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1. (WO2009135885) FUSED PYRAZINE COMPOUNDS USEFUL FOR THE TREATMENT OF DEGENERATIVE AND INFLAMMATORY DISEASES
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WHAT IS CLAIMED IS:

A compound according to Formula Ia:


(Ia) wherein each of W, W, Y, and Y' is independently CR2a or N; provided that no more than two of W,

W, Y, and Y' can be N at the same time;

X is N or CH;

L is selected from a single bond, -CO-, -SO-, -SO2-, -N(R2c)C0-, and -N(R2c)SO2-; the ring P is substituted or unsubstituted:


R1 is H, or substituted or unsubstituted Ci-Cδ alkyl; each R2a is independently selected from H, substituted or unsubstituted Ci-Cβ alkyl, unsubstituted Ci-Ce haloalkyl, substituted or unsubstituted Ci-Cβ alkoxy, cyano, and halo; each R c is independently selected from H and Ci-Ce alkyl;

R2d is H, C3-C8 cycloalkyl, or Ci-Ce alkyl optionally substituted with halo, amido, or C3-C8 cycloalkyl; each ml, m2 and m3 is independently 1 or 2; and R3 is selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; or a pharmaceutically acceptable salt thereof; or a solvate of the compound or the pharmaceutically acceptable salt; and stereoisomers, isotopic variants and tautomers thereof. A compound according to Formula Ib:

(Ib) wherein each of W, W, Y, and Y' is independently CR2a or N; provided that no more than two of W,

W, Y, and Y' can be N at the same time;

X is N or CH;

L is selected from a single bond, -CO-, -SO-, -SO2-, -N(R2c)C0-, and -N(R2c)SO2-; the ring P is substituted or unsubstituted:


R1 is H, or substituted or unsubstituted Ci-C6 alkyl; each R2a is independently selected from H, substituted or unsubstituted CpC6 alkyl, unsubstituted CpC6 haloalkyl, substituted or unsubstituted CpC6 alkoxy, cyano, and halo; each R c is independently selected from H and CrC6 alkyl;

R2d is H, C3-C8 cycloalkyl, or CpC6 alkyl optionally substituted with halo, amido, or C3-C8 cycloalkyl; each ml, m2 and m3 is independently 1 or 2; R3 is selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and or a pharmaceutically acceptable salt thereof; or a solvate of the compound or the pharmaceutically acceptable salt.

3. A compound or a pharmaceutically acceptable salt according to Claim 1 or 2, wherein L is a single bond, -CO-, or -N(R2c)C0-.

4. A compound or a pharmaceutically acceptable salt according to any one of claims 1-3, wherein R1 is Me, Et, n-Pr, or i-Pr.

5. A compound or a pharmaceutically acceptable salt according to any one of claims 1-3, wherein R1 is H A compound or a pharmaceutically acceptable salt according to claim 1 wherein the compound is according to formula Ha, lib, Hc, or Hd


wherein L and the πng P are as in claim 1; each R a is independently selected from H, substituted or unsubstituted Ci-C6 alkyl, substituted or unsubstituted Ci-C6 alkoxy, cyano, and halo, and R3 is independently selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.

7. A compound or a pharmaceutically acceptable salt according to claim 2 wherein the compound is according to formula He, Hf, or Hg


wherein L and the ring P are as in claim 1 , each R a is independently selected from H, substituted or unsubstituted Ci-C6 alkyl, substituted or unsubstituted Ci-C6 alkoxy, cyano, and halo, and R3 is independently selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl

A compound or a pharmaceutically acceptable salt according to any one of claim 1-7, wherein the ring P is substituted or unsubstituted


and wherein R and ml are as in claim 1 A compound or a pharmaceutically acceptable salt according to any one of claims 1-8, wherein R2a is H, unsubstituted Ci-C6 alkyl, unsubstituted Ci-C6 haloalkyl, unsubstituted d- C6 alkoxy, cyano, or halo A compound or a pharmaceutically acceptable salt according to claim 9, wherein R2a is Me, Et, Pr, lso-Pr, Cl, F, CN, OMe, or CF3 A compound or a pharmaceutically acceptable salt according to any one claims 1-8, wherein R2a is H A compound or a pharmaceutically acceptable salt according to any one of claims 1-11, wherein R is selected from substituted or unsubstituted aryl A compound or a pharmaceutically acceptable salt according to any one of claims 1-11, wherein R3 is phenyl optionally substituted with halo, cyano, amido optionally substituted with unsubstituted Ci-Ce alkyl, or unsubstituted CpC6 alkoxy A compound or a pharmaceutically acceptable salt according to any one of claims 1-11, wherein R is phenyl optionally substituted with F, Cl, Br, cyano, OMe, OEt, O-«-Pr, O-z-Pr or amido optionally substituted with Me, Et, «-Pr, or z-Pr A compound or a pharmaceutically acceptable salt according to any one of claims 1 11, wherein R3 is selected from substituted or unsubstituted heteroaryl A compound or a pharmaceutically acceptable salt according to any one of claims 1-11, wherein R3 is selected from phenyl, pyπdyl, indolyl, lsomdolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, and thiazolyl, each of which may be unsubstituted or substituted with hydroxyl, cyano, halo, or amido optionally substituted with unsubstituted Ci-C6 alkyl A compound or a pharmaceutically acceptable salt according to any one of claims 1-11, wherein R3 is selected from phenyl, pyπdyl, indolyl, lsomdolyl, pyrrolyl, furanyl, thienyl, pyrazolyl, oxazolyl, and thiazolyl, each of which may be unsubstituted or substituted with hydroxyl, cyano, F, Cl, Br, or amido optionally substituted with Me, Et, n-Pr, or z-Pr A compound or a pharmaceutically acceptable salt according to any one of claims 1-11, wherein R3 is


and each of A1, A2 and A3 is independently selected from S, O, N, NR3a, and CR3a, each of R3a is independently H or substituted or unsubstituted Ci-C6 alkyl, and R3b is CONH2, CONHMe, or CN A compound or a pharmaceutically acceptable salt according to any one of claims 1-11, wherein R3 is

20. A compound or a pharmaceutically acceptable salt according to any one of claims 1-11, wherein R3 is


21. A compound or a pharmaceutically acceptable salt according to any one of claims 1-11, wherein R3 is


22. A compound or a pharmaceutically acceptable salt according to any one of claims 1-11, wherein R3 is


and wherein the subscript m is selected from 0, 1, 2, 3, and 4; and each R3d is independently substituted or unsubstituted Ci-C6 alkyl or halo.

23. A compound or a pharmaceutically acceptable salt according to any one of claims 1-11, wherein R3 is
and wherein the subscript m is selected from 0, 1, 2, 3, and 4; and each R3d is independently substituted or unsubstituted Ci-C6 alkyl or halo.

24. A compound or a pharmaceutically acceptable salt according to any one of claims 1-11, wherein R3 is


and wherein the subscript m is selected from 0, 1, 2, or 3; and each R3d is independently substituted or unsubstituted CpC6 alkyl or halo.

25. A compound or a pharmaceutically acceptable salt according to any one of claims 22-24, wherein m is 1 or 2; and each R3d is independently Me, Cl or F.

26. A compound or a pharmaceutically acceptable salt according to any one of claims 22-24, wherein m is 0.

27. A compound or a pharmaceutically acceptable salt according to Claim 1, wherein the compound is according to formula Ilia, IHb, or IHc:


Ilia , IHb or mc and X is as in claim 1 ; L is a single bond, -CO-, or -NHCO-; the ring P is


and R2d is H, C3-C8 cycloalkyl, or Ci-C6 alkyl optionally substituted with halo, amido, or C3-C8 cycloalkyl.

28. A compound or a pharmaceutically acceptable salt according to Claim 2, wherein the compound is according to formula IHd, or IHe:


H Id , IHe and X is as in claim 1 ; L is a single bond, -CO-, or -NHCO-; the ring P is


and R2d is H, C3-C8 cycloalkyl, or CpC6 alkyl optionally substituted with halo, amido, or C3-C8 cycloalkyl.

29. A compound or a pharmaceutically acceptable salt according to Claim 1, wherein the compound is according to formula IVa, IVb, or IVc:


IVa , IVb or IVc and X is as in claim 1 ; L is a single bond, -CO-, or -NHCO-; the ring P is


and R2d is H, C3-C8 cycloalkyl, or Ci-C6 alkyl optionally substituted with halo, amido, or C3-C8 cycloalkyl.

30. A compound or a pharmaceutically acceptable salt according to Claim 2, wherein the compound is according to formula IVd, or IVe:


IVd , IVe and X is as in claim 1 ; L is a single bond, -CO-, or -NHCO-; the ring P is


and R2d is H, C3-C8 cycloalkyl, or Ci-Cβ alkyl optionally substituted with halo, amido, or C3-C8 cycloalkyl.

31. A compound or a pharmaceutically acceptable salt according to Claim 1 , wherein the compound is according to formula Va, Vb, or Vc:


Va Vb or Vc and X is as in claim 1 ; L is a single bond, -CO-, or -NHCO-; the ring P is


and R2d is H, C3-C8 cycloalkyl, or Ci-Cβ alkyl optionally substituted with halo, amido, or C3-C8 cycloalkyl

32. A compound or a pharmaceutically acceptable salt according to Claim 2, wherein the compound is according to formula Vd, or Ve:

Vd ■ Ve and X is as in claim 1 ; L is a single bond, -CO-, or -NHCO-; the ring P is


and R2d is H, C3-C8 cycloalkyl, or Ci-C6 alkyl optionally substituted with halo, amido, or C3-C8 cycloalkyl

33. A compound or a pharmaceutically acceptable salt according to Claim 1, wherein the compound is according to formula Via, VIb, or VIc:


Via , VIb or VIc and X is as in claim 1 ; L is a single bond, -CO-, or -NHCO-; the ring P is


and R2d is H, C3-C8 cycloalkyl, or Ci-C6 alkyl optionally substituted with halo, amido, or C3-C8 cycloalkyl.

34. A compound or a pharmaceutically acceptable salt according to Claim 2, wherein the compound is according to formula VId, or VIe:

VId , VIe and X is as in claim 1 ; L is a single bond, -CO-, or -NHCO-; the ring P is


and R2d is H, C3-C8 cycloalkyl, or Ci-C6 alkyl optionally substituted with halo, amido, or C3-C8 cycloalkyl.

35. A compound or a pharmaceutically acceptable salt according to any one of Claims 1-34, wherein L is a single bond.

36. A compound or a pharmaceutically acceptable salt according to any one of Claims 1 -34, wherein L is -CO-.

37. A compound or a pharmaceutically acceptable salt according to any one of Claims 1 -34, wherein L is -NHCO-.

38. A compound or a pharmaceutically acceptable salt according to any one of Claims 1 -37, wherein R2d is H, Me, i-Pr, t-Bu, CH2CONH2, cyclopropylmethyl, or CH2CF3.

39. A compound or a pharmaceutically acceptable salt according to any one of Claims 1 -37, wherein R2d is H.

40. A compound or a pharmaceutically acceptable salt according to any one of Claims 1 -37, wherein R2d is i-Pr.

41. A compound or a pharmaceutically acceptable salt according to any one of Claims 1 -37, wherein R2d is t-Bu.

42. A compound or a pharmaceutically acceptable salt according to any one of Claims 1 -37, wherein R2d is cyclopropylmethyl.

43. A compound or a pharmaceutically acceptable salt according to any one of Claims 1 -34, wherein L is a single bond; and the ring P is

44. A compound or a pharmaceutically acceptable salt according to Claim 1-34, wherein L is a single bond; and the ring P is


45. A compound or a pharmaceutically acceptable salt according to Claim 1-34, wherein L is a single bond; and the ring P is


46. A compound or a pharmaceutically acceptable salt according to any one of Claims 1 -45, wherein X is CH.

47. A compound or a pharmaceutically acceptable salt according to any one of Claims 1 -45, wherein X is N.

48. A compound or a pharmaceutically acceptable salt according to claim 1 wherein the compound is selected from:

5-(8-(4-((l S,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)phenylamino)- [l,2,4]triazolo[l,5-a]pyrazin-5-yl)isoindolin-l-one;

4-(8-(4-((l S,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)phenylamino)- [1 ,2,4]triazolo[l ,5-a]pyrazin-5-yl)furan-2-carboxamide;

4-(8-(4-((lS,4R)-5-tert-butyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenylamino)- [1 ,2,4]triazolo[l ,5-a]pyrazin-5-yl)furan-2-carboxamide;

4-(8-(4-((lS,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenylamino)imidazo[l,2- a]pyrazin-5-yl)furan-2-carboxamide;

5-{8-(4-((lS,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl-amino)- [l,2,4]triazolo[l,5-a]pyrazin-5-yl}-lH-pyrazole-3- carboxylic acid amide;

4-{8-(4-((lS,4S)-5-tert-butyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)-phenyl-amino)imidazo[l,2- a]pyrazin-5-yl}-furan-2 -carboxylic acid amide;

4-{8-(6-((lS,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-ylamino)- [l,2,4]triazolo[l,5-a]pyrazin-5-yl}-furan-2-carboxylic acid amide;

4-{8-(4-((lS,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl-amino)imidazo[l,2- a]pyrazin-5-yl} - 1 H-pyridin-2-one;

4-{8-(4-(5-isopropyl-2,5-diazabicyclo[2.2.2]octan-2-yl)phenylamino)[l,2,4]-triazolo[l,5- a]pyrazin-5-yl}-furan-2 -carboxylic acid amide;

4-{8-(4-(5-isopropyl-2,5-diazabicyclo[2.2.2]octan-2-yl)phenylamino)-imidazo[l,2-a]pyrazin- 5-yl}-furan-2-carboxylic acid amide;

4-{8-(4-(3-isopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl)phenylamino)-imidazo[l,2-a]pyrazin- 5-yl}-furan-2-carboxylic acid amide;

4-{8-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenylamino)[l,2,4]-triazolo[l,5- a]pyrazin-5-yl}-furan-2 -carboxylic acid amide;

4-{8-(4-(3-isopropyl-3,8-diazabicyclo[3.2.1]octan-8-yl)phenylamino)[l,2,4]-triazolo[l,5- a]pyrazin-5-yl}-furan-2 -carboxylic acid amide;

4-{8-(4-(8-isopropyl-3,8-diazabicyclo[3.2.1]octan-3-yl)phenylamino)-imidazo[l,2-a]pyrazin- 5-yl}-furan-2-carboxylic acid amide;

5-{8-(6-((lS,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-ylamino)- [l,2,4]triazolo[l,5-a]pyrazin-5-yl}-lH-pyrazole-3- carboxylic acid amide;

5-{8-(4-((lS,4S)-5-tert-butyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenylamino) - [l,2,4]triazolo-[l,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-l-one;

5-{8-(4-((lS,4S)-5-tert-butyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl-amino)- [l,2,4]triazolo[l,5-a]pyrazin-5-yl}-lH-pyrazole-3- carboxylic acid amide; and

5-{8-(6-((lS,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)pyridin-3-ylamino)- [l,2,4]triazolo[l,5-a]pyrazin-5-yl}-2,3-dihydro-isoindol-l-one; or a solvate of the compound or the pharmaceutically acceptable salt, and stereoisomers, isotopic variants and tautomers thereof.

49. A compound or a pharmaceutically acceptable salt according to claim 2 wherein the compound is selected from:

4-(8-(3-((l S,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1 ]heptan-2-yl)phenylamino)- [1 ,2,4]triazolo[l ,5-a]pyrazin-5-yl)furan-2-carboxamide;

4-(8-(3-((lS,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenylamino)imidazo[l,2- a]pyrazin-5-yl)furan-2-carboxamide;

5-(8-(3-((lS,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenylamino)- [l,2,4]triazolo[l,5-a]pyrazin-5-yl)isoindolin-l-one; or a solvate of the compound or the pharmaceutically acceptable salt, and stereoisomers, isotopic variants and tautomers thereof.

50. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 49.

51. The pharmaceutical composition of claim 50, wherein the carrier is a parenteral carrier.

52. The pharmaceutical composition of claim 50, wherein the carrier is an oral carrier.

53. The pharmaceutical composition of claim 50, wherein the carrier is a topical carrier.

54. The use of a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 49 in the manufacture of a medicament for treatment or prophylaxis of a condition characterized by ECM degradation.

55. The use of a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 49 in the manufacture of a medicament for treatment or prophylaxis of a condition selected from diseases involving inflammation.

56. The use of a compound or a pharmaceutically acceptable salt according to claim 50, wherein said disease is rheumatoid arthritis.

57. The use of a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 50 in the manufacture of a medicament for treatment or prophylaxis of a condition prevented, ameliorated or eliminated by administration of an inhibitor of Mitogen- Activated Protein Kinase- Activated Protein Kinase 5.

58. A method of treatment of a condition characterised by abnormal matrix metallo proteinase activity, which comprises administering a therapeutically effective amount of a matrix metallo proteinase inhibiting compound or a pharmaceutically acceptable salt according to any one of claims 1 to 50.

59. A method of treatment of a condition selected from diseases involving degradation of extracellular matrix, which comprises administering a therapeutically effective matrix metallo proteinase inhibiting amount of a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 50.

60. A method of treatment of a condition selected from diseases involving abnormal cellular expression of MMPl, which comprises administering a therapeutically effective matrix metallo proteinase inhibiting amount of a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 50.

61. A method of treatment or prevention of inflammatory diseases, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 50.

62. A method of treatment or prevention of rheumatoid arthritis, which comprises administering to a subject in need thereof, a therapeutically effective amount of a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 50.

63. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 50 for use in the treatment or prophylaxis of a condition prevented, ameliorated or eliminated by administration of an inhibitor of Mitogen- Activated Protein Kinase- Activated Protein Kinase 5.

64. The compound of claim 63, wherein the condition is selected from diseases involving degradation of extra-cellular matrix, diseases involving abnormal cellular expression of MMPl, and inflammatory diseases.