IP Library › Granted Patent US 7,501,411

Granted Patent B2

US 7,501,411 · App. 11/809,294 · Granted Mar 10, 2009

Triazolopyrazine compounds useful for the treatment of degenerative and inflammatory diseases

Assignee: Galapagos, NV

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Quick Facts

Patent No.: US 7,501,411
App. No.: 11/809,294
Granted: Mar 10, 2009
Kind: B2

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Abstract

Novel [1.2.4]triazolo[1,5-a]pyrazine compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, and others.

Claims (232)

1. A compound according to formula III:

wherein

R 1 is H, or substituted or unsubstituted alkyl;

R 8 is

L is selected from a single bond, alkylene, —O—, —N(R 8e )—, —CO—, —CO 2 —, —SO—, —SO 2 —, —CON(R 8e )—, —SO 2 N(R 8e )—, —N(R 8e )CO—, —N(R 8e )SO 2 —, —N(R 8e )CO N(R 8e )—, —N(R 8e )SO 2 N(R 8e )—; —O(CR 8e 2 ) m1 —, or —CON(R 8e )(CR 8e 2 ) m1 —;

each R 8a is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, and halo;

R 8d is selected from substituted or unsubstituted heterocycloalkyl;

R 8e is selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl;

the subscript m1 is 1, 2, 3, or 4; the subscript n is 1, 2, 3, or 4;

and R 9 is independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; or a pharmaceutically acceptable salt thereof; and stereoisomers and tautomers thereof.

2. A compound according to claim 1 , wherein R 8 is

wherein L, the subscript n, R 8a , and R 8d are as in claim 1 .

3. A compound according to claim 2 , wherein L is a single bond, —CO—, —O(CH 2 ) m1 —, —CON(H)(CH 2 ) m1 —, or —NHCO—; the subscript m1 is selected from 1-4; and R 8d is

and wherein the ring P is substituted or unsubstituted heterocycloalkyl.

4. A compound according to formula IVa, IVb, or IVc:

and wherein L is a single bond, —CO—, —O(CH 2 ) m1 —, —CON(H)(CH 2 ) m1 —, or —NHCO—; the subscript m1 is selected from 1-4; the ring P is substituted or unsubstituted heterocycloalkyl; the subscript n, is selected from 1-4; each R 8a is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, and halo; and R 9 is independently selected from substituted or unsubstituted aryl and heteroaryl; or a pharmaceutically acceptable salt thereof; and stereoisomers and tautomers thereof.

5. A compound according to claim 4 , wherein L is a single bond.

6. A compound according to claim 4 , wherein L is —CO—.

7. A compound according to claim 4 , wherein L is —NHCO—.

8. A compound according to claim 4 , wherein L is —CON(H)—CH 2 —CH 2 —, or —N(H)—CO—CH 2 —CH 2 —.

9. A compound according to claim 4 , wherein L is —OCH 2 —CH 2 — or —NHCH 2 —CH 2 —.

10. A compound according to any one of claims 4 - 9 , wherein the ring P is substituted or unsubstituted piperidine, morpholine or piperazine.

11. A compound according to claim 4 , wherein each R 8a is H.

12. A compound according to claim 4 , wherein subscript n is 1 and R 8a is Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, or CF 3 .

13. A compound according to claim 1 , wherein the compound is according to formula Va, Vb, Vd, or Ve:

and wherein R 9 is as in claim 1 and R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.

14. A compound according to claim 13 , wherein R 8b is H.

15. A compound according to claim 13 , wherein R 8b is substituted or unsubstiuted alkyl or substituted or unsubstituted cycloalkyl.

16. A compound according to claim 13 , wherein R 8b is Me, Et, Pr, i-Pr, t-Bu, i-Bu, CH 2 CONH 2 , cyclopropyl or cyclopropylmethyl.

17. A compound according to claim 1 , wherein R 9 is selected from substituted or unsubstituted aryl.

18. A compound according to claim 1 , wherein R 9 is selected from substituted or unsubstituted phenyl.

19. A compound according to claim 1 , wherein R 9 is selected from substituted or unsubstituted heteroaryl.

20. A compound according to claim 1 , wherein R 9 is selected from substituted or unsubstituted phenyl, pyridyl, indolyl, isoindolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, and thiazolyl.

21. A compound according to any one of claims 2 , 4 and 13 , wherein R 9 is

and each of A 1 , A 2 and A 3 is independently selected from S, O, N, NR 9a , and CR 9a ; each of R 9a is independently H or substituted or unsubstituted alkyl; and R 9b is CONH 2 , CONHMe, or CN.

22. A compound according to any one of claims 2 , 4 and 13 , wherein R 9 is

23. A compound according to any one of claims 2 , 4 and 13 , wherein R 9 is

24. A compound according to any one of claims 2 , 4 and 13 , wherein R 9 is

and wherein the subscript m is selected from 1-4 and each R 9d is independently H, substituted or unsubstituted alkyl or halo.

25. A compound according to any one of claims 2 , 4 and 13 , wherein R 9 is

and wherein the subscript m is selected from 1-4 and each R 9d is independently H, substituted or unsubstituted alkyl or halo.

26. A compound according to any one of claims 1 , 4 and 13 , wherein R 9 is

and wherein the subscript m is selected from 1-3 and each R 9d is independently H, substituted or unsubstituted alkyl or halo.

27. A compound according to claims 24 , wherein each R 9d is H.

28. A compound according to claim 24 , wherein m is 1 or 2 and each R 9d is Me, Cl or F.

29. A compound according to claim 1 , wherein the compound is according to formula VIa, VIb, VId, or VIe: