditions mediated by MMPs, ADAMs, TACE, TNF- or combinations thereof.

Claims (484)

1. A compound represented by Formula (I):

or a pharmaceutically acceptable salt, solvate or isomer thereof, wherein:

X is selected from the group consisting of —S—, —C(R 4 ) 2 — or —N(R 4 )—;

T is selected from the group consisting of H (with U and V being absent), alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl, and arylalkyl, said aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the aforementioned alkyl, alkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl groups of T is unsubstituted or optionally independently substituted with one to four R 10 moieties;

U is selected from the group consisting of a covalent bond, —N(R 4 )—, —N(R 4 )C(R 4 ) 2 —, —N(R 4 )C(O)—, —O—, —N(R 4 )S(O) 2 —, —N(R 4 )C(O)N(R 4 )—, and —N(R 4 )C(S)N(R 4 )—;

V is absent or present, and if present V is selected from the group consisting of alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl, said aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of any of the aforementioned alkyl, aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one to four R 10 moieties;

Y is selected from the group consisting of a covalent bond, —(C(R 4 ) 2 ) n —, —N(R 4 )—, —C(O)N(R 4 )—, —N(R 4 )C(O)—, —N(R 4 )C(O)N(R 4 )—, —S(O) 2 N(R 4 )—, —N(R 4 ) —S(O) 2 , —O—, —S—, —C(O)—, —S(O)—, and —S(O) 2 —;

Z is selected from the group consisting of a covalent bond, —(C(R 4 ) 2 ) n —, —N(R 4 )—, —C(O)N(R 4 )—, —N(R 4 )C(O)—, —N(R 4 )C(O)N(R 4 )—, —S(O) 2 N(R 4 )—, —N(R 4 ) —S(O) 2 —, —O—, —S—, —C(O)—, —S(O)—, and —S(O) 2 —;

n is 1 to 3;

R 1 is selected from the group consisting of H, —OR 4 , halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl groups of R 1 is unsubstituted or optionally independently substituted with one to four R 20 moieties, with the proviso that when Y is present and Y is N, S or O, then R 1 is not halogen;

R 2 is selected from the group consisting of H, —OR 4 , halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, alkylaryl, alkylheteroaryl and arylalkyl groups of R 2 is unsubstituted or optionally independently substituted with one to four R 20 moieties, with the proviso that when Z is present and Z is N, S or O, then R 2 is not halogen;

each R 4 is the same or different and is independently selected from the group consisting of H, alkyl, —CH 2 C≡CCH 3 , —CH 2 C≡CCH 2 OH, and —CH 2 -cyclopropyl;

R 10 is selected from the group consisting of —OR 4 , —N(R 4 ) 2 , —O(fluoroalkyl), halogen, alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl, wherein each of the alkyl, fluoroalkyl, aryl, heteroaryl, heterocyclyl, cycloalkyl, alkylaryl and arylalkyl groups of R 10 is unsubstituted or optionally independently substituted with one to four R 30 moieties which can be the same or different, each R 30 moiety being independently selected from the group of R 30 moieties below;

R 20 is selected from the group consisting of halogen, alkyl, fluoroalkyl; and

R 30 is selected from the group consisting of halogen, alkyl, and fluoroalkyl.

2. The compound of claim 1 , wherein said isomer is a stereoisomer.

3. The compound of claim 1 wherein T is alkyl or aryl; X is —C(R 4 ) 2 —; Y is absent; R 2 is selected from the group consisting of H, halogen and alkyl; and Z is selected from the group consisting of a covalent bond and —O—.

4. The compound of claim 1 wherein T is alkyl or aryl; X is —C(R 4 ) 2 —; Y is absent; Z is selected from the group consisting of a covalent bond and —O—; and R 2 is selected from the group consisting of alkylaryl and alkylheteroaryl.

5. The compound of claim 1 wherein T is alkyl or aryl; X is —N(R 4 )—; Y is absent; R 2 is selected from the group consisting of H, halogen and alkyl; and Z is selected from the group consisting of a covalent bond and —O—.

6. The compound of claim 1 wherein X is —CH 2 — or —N(R 4 )—.

7. The compound of claim 6 wherein X is —CH 2 —.

8. The compound of claim 6 wherein X is —N(R 4 )—.

9. The compound of claim 8 wherein R 4 is H.

10. The compound of claim 1 wherein T is alkyl.

11. The compound of claim 10 wherein T is —CH 3 .

12. The compound of claim 1 wherein T is aryl and said aryl is unsubstituted or optionally independently substituted with one to five R 10 moieties.

13. The compound of claim 12 wherein R 10 is halogen.

14. The compound of claim 12 wherein R 10 is heteroaryl.

15. The compound of claim 12 wherein R 10 is aryl.

16. The compound of claim 1 wherein U selected from the group consisting of a covalent bond, —N(R 4 )—, —N(R 4 )C(O)—, and —N(R 4 )S(O) 2 —.

17. The compound of claim 16 wherein U is a covalent bond.

18. The compound of claim 16 wherein U is —N(R 4 )—.

19. The compound of claim 16 wherein U is —N(R 4 )C(O)—.

20. The compound of claim 1 wherein V is selected from the group consisting of aryl, heteroaryl, heterocyclyl and cycloalkyl, said aryl, heteroaryl, heterocyclyl, and cycloalkyl being optionally fused with one or more moieties selected from the group consisting of aryl, heteroaryl, heterocyclyl, or cycloalkyl, wherein each of any of said aryl, heteroaryl, heterocyclyl and cycloalkyl is unsubstituted or optionally independently substituted with one to four R 10 moieties.

21. The compound of claim 1 wherein Y is selected from the group consisting of a covalent bond, —(C(R 4 ) 2 ) n —, —C(O)— and —O—.

22. The compound of claim 21 wherein Y is —O—.

23. The compound of claim 21 wherein Y is —(C(R 4 ) 2 ) n —.

24. The compound of claim 21 wherein Y is —C(O)—.

25. The compound of claim 21 wherein Y is a covalent bond.

26. The compound of claim 1 wherein R 1 is selected from the group consisting of —OR 4 , H, alkyl, fluoroalkyl, alkylaryl, halogen, and heteroaryl.

27. The compound of claim 26 wherein R 1 is H.

28. The compound of claim 26 wherein R 1 is alkylaryl.

29. The compound of claim 26 wherein R 1 is alkyl.

30. The compound of claim 26 wherein R 1 is fluoroalkyl.

31. The compound of claim 26 wherein R 1 is halogen.

32. The compound of claim 26 wherein R 1 is —OR 4 .

33. The compound of claim 32 wherein R 4 is —CH 2 C≡CCH 3 .

34. The compound of claim 32 wherein R 4 is —CH 2 C≡CCH 2 OH.

35. The compound of claim 32 wherein R 4 is

36. The compound of claim 29 wherein said alkyl is —CH 3 .

37. The compound of claim 29 wherein said alkyl is —CH 2 CH 3 .

38. The compound of claim 1 wherein T, U, and V when taken together form