Pyridine and pyrimidine derivatives as mGIuR2 antagonists

Abstract

The present invention relates to compounds of formula (I), a process for the manufacture thereof, pharmaceutical compositions containing them, and their use for treating CNS disorders:

Description

Claims

1. A compound of formula (I):

2. The compound of claim 1, wherein B is H or cyano.

3. The compound of claim 1, wherein: B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of: halo,nitro,C1-6-alkyl optionally substituted by hydroxy,NRaRb, wherein Ra and Rb are independently H or —(CO)—C1-6-alkyl,S—C1-6-alkyl,(SO2)—OH,(SO2)—C1-6-alkyl,(SO2)—NRcRd, wherein Rc and Rd are independently: H,C1-6-alkyl optionally substituted by hydroxy,C1-6-haloalkyl, orC1-6-alkoxy,(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or C1-6-alkoxy,(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1,5 or 6-membered heterocycloalkyl,(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by a substituent selected from the group consisting of hydroxy, C1-6-alkyl, C1-6-alkoxy optionally substituted by hydroxy, and 5 or 6 membered heteroaryloxy,NHSO2—C1-6-alkyl, andNHSO2—NRhRi wherein Rh and Ri are independently H, C1-6-alkyl, —(CO)O—C1-6-alkyl, or Rh and Ri together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by C1-6-alkyl.

4. The compound of claim 1, having the formula:

5. The compound of claim 1, having formula (Ia):

6. The compound of claim 5, wherein: A is aryl or 5 or 6 membered heteroaryl, each of which is optionally substituted by C1-6-alkyl;B is H or cyano;R1 is C1-6-alkyl or C1-6-haloalkyl;R2 is halogen or C1-6-haloalkyl;R3 is H, halogen, C1-6-alkoxy, C1-6-haloalkyl, C1-6-alkyl or C1-6-haloalkoxy;R4 is H or halo;or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5, wherein: A is aryl or 5 or 6 membered heteroaryl;B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of: C1-6-alkyl optionally substituted by hydroxy,NRaRb, wherein Ra and Rb are independently H or —(CO)—C1-6-alkyl,(SO2)—C1-6-alkyl,(SO2)—NRcRd, wherein Rc and Rd are independently: H, orC1-6-alkyl optionally substituted by hydroxy,(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,(CH2)m-aryl, wherein m is 1 or 2,(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1,(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by a substituent selected from the group consisting of hydroxyl or C1-6-alkyl,NHSO2—C1-6-alkyl, andNHSO2—NRhRi wherein Rh and Ri are independently H or C1-6-alkyl;R1 is C1-6-alkyl or C1-6-haloalkyl;R2 is halogen or C1-6-haloalkyl;R3 is H, halogen, C1-6-alkoxy, C1-6-haloalkyl, C1-6-alkyl or C1-6-haloalkoxy;R4 is H or halo;or a pharmaceutically acceptable salt thereof.

8. The compound of claim 5, having formula (Ia1):

9. The compound of claim 8, wherein: B is H or cyano;R1 is C1-6-alkyl or C1-6-haloalkyl;R2 is halogen or C1-6-haloalkyl;R3 is H, halogen, C1-6-alkoxy, C1-6-haloalkyl, C1-6-alkyl or C1-6-haloalkoxy;R4 is H or halo;or a pharmaceutically acceptable salt thereof.

10. The compound of claim 8, wherein: B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of: C1-6-alkyl optionally substituted by hydroxy,NRaRb, wherein Ra and Rb are independently H,(SO2)—C1-6-alkyl,(SO2)—NRcRd, wherein Rc and Rd are independently: H, orC1-6-alkyl optionally substituted by hydroxy,NHSO2—C1-6-alkyl, andNHSO2—NRhRi wherein Rh and Ri are independently H, C1-6-alkyl;R1 is C1-6-alkyl or C1-6-haloalkyl;R2 is halogen or C1-6-haloalkyl;R3 is H, halogen, C1-6-alkoxy, C1-6-haloalkyl, C1-6-alkyl or C1-6-haloalkoxy;R4 is H or halo;or a pharmaceutically acceptable salt thereof.

11. The compound of claim 8, wherein B is an unsubstituted aryl or an unsubstituted 5 or 6 membered heteroaryl.

12. The compound of claim 11, selected from the group consisting of:

13. The compound of claim 8, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of C1-6-alkyl optionally substituted by hydroxy.

14. The compound of claim 13, selected from the group consisting of:

15. The compound of claim 8, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of NRaRb, wherein Ra and Rb are independently H.

16. The compound of claim 15, selected from the group consisting of:

17. The compound of claim 15, selected from the group consisting of:

18. The compound of claim 8, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of —(SO2)—C1-6-alkyl and —(SO2)—NRcRd, wherein Rc and Rd are independently H or C1-6-alkyl optionally substituted by hydroxyl.

19. The compound of claim 18, selected from the group consisting of:

20. The compound of claim 18, selected from the group consisting of:

21. The compound of claim 18, selected from the group consisting of:

22. The compound of claim 18, selected from the group consisting of:

23. The compound of claim 8, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is NHSO2—C1-6-alkyl.

24. The compound of claim 23, which is {3′-[4-Trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidin-2-yl]-biphenyl-3-yl}-methanesulfonamide.

25. The compound of claim 8, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is NHSO2—NRhRi wherein Rh and Ri are independently H or C1-6-alkyl.

26. The compound of claim 25, selected from the group consisting of:

27. The compound of claim 5, having formula (Ia2):

28. The compound of claim 27, wherein the 5 or 6 membered heteroaryl is selected from the group consisting of: imidazolyl, [1,2,4]oxadiazolyl], pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4]triazolyl, thiazolyl, pyrimidinyl and thiophenyl.

29. The compound of claim 27, wherein: B is H or cyano;R1 is C1-6-alkyl or C1-6-haloalkyl;R2 is halogen or C1-6-haloalkyl;R3 is H, halogen, C1-6-alkoxy, C1-6-haloalkyl, C1-6-alkyl or C1-6-haloalkoxy;R4 is H or halo;or a pharmaceutically acceptable salt thereof.

30. The compound of claim 27, wherein B is H.

31. The compound of claim 30, selected from the group consisting of:

32. The compound of claim 27, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of: C1-6-alkyl optionally substituted by hydroxy,NRaRb, wherein Ra and Rb are independently H or —(CO)—C1-6-alkyl,(SO2)—C1-6-alkyl,(SO2)—NRcRd, wherein Rc and Rd are independently: H, orC1-6-alkyl optionally substituted by hydroxy,(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,(CH2)m-aryl, wherein m is 1 or 2,(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1, and(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by a substituent selected from the group consisting of hydroxy and C1-6-alkyl;

33. The compound of claim 32, wherein B is unsubstituted aryl or unsubstituted 5 or 6 membered heteroaryl.

34. The compound of claim 33, selected from the group consisting of:

35. The compound of claim 32, wherein B is optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is NRaRb, wherein Ra and Rb are independently H or —(CO)—C1-6-alkyl.

36. The compound of claim 35, selected from the group consisting of:

37. The compound of claim 35, selected from the group consisting of:

38. The compound of claim 35, selected from the group consisting of:

39. The compound of claim 35, selected from the group consisting of:

40. The compound of claim 35, selected from the group consisting of:

41. The compound of claim 35, selected from the group consisting of:

42. The compound of claim 35, selected from the group consisting of:

43. The compound of claim 32, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl) wherein the substituent is —(SO2)—C1-6-alkyl.

44. The compound of claim 43, selected from the group consisting of:

45. The compound of claim 32, wherein B is optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is —(SO2)—NRcRd, wherein Rc and Rd are independently: H,C1-6-alkyl optionally substituted by hydroxy,(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,(CH2)m-aryl, wherein m is 1 or 2, or(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1.

46. The compound of claim 45, from the group consisting of:

47. The compound of claim 45, from the group consisting of:

48. The compound of claim 45, from the group consisting of:

49. The compound of claim 45, from the group consisting of:

50. The compound of claim 45, from the group consisting of:

51. The compound of claim 45, from the group consisting of:

52. The compound of claim 45, from the group consisting of:

53. The compound of claim 45, from the group consisting of:

54. The compound of claim 45, from the group consisting of:

55. The compound of claim 45, from the group consisting of:

56. The compound of claim 32, wherein B is optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is —(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by hydroxy or C1-6-alkyl.

57. The compound of claim 56, selected from the group consisting of:

58. The compound of claim 1, having formula (I-b):

59. The compound of claim 58, wherein: A is aryl or 5 or 6 membered heteroaryl each of which is optionally substituted by C1-6-alkyl;B is H, cyano, oran optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of: halo,nitro,C1-6-alkyl optionally substituted by hydroxy,NRaRb, wherein Ra and Rb are independently H or —(CO)—C1-6-alkyl,S—C1-6-alkyl,(SO2)—OH,(SO2)—C1-6-alkyl,(SO2)—NRcRd, wherein Rc and Rd are independently: H,C1-6-alkyl optionally substituted by hydroxy,C1-6-haloalkyl, orC1-6-alkoxy,(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or C1-6-alkoxy,(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1,5 or 6-membered heterocycloalkyl,(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by a substituent selected from the group consisting of hydroxy, C1-6-alkyl, C1-6-alkoxy optionally substituted by hydroxy, and 5 or 6 membered heteroaryloxy,NHSO2—C1-6-alkyl, andNHSO2—NRhRi wherein Rh and Ri are independently H, C1-6-alkyl, —(CO)O—C1-6-alkyl, or Rh and Ri together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by C1-6-alkyl;R1 is H, halogen, C1-6-alkyl optionally substituted by hydroxy, C1-6-alkoxy, C1-6-haloalkyl, or C3-6-cycloalkyl;R2 is H, cyano, halogen, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C1-6-alkyl or C3-6-cycloalkyl;R3 is halogen, H, C1-6-alkoxy, C1-6-haloalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-haloalkoxy, or is NRjRk wherein Rj and Rk are independently selected from the group consisting of: H, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms, and C1-6-alkyl each of which is optionally substituted by one or more substituent(s) selected from the group consisting of halogen, hydroxy, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms, and —NRlRm, wherein Rl and Rm are independently selected from the group consisting of H and C1-6-alkyl;or Rj and Rk can, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic group comprising 5 to 12 ring atoms optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, wherein said heteroaryl group is optionally substituted by one, two, three, four or five substituents selected from the group consisting of halogen, hydroxy, C1-6-alkyl and C1-6-haloalkyl;or R2 and R3 can together form a dioxo bridge;R4 is H or halo;or a pharmaceutically acceptable salt thereof.

60. The compound of claim 59, wherein: A is aryl or 5 or 6 membered heteroaryl each of which is optionally substituted by C1-6-alkyl;B is H or cyano;R1 is H, halogen, C1-6-alkyl optionally substituted by hydroxy, C1-6-alkoxy, C1-6-haloalkyl, or C3-6-cycloalkyl;R2 is H, cyano, halogen, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C1-6-alkyl or C3-6-cycloalkyl;R3 is H, halogen, C1-6-alkoxy, C1-6-haloalkyl, C1-6-alkyl or C1-6-haloalkoxy;or R2 and R3 can together form a dioxo bridge;R4 is H or halo;or a pharmaceutically acceptable salt thereof.

61. The compound of claim 58, wherein: A is aryl or 5 or 6 membered heteroaryl each of which is optionally substituted by C1-6-alkyl;B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of: halo,nitro,C1-6-alkyl,NRaRb, wherein Ra and Rb are independently H or —(CO)—C1-6-alkyl,S—C1-6-alkyl,(SO2)—OH,(SO2)—C1-6-alkyl,(SO2)—NRcRd, wherein Rc and Rd are independently: H,C1-6-alkyl optionally substituted by hydroxy,C1-6-haloalkyl, orC1-6-alkoxy,—(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,—(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or C1-6-alkoxy,(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1,5 or 6-membered heterocycloalkyl,(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by a substituent selected from the group consisting of hydroxy, C1-6-alkyl, C1-6-alkoxy optionally substituted by hydroxy, and 5 or 6 membered heteroaryloxy,NHSO2—C1-6-alkyl, andNHSO2—NRhRi wherein Rh and Ri are independently H, C1-6-alkyl or —(CO)O—C1-6-alkyl;R1 is H, halogen, C1-6-alkyl optionally substituted by hydroxy, C1-6-alkoxy, C1-6-haloalkyl, or C3-6-cycloalkyl;R2 is H, cyano, halogen, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C1-6-alkyl or C3-6-cycloalkyl;R3 is H, halogen, C1-6-alkoxy, C1-6-haloalkyl, C1-6-alkyl or C1-6-haloalkoxy;or R2 and R3 can together form a dioxo bridge;R4 is H or halo;or a pharmaceutically acceptable salt thereof.

62. The compound of claim 58, having formula (Ib1):

63. The compound of claim 62, wherein B is an unsubstituted aryl or an unsubstituted 5 or 6 membered heteroaryl.

64. The compound of claim 63, selected from the group consisting of:

65. The compound of claim 62, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is cyano.

66. The compound of claim 65, which is 3-[6-Methyl-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-benzonitrile.

67. The compound of claim 62, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is halo.

68. The compound of claim 67, which is 4,6-Difluoro-3′-[6-methyl-4-(4-trifluoromethylphenyl)-pyridin-2-yl]-biphenyl-3-sulfonic acid amide.

69. The compound of claim 62, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is C1-6-alkyl.

70. The compound of claim 69, which is 2-Methyl-6-[3-(4-methyl-imidazol-1-yl)-phenyl]-4-(4-trifluoromethyl-phenyl)-pyridine.

71. The compound of claim 62, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is NRaRb, wherein Ra and Rb are independently H or —(CO)—C1-6-alkyl.

72. The compound of claim 71, selected from the group consisting of

73. The compound of claim 71, selected from the group consisting of

74. The compound of claim 62, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is —(SO2)—C1-6-alkyl.

75. The compound of claim 74, which is 2-(3′-Methanesulfonyl-biphenyl-3-yl)-6-methyl-4-(4-trifluoromethyl-phenyl)-pyridine.

76. The compound of claim 62, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is —(SO2)—NRcRd, wherein Rc and Rd are independently: H,C1-6-alkyl optionally substituted by hydroxy,C1-6-haloalkyl,C1-6-alkoxy,(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or C1-6-alkoxy, or(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1 or 5 or 6-membered heterocycloalkyl.

77. The compound of claim 76, selected from the group consisting of:

78. The compound of claim 62, having formula (I-b11):

79. The compound of claim 58, having formula (Ib2):

80. The compound of claim 79, wherein B the 5 or 6 membered heteroaryl group is selected from the group consisting of: imidazolyl, [1,2,4]oxadiazolyl], pyrrolyl, 1H-pyrazolyl, pyridinyl, triazolyl, thiazolyl, pyrimidinyl and thiophenyl.

81. The compound of claim 79, wherein: B is H or cyano; R1 is C1-6-alkyl or C1-6-haloalkyl;R2 is halogen or C1-6-haloalkyl;R3 is H, halogen, C1-6-alkoxy, C1-6-haloalkyl, C1-6-alkyl or C1-6-haloalkoxy;R4 is H or halo;or a pharmaceutically acceptable salt thereof.

82. The compound of claim 81, selected from the group consisting of:

83. The compound of claim 79, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of: nitro,C1-6-alkyl optionally substituted by hydroxy,C1-6-haloalkyl,NRaRb, wherein Ra and Rb are independently H or —(CO)—C1-6-alkyl,S—C1-6-alkyl,NHSO2—C1-6-alkyl,NHSO2—NRhRi wherein Rh and Ri are independently H, C1-6-alkyl or —(CO)O—C1-6-alkyl(SO2)—C1-6-alkyl,(SO2)—OH,(SO2)—NRcRd, wherein Rc and Rd are independently: H, orC1-6-alkyl optionally substituted by hydroxy or halo,(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or C1-6-alkoxy,(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1,5 or 6-membered heterocycloalkyl, and(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by a substituent selected from the group consisting of hydroxy, C1-6-alkyl, C1-6-alkoxy optionally substituted by hydroxy, or heteroaryloxy;

84. The compound of claim 83, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is nitro.

85. The compound of claim 84, selected from the group consisting of

86. The compound of claim 83, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is NRaRb, wherein Ra and Rb are independently H or —(CO)—C1-6-alkyl.

87. The compound of claim 86, selected from the group consisting of:

88. The compound of claim 86, selected from the group consisting of:

89. The compound of claim 86, selected from the group consisting of:

90. The compound of claim 83, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is S—C1-6-alkyl.

91. The compound of claim 90, which is 6-Methyl-6′-(3-methylsulfanyl-phenyl)-4-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl.

92. The compound of claim 83, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is S(O)2—C1-6-alkyl.

93. The compound of claim 92, selected from the group consisting of:

94. The compound of claim 83, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is —(SO2)—NRcRd, wherein Rc and Rd are independently: H,C1-6-alkyl optionally substituted by hydroxyl or halo,(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,(CH2)m-aryl optionally substituted by halo or C1-6-alkoxy, wherein m is 1 or 2 and the aryl is optionally substituted by halo, C1-6-alkoxy or —(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1 and5 or 6-membered heterocycloalkyl.

95. The compound of claim 94, selected from the group consisting of:

96. The compound of claim 94, selected from the group consisting of:

97. The compound of claim 94, selected from the group consisting of:

98. The compound of claim 94, selected from the group consisting of:

99. The compound of claim 94, selected from the group consisting of:

100. The compound of claim 94, selected from the group consisting of:

101. The compound of claim 83, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is NHSO2—C1-6-alkyl.

102. The compound of claim 101, selected from the group consisting of:

103. The compound of claim 83, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is —SO2—OH.

104. The compound of claim 103, which is 3-[6′-Methyl-4′-(4-trifluoromethyl-phenyl)-[2,2′]bipyridinyl-6-yl]-benzenesulfonic acid.

105. The compound of claim 83, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is NHSO2—NRhRi wherein Rh and Ri are independently H, C1-6-alkyl or —(CO)O—C1-6-alkyl.

106. The compound of claim 105, selected from the group consisting of:

107. The compound of claim 83, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is —(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by a substituent selected from the group consisting of hydroxy, C1-6-alkyl, C1-6-alkoxy optionally substituted by hydroxy, and heteroaryloxy.

108. The compound of claim 107, selected from the group consisting of:

109. The compound of claim 107, selected from the group consisting of:

110. The compound of claim 1, having formula (I-c):

111. The compound of claim 110, wherein: A is aryl or 5 or 6 membered heteroaryl each of which is optionally substituted by C1-6-alkyl;B is H or cyano;R1 is halogen, C1-6-alkyl optionally substituted by hydroxy, C1-6-alkoxy, C1-6-haloalkyl, or C3-6-cycloalkyl;R2 is halogen, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C1-6-alkyl or C3-6-cycloalkyl;R3 is halogen, H, C1-6-alkoxy, C1-6-haloalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-haloalkoxy, or is NRjRk wherein Rj and Rk are independently selected from the group consisting of: H, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms, and C1-6-alkyl each of which is optionally substituted by one or more substituent(s) selected from the group consisting of halogen, hydroxy, C3-8-cycloalkyl, aryl, heteroaryl having from 5 to 12 ring atoms, and —NRlRm, wherein Rl and Rm are independently selected from the group consisting of H and C1-6-alkyl;or Rl and Rm can, together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic group comprising 5 to 12 ring atoms optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, wherein said heteroaryl group is optionally substituted by one, two, three, four or five substituents selected from the group consisting of halogen, hydroxy, C1-6-alkyl and C1-6-haloalkyl;or R2 and R3 can together form a dioxo bridge;or a pharmaceutically acceptable salt thereof.

112. The compound of claim 110, wherein: A is aryl or 5 or 6 membered heteroaryl each of which is optionally substituted by C1-6-alkyl; B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents are selected from the group consisting of: halo,nitro,C1-6-alkyl optionally substituted by hydroxy,NRaRb, wherein Ra and Rb are independently H or —(CO)—C1-6-alkyl,S—C1-6-alkyl,(SO2)—OH,(SO2)—C1-6-alkyl,(SO2)—NRcRd, wherein Rc and Rd are independently: H,C1-6-alkyl optionally substituted by hydroxy,C1-6-haloalkyl, orC1-6-alkoxy,(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or C1-6-alkoxy,(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1,5 or 6-membered heterocycloalkyl,(SO2)—NRfRg, wherein Rf and Rg together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen, sulphur and an SO2 group, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by a substituent selected from the group consisting of hydroxy, C1-6-alkyl, C1-6-alkoxy optionally substituted by hydroxy, and 5 or 6 membered heteroaryloxy,NHSO2—C1-6-alkyl, andNHSO2—NRhRi wherein Rh and Ri are independently H, C1-6-alkyl, —(CO)O—C1-6-alkyl, or Rh and Ri together with the nitrogen atom to which they are attached form a 4, 5 or 6 membered heterocycloalkyl ring optionally containing a further heteroatom selected from nitrogen, oxygen and sulphur, wherein said 4, 5 or 6 membered heterocycloalkyl ring is optionally substituted by C1-6-alkyl;R1 is halogen, C1-6-alkyl optionally substituted by hydroxy, C1-6-alkoxy, C1-6-haloalkyl, or C3-6-cycloalkyl;R2 is halogen, C1-6-haloalkyl, C1-6-alkoxy, C1-6-haloalkoxy, C1-6-alkyl or C3-6-cycloalkyl;R3 is halogen, H, C1-6-alkoxy, C1-6-haloalkyl, C1-6-alkyl, C3-6-cycloalkyl, or C1-6-haloalkoxy;or R2 and R3 can together form a dioxo bridge;or a pharmaceutically acceptable salt thereof.

113. The compound of claim 110, having formula (Ic1):

114. The compound of claim 113, wherein B is an unsubstituted aryl or an unsubstituted 5 or 6 membered heteroaryl.

115. The compound of claim 114, which is 2-(3-Pyridin-3-yl-phenyl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyridine.

116. The compound of claim 113, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is NRaRb, wherein Ra and Rb are independently H or —(CO)—C1-6-alkyl.

117. The compound of claim 116, selected from the group consisting of:

118. The compound of claim 113, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is —(SO2)—NRcRd, wherein Rc and Rd are independently H,C1-6-alkyl optionally substituted by hydroxy,C1-6-haloalkyl,C1-6-alkoxy,(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or C1-6-alkoxy or by —(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1 or by 5 or 6-membered heterocycloalkyl.

119. The compound of claim 118, selected from the group consisting of:

120. The compound of claim 114, having formula (Ic11):

121. The compound of claim 110, having formula (Ic2):

122. The compound of claim 121, wherein the 5 or 6 membered heteroaryl is selected from the group consisting of: imidazolyl, [1,2,4]oxadiazolyl], pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4]triazolyl, thiazolyl, pyrimidinyl and thiophenyl.

123. The compound of claim 122, wherein B is an unsubstituted aryl or an unsubstituted 5 or 6 membered heteroaryl.

124. The compound of claim 123, which is 2-(4-Chloro-phenyl)-6-(4-pyridin-3-yl-imidazol-1-yl)-4-trifluoromethyl-pyridine.

125. The compound of claim 122, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituent is C1-6-alkyl.

126. The compound of claim 97, selected from the group consisting of:

127. The compound of claim 122, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents is NRaRb, wherein Ra and Rb are independently H or —(CO)—C1-C6-alkyl.

128. The compound of claim 12799, selected from the group consisting of:

129. The compound of claim 122, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents is —(SO2)—C1-C6-alkyl.

130. The compound of claim 129, selected from the group consisting of:

131. The compound of to claim 122, wherein B is an optionally substituted aryl or an optionally substituted 5 or 6 membered heteroaryl, wherein the substituents is —(SO2)—NRcRd, wherein Rc and Rd are independently H,C1-6-alkyl optionally substituted by hydroxy,C1-6-haloalkyl,C1-6-alkoxy,(CO)C1-6-alkyl optionally substituted by C1-6-alkoxy,(CH2CH2O)nCHRe, wherein Re is H or CH2OH and n is 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,(CH2)m-aryl, wherein m is 1 or 2 and the aryl is optionally substituted by halo or by C1-6-alkoxy, —(CH2)p—C3-6-cycloalkyl, wherein p is 0 or 1, 5 or 6-membered heterocycloalkyl.

132. The compound of claim 131, selected from the group consisting of:

133. The compound of claim 131, selected from the group consisting of:

134. The compound of claim 131, selected from the group consisting of:

135. The pharmaceutical composition comprising a compound of formula (I)