Fused pyrazine compounds useful for the treatment of degenerative and inflammatory diseases
Novel fused 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, inflammation, rheumatoid arthritis and others.
1. A compound according to formula I:
wherein
Z is CH; R 1 is H, or substituted or unsubstituted C 1 -C 6 alkyl; R 2 is H, C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or C 3 -C 7 cycloalkyl-C 1 -C 6 alkyl, optionally substituted with one or more of F and Cl; R 8 is substituted or unsubstituted heteroaryl; R 9 is selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
2. The compound according to claim 1 wherein R 8 is substituted or unsubstituted 5-membered heteroaryl.
3. The compound according to claim 2 wherein R 8 is selected from substituted or unsubstituted pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, 1,3,4-thiadiazolyl, and 1,2,4-thiadiazolyl.
4. The compound according to claim 3 wherein R 8 is selected from substituted pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, 1,3,4-thiadiazolyl, and 1,2,4-thiadiazolyl and the substitution is selected from C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, carbamoyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, cyano, amino, sulfo, aryl, C 3 -C 7 cycloalkyl, aralkyl, 3-7-membered heterocycloalkyl and heteroaryl.
5. The compound according to claim 4 wherein R 8 is selected from substituted pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, 1,3,4-thiadiazolyl, and 1,2,4-thiadiazolyl and the substitution is selected from is Me, i-Pr, cyclopropyl, CH 2 OH, CONH 2 , CONMe 2 , NMe 2 , NEt 2 , SO 2 Me, or SO 2 Et.
6. The compound according to claim 1 wherein R 8 is selected from substituted pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, imidazolyl, thiazolyl, 1,3,4-thiadiazolyl, and 1,2,4-thiadiazolyl and the substitution is -L-R 8d ;
wherein
L is selected from bond, alkylene, heteroalkylene, —O—, —N(R 8c )—, —CO—, —CO 2 —, —SO—, —SO 2 —, —CON(R 8e )—, —SO 2 N(R 8c )—, —N(R 8c )CO—, —N(R 8c )SO 2 —, —N(R 8e )CON(R 8c )—, —N(R 8c )SO 2 N(R 8c )—; and
R 8d is selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 3-7-membered heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl and substituted or unsubstituted aminoalkyl; and
R 8e is selected from H, substituted or unsubstituted C 1 -C 6 alkyl and substituted or unsubstituted C 3 -C 7 cycloalkyl.
7. The compound according to claim 6 , wherein R 8 is
wherein L, and R 8d are as in claim 6 ; and R 8e is independently selected from hydrogen, and substituted or unsubstituted C 1 -C 6 alkyl.
8. The compound according to claim 7 , wherein L is —CON(R 8c )— or SO 2 N(R 8e )—; R 8d is selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 3-7-membered heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroaryl alkyl and substituted or unsubstituted aminoalkyl; and
R 8e is selected from H, substituted or unsubstituted C 1 -C 6 alkyl.
9. The compound according to claim 7 or 8 , wherein L is —CONH— or SO 2 NH—; and
R 8d is selected from H, C 1 -C 6 alkylaminoethyl, dialkylaminoethyl, C 3 -C 7 cycloalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl.
10. The compound according to claim 9 , wherein L is —CONH— or SO 2 NH—; and R 8d is selected from H, methylaminoethyl, ethylaminoethyl, dimethylaminoethyl, diethylaminoethyl, substituted or unsubstituted pyrrolidinyl, benzyl and pyridylmethyl.
11. The compound according to claim 7 , wherein L is bond, —CO—, SO 2 , —(CH 2 ) m1 —, —O(CH 2 ) m1 , —NH(CH 2 ) m1 —, —CON(H)(CH 2 ) m1 —, or —SO 2 NH(CH 2 ) m1 —; the subscript m1 is selected from 1-4; and R 8d is
and wherein the ring P is substituted or unsubstituted heterocycloalkyl.
12. A compound according to formula IIa, IIb, IIc, IId, IIe, or IIf:
and wherein Z is CH, L is bond, —CO—, SO 2 , —(CH 2 ) m1 —, —O(CH 2 ) m1 —, —NH(CH 2 ) m1 —, —CON(H)(CH 2 ) m1 —, or —SO 2 NH(CH 2 ) m1 ; the subscript m1 is selected from 1-4, R 8c is independently selected from hydrogen, and substituted or unsubstituted C 1 -C 6 alkyl, and the ring P is substituted or unsubstituted heterocycloalkyl; and R 9 is independently selected from substituted or unsubstituted aryl and heteroaryl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
13. The compound according to claim 12 , wherein L is a bond.
14. The compound according to claim 12 , wherein L is —CO—.
15. The compound according to claim 12 , wherein L is —SO 2 —.
16. The compound according to claim 12 , wherein L is —CON(H)—CH 2 —CH 2 —, or —SO 2 NH—CH 2 —CH 2 —.
17. The compound according to claim 12 , wherein L is —OCH 2 —CH 2 — or —NHCH 2 —CH 2 —.
18. The compound according to any one of claims 12 - 17 , wherein the ring P is substituted or unsubstituted piperidine, morpholine or piperazine.
19. The compound according to any one of claims 12 - 17 , wherein the ring P is substituted or unsubstituted:
and R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl.
20. The compound according to claim 19 wherein R 8b is H, Me, Et, Pr, i-Pr, t-Bu, i-Bu, CH 2 CONH 2 , cyclopropyl or cyclopropylmethyl.
21. The compound according to claim 1 wherein the compound is according to formula IIIa, IIIb, IIIc, IIId, IIIe, IIIf, IIIg, IIIh, IIIi, IIIj, IIIk, IIIl, or IIIm.
and wherein L is bond, —CO—, SO 2 , —(CH 2 ) m1 —, —O(CH 2 ) m1 —, —CON(H)(CH 2 ) m1 —, or —SO 2 NH(CH 2 ) m1 —; the subscript m1 is selected from 1-4; R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; and R 9 is independently selected from substituted or unsubstituted aryl and heteroaryl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
22. The compound according to claim 1 wherein the compound is according to formula IIIn, IIIo, IIIp, IIIq, IIIs, IIIt, IIIu, IIIv, IIIw, IIIx, or IIIy:
and wherein L is bond, —CO—, SO 2 , —(CH 2 ) m1 —, —O(CH 2 ) m1 —, —NH(CH 2 ) m1 , —CON(H)(CH 2 ) m1 —, or —SO 2 NH(CH 2 ) m1 —; the subscript m 1 is selected from 1-4; R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; and R 9 is independently selected from substituted or unsubstituted aryl and heteroaryl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
23. The compound according to claim 21 or 22 , wherein L is a bond.
24. The compound according to claim 21 or 22 , wherein L is —CH 2 —.
25. The compound according to claim 21 or 22 , wherein L is —CO—.
26. The compound according to claim 21 or 22 , wherein L is —SO 2 —.
27. The compound according to claim 21 or 22 , wherein L is —CON(H)—CH 2 —CH 2 —, or —SO 2 NH—CH 2 —CH 2 —.
28. The compound according to claim 21 or 22 , wherein L is —OCH 2 —CH 2 — or —NHCH 2 —CH 2 —.
29. The compound according to claim 21 or 22 wherein R 8b is H, Me, Et, Pr, i-Pr, t-Bu, i-Bu, cyclopropyl or cyclopropylmethyl.
30. The compound according to any one of claims 1 - 29 , wherein R 9 is selected from substituted or unsubstituted phenyl.
31. The compound according to any one of claims 1 - 29 , wherein R 9 is selected from substituted or unsubstituted pyridyl, indolyl, isoindolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, and thiazolyl.
32. The compound according to any one of claims 1 - 29 , 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 C 1 -C 6 alkyl; and R 9b is CONH 2 , CONHMe, or CN.
33. The compound according to any one of claims 1 - 29 , wherein R 9 is
34. The compound according to any one of claims 1 - 29 , wherein R 9 is
35. The compound according to any one of claims 1 - 29 , wherein R 9 is
and wherein the subscript m is selected from 0-4 and each R 9d is independently substituted or unsubstituted C 1 -C 6 alkyl or halo.
36. The compound according to any one of claims 1 - 29 , wherein R 9 is
and wherein the subscript m is selected from 0-4 and each R 9d is independently substituted or unsubstituted C 1 -C 6 alkyl or halo.
37. The compound according to any one of claims 1 - 29 , wherein R 9 is
wherein the subscript m is selected from 0-3 and each R 9d is independently substituted or unsubstituted C 1 -C 6 alkyl or halo.
38. The compound according to any one of claims 35 - 37 , wherein m is 1 or 2 and each R 9d is Me, Cl or F.
39. The compound according to claim 1 wherein the compound is according to formula IVa, IVb, IVc, IVd, IVe, IVg, IVh, IVi, IVj, IVk or IVl:
wherein R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
40. The compound according to claim 1 wherein the compound is according to formula IVm, IVn, IVo, IVp, IVq, IVr, IVs, IVt, IVu, IVv, IVw or IVx:
wherein R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
41. The compound according to claim 1 wherein the compound is according to formula Va, Vb, Vc, Vd, Ve, Vf, Vg, Vh, Vi, Vj, Vk or Vl:
wherein R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; and R 9e is hydrogen, Me, or CN; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
42. The compound according to claim 1 wherein the compound is according to formula Vm, Vn, Vo, Vp, Vq, Vr, Vs, Vt, Vu, Vv, Vw or Vx:
wherein R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; and R 9e is hydrogen, Me, or CN; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
43. The compound according to claim 1 wherein the compound is according to formula VIa, VIb, VIc, VId, VIe, VIf, VIg, VIh, VIi, VIj, VIk or VIl:
wherein R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
44. The compound according to claim 1 wherein the compound is according to formula VIm, VIn, VIo, VIp, VIq, VIr, VIs, VIt, VIu, VIv, VIw or VIx:
wherein R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
45. The compound according to claim 1 wherein the compound is according to formula VIIa, VIIIb, VIIc, VIId, VIIe, VIIf, VIIg, VIIh, VIIi, VIIj, VIIk or VIIl:
wherein R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
46. The compound according to claim 1 wherein the compound is according to formula VIIm, VIIn, VIIo, VIIp, VIIq, VIIr, VIIs, VIIt, VIIu, VIIv, VIIw or VIIx:
wherein R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
47. The compound according to claim 1 wherein the compound is according to formula VIIIa, VIIIb, VIIIe, VIIId, VIIIe, VIII, VIIIg, VIIIh, VIIIi, VIIIj, VIIIk or VIIIl:
wherein R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; and R 9e is hydrogen, Me; or CN; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
48. The compound according to claim 1 wherein the compound is according to formula VIIIm, VIIIn, VIIIo, VIIIp, VIIIq, VIIIr, VIIIs, VIIIt, VIIiu, VIIIy, VIIIw or VIIIx:
wherein R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; and R 9e is hydrogen, Me, or CN; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
49. The compound according to claim 1 wherein the compound is according to formula IXa, IXb, IXc, IXd, IXe, IXf, Ixg, IXh, IXi, IXj, IXk or IXl:
wherein R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
50. The compound according to claim 1 wherein the compound is according to formula IXm, IXn, IXo, IXp, IXq, IXr, IXs, IXt, IXu, IXv, IXw or IXx:
wherein R 8b is hydrogen, substituted or unsubstituted C 1 -C 6 alkyl or substituted or unsubstituted C 3 -C 7 cycloalkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
51. The compound according to any one of claims 39 - 50 , wherein R 8b is H.
52. The compound according to any one of claims 39 - 50 , wherein R 8b is C 3 -C 2 cycloalkyl.
53. The compound according to claim 52 , wherein R 8b is cyclopropyl.
54. The compound according to any one of claims 39 - 50 , wherein R 8b is substituted or unsubstituted C 1 -C 6 alkyl.
55. The compound according to any one of claims 39 - 50 , wherein R 8b is Me, Et, Pr, i-Pr, t-Bu, i-Bu, CF 3 , CH 2 CF 3 , or cyclopropylmethyl.
56. The compound according to claim 1 wherein the compound is according to formula Xa, Xb or Xc:
wherein R 8c is hydrogen, or substituted or unsubstituted C 1 -C 6 alkyl.
57. The compound according to claim 1 wherein the compound is according to formula Xd, Xe or Xf:
wherein R 8c is hydrogen, or substituted or unsubstituted C 1 -C 6 alkyl; and R 9e is hydrogen, Me, or CN; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
58. The compound according to claim 1 wherein the compound is according to formula Xg, Xh or Xi:
and wherein R 8c is hydrogen, or substituted or unsubstituted C 1 -C 6 alkyl; or a pharmaceutically acceptable salt, solvate or prodrug thereof; and stereoisomers, and tautomers thereof.
59. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound according to any one of claims 1 to 58 .
60. The pharmaceutical composition of claim 59 , wherein the carrier is a parenteral carrier.
61. The pharmaceutical composition of claim 59 , wherein the carrier is an oral carrier.
62. The pharmaceutical composition of claim 59 , wherein the carrier is a topical carrier.