Imidazolopyrazine compounds useful for the treatment of degenerative and inflammatory diseases
Novel imidazo[1,2-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, arthritis, inflammation, and others.
1. A compound according to formula III:
wherein
R 1 is H, or substituted or unsubstituted alkyl;
R 2 is H, lower alkyl, lower cycloalkyl and lower alkyl-lower cycloalkyl, optionally substituted with one or more of F and Cl;
R 8 is substituted or unsubstituted pyrimidine; and
R 9 is selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl;
or a pharmaceutically acceptable salt or stereoisomer or tautomer of said compound according to formula III.
2. A compound according to claim 1 , wherein R 8 is substituted pyrimidine; and the substitution is -L-R 8d ; and wherein
L is selected from bond, alkylene, heteroalkylene, —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 )CON(R 8e )—, —N(R 8e )SO 2 N(R 8e )—; and
R 8d is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted 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 alkyl and substituted or unsubstituted cycloalkyl.
3. A compound according to claim 1 , wherein R 8 is
and wherein
L is selected from bond, alkylene, heteroalkylene, —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 )CON(R 8e )—, —N(R 8e )SO 2 N(R 8e )—; and
R 8d is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted amino, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl and substituted or unsubstituted aminoalkyl;
R 8e is selected from H, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl;
the subscript n is selected from 1-4; and
each R 8a is independently selected from hydrogen, substituted or unsubstituted alkyl, alkoxy, cyano, and halo.
4. A compound according to claim 3 , wherein L is —CON(R 8e )— or SO 2 N(R 8e )—;
R 8d is selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, and substituted or unsubstituted aminoalkyl; and
R 8e is selected from H, substituted or unsubstituted alkyl.
5. A compound according to claim 3 , wherein L is —CONH— or SO 2 NH—; and
R 8d is selected from alkylaminoethyl, dialkylaminoethyl, cycloalkyl, heterocycloalkyl, arylalkyl, and heteroarylalkyl.
6. A compound according to claim 3 , wherein L is —CONH— or SO 2 NH—; and
R 8d is selected from methylaminoethyl, ethylaminoethyl, dimethylaminoethyl, diethylaminoethyl, substituted or unsubstituted pyrrolidinyl, benzyl and pyridylmethyl.
7. A compound according to claim 1 , wherein R 8 is substituted pyrimidine;
and the substitution is -L-R 8d ; and wherein
L is selected from —(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.
8. A compound according to formula IVd:
wherein
L is selected from a 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;
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 or stereoisomer or tautomer of said compound according to formula IVd.
9. A compound according to claim 8 , wherein L is a bond.
10. A compound according to claim 8 , wherein L is —CO—.
11. A compound according to claim 8 , wherein L is —SO 2 —.
12. A compound according to claim 8 , wherein L is —CON(H)—CH 2 —CH 2 —, or —SO 2 NH—CH 2 —CH 2 —.
13. A compound according to claim 8 , wherein L is —OCH 2 —CH 2 — or —NHCH 2 —CH 2 —.
14. A compound according to claim 8 , wherein the ring P is substituted or unsubstituted piperidine, morpholine or piperazine.
15. A compound according to claim 8 , wherein each R 8a is H.
16. A compound according to claim 8 , wherein subscript n is 1 and R 8a is Me, Et, Pr, iso-Pr, Cl, F, CN, OMe, or CF 3 .
17. A compound according to claim 1 , wherein the compound is according to formula Vc or Vf:
wherein R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
18. A compound according to claim 17 , wherein R 8b is H.
19. A compound according to claim 17 , wherein R 8b is substituted or unsubstiuted alkyl or substituted or unsubstituted cycloalkyl.
20. A compound according to claim 17 , wherein R 8b is Me, Et, Pr, i-Pr, t-Bu, i-Bu, CH 2 CONH 2 , cyclopropyl or cyclopropylmethyl.
21. A compound according to claim 1 , wherein R 9 is selected from substituted or unsubstituted aryl.
22. A compound according to claim 1 , wherein R 9 is selected from substituted or unsubstituted phenyl.
23. A compound according to claim 1 , wherein R 9 is selected from substituted or unsubstituted heteroaryl.
24. 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.
25. A compound according to any one of claims 1 , 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.
26. A compound according to any one of claims 1 , wherein R 9 is
27. A compound according to any one of claims 1 , wherein R 9 is
28. A compound according to any one of claims 1 , wherein R 9 is
the subscript m is selected from 1-4;
and each R 9d is independently H, substituted or unsubstituted alkyl or halo.
29. A compound according to any one of claims 1 , wherein R 9 is
the subscript m is selected from 1-4;
and each R 9d is independently H, substituted or unsubstituted alkyl or halo.
30. A compound according to any one of claims 1 , wherein R 9 is
the subscript m is selected from 1-3;
and each R 9d is independently H, substituted or unsubstituted alkyl or halo.
31. A compound according to any one of claims 28 - 30 , wherein each R 9d is H.
32. A compound according to any one of claims 28 - 30 , wherein m is 1 or 2 and each R 9d is Me, Cl or F.
33. A compound according to claim 1 , wherein the compound is according to formula VIc or VIf:
wherein R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
34. A compound according to claim 1 , wherein the compound is according to formula VIIc or VIIf:
wherein R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
35. A compound according to claim 1 , wherein the compound is according to formula VIIIc or VIIIf:
wherein R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
36. A compound according to claim 1 , wherein the compound is according to formula IXc or IXf:
wherein R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
37. A compound according to claim 1 , wherein the compound is according to formula Xc or Xf:
wherein R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl.
38. A compound according to claim 1 , wherein the compound is according to formula XIc or XIf:
wherein R 8b is hydrogen, substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; and
R 9e is hydrogen, Me, or CN.
39. A compound according to any one of claims 33 - 38 , wherein R 8b is H.
40. A compound according to any one of claims 33 - 38 , wherein R 8b is cycloalkyl.
41. A compound according to any one of claims 33 - 38 , wherein R 8b is cyclopropyl.
42. A compound according to any one of claims 33 - 38 , wherein R 8b is substituted or unsubstituted alkyl.
43. A compound according to any one of claims 33 - 38 , wherein R 8b is Me, Et, Pr, i-Pr, t-Bu, i-Bu, CF 3 , CH 2 CF 3 , CH 2 CONH 2 , or cyclopropylmethyl.
44. A compound according to claim 1 , wherein the compound is according to formula XIVa, XIVb, XIVc or XIVd:
45. A compound according to claim 1 , wherein the compound is according to formula XVc:
wherein L is selected from a 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;
ring P is
and R 8b is H, Me, i-Pr, t-Bu, CH 2 CONH 2 , cyclopropylmethyl, or CH 2 CF 3 .
46. A compound according to claim 45 , wherein L is a bond and the ring P is
47. A compound selected from
N-(2-Diethylamino-ethyl)-4-[5-(2,4-dihydroxy-pyrimidin-5-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-benzamide;
N-(2-Diethylamino-ethyl)-4-(5-pyrimidin-5-yl-imidazo[1,2-a]pyrazin-8-ylamino)-benzamide;
5-[8-(Pyrimidin-5-ylamino)-imidazo[1,2-a]pyrazin-5-yl]-2,3-dihydro-isoindol-1-one;
and pharmaceutically acceptable salts thereof.
48. A compound selected from
5-[8-(2-Morpholin-4-yl-pyrimidin-5-ylamino)-imidazo[1,2-a]pyrazin-5-yl]-2,3-dihydro-isoindol-1-one;
5-{8-[2-(4-Isopropyl-piperazin-1-yl)-pyrimidin-5-ylamino]-imidazo[1,2-a]pyrazin-5-yl}-2,3-dihydro-isoindol-1-one; and
pharmaceutically acceptable salts thereof.
49. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of claim 1 .
50. The pharmaceutical composition of claim 49 , wherein the carrier is a parenteral carrier.
51. The pharmaceutical composition of claim 49 , wherein the carrier is an oral carrier.
52. The pharmaceutical composition of claim 49 , wherein the carrier is a topical carrier.
53. A method of treatment of rheumatoid arthritis, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 1 .