Therapeutic agents useful for treating pain

1. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein

Ar 1 is

Ar 2 is

V is N;

X is O or S;

Y 1 and Y 2 are —CH 2 — and —CH 2 —, —O— and —O—, —NH— and —NH—, —S— and —S—, —CH 2 — and —O—, —CH 2 — and —NH—, —CH 2 — and —S—, —O— and —CH 2 —, —NH— and —CH 2 —, —S— and —CH 2 —, —O— and —NH—, —NH— and —O—, —S— and —NH—, or —NH— and —S— respectively;

R 1 is —H, -halo, —(C 1 -C 4 )alkyl, —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);

each R 2 is independently:

(a) -halo, —CN, —OH, —NO 2 , or —NH 2 ,

(b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups, or

(c) -phenyl, -naphthyl, —(C 14 )aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R 6 groups;

each R 3 is independently:

(a) -halo, —CN, —OH, —NO 2 , or —NH 2 ,

(b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups, or

(c) -phenyl, -naphthyl, —(C 14 )aryl or -(5- to 10-membered) heteroaryl, each of which is unsubstituted or substituted with one or more R 6 groups;

R 4 is —H or —(C 1 -C 6 )alkyl;

each R 5 is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ;

each R 6 is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ;

each R 7 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, —C(halo) 3 , —CH(halo) 2 , or CH 2 (halo);

each R 8 is independently —H, —(C 1 -C 10 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , —S(O) 2 R 7 , —R 7 OR 7 , —R 7 COR 7 , —R 7 C(O)OR 7 , —R 7 OC(O)R 7 , —R 7 OC(O)OR 7 , —R 7 SR 7 , —R 7 S(O)R 7 , —R 7 S(O) 2 R 7 , —C(halo) 2 C(halo) 3 , —C(halo) 2 CH(halo) 2 , —CH(C(halo) 3 ) 2 , —CH(C(halo) 3 )(CH 3 ), —OC(halo) 2 C(halo) 3 , —OC(halo) 2 CH(halo) 2 , —OCH(C(halo) 3 ) 2 , —OCH(C(halo) 3 )(CH 3 ), —C(OH)(CF 3 ) 2 , —(C 1 -C 10 )alkyl, or -(3- to 7-membered)heterocycle;

each R 9 is independently —H, -halo or —(C 1 -C 6 )alkyl;

each R 11 is independently —CN, —OH, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , or —OC(O)OR 7 ;

each halo is independently —F, —Cl, —Br, or —I;

m is 0 or 1 and when m is 1, R 3 is attached to the 2-, 3-, 5-, or 6-position of the cyclo(hetero)alkenyl ring;

n is an integer ranging from 0 to 3;

p is an integer ranging from 0 to 2;

q is an integer ranging from 0 to 6;

r is an integer ranging from 0 to 5; and

s is an integer ranging from 0 to 4.

2. The compound of claim 1 , wherein Ar 2 is

3. The compound of claim 1 , wherein Ar 1 is

4. The compound of claim 1 , wherein each R 8 is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 .

5. The compound of claim 3 , wherein each R 8 is independently -(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 .

6. The compound of claim 1 , wherein R 4 is —H; R 1 is —H, -halo, —CH 3 , —NO 2 , —CN, —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo); and each R 8 is independently —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, —OH, -halo, —N 3 , —NO 2 , —N(R 7 ) 2 , —CH═NR 7 , —NR 7 OH, —OR 7 , —COR 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 .

7. The compound of claim 6 , wherein n or p is 1 and R 2 is —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 8 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.

8. The compound of claim 6 , wherein X is O.

9. The compound of claim 8 , wherein Ar 1 is pyridyl; n is 1 and R 2 is —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 8 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.

10. The compound of claim 8 , wherein m is 0; n is 0; and Ar 1 is

11. The compound of claim 10 , wherein R 1 is Cl and Ar 2 is

12. The compound of claim 11 , wherein r is 1 and R 8 is halo or —(C 1 -C 6 )alkyl.

13. The compound of claim 12 , wherein Ar 2 is substituted in the 4-position.

14. The compound of claim 13 , wherein the —(C 1 -C 6 )alkyl is tert-butyl group.

15. The compound of claim 13 , wherein R 8 is halo.

16. The compound of claim 8 , wherein n is 0, m is 1, R 1 is —CH 3 , and Ar 1 is pyridyl.

17. The compound of claim 16 , wherein Ar 2 is

18. The compound of claim 17 , wherein r is 1 and R 8 is halo or —(C 1 -C 6 )alkyl.

19. The compound of claim 17 , wherein the —(C 1 -C 6 )alkyl is tert-butyl group and Ar 2 is substituted at 4-position.

20. The compound of claim 17 , wherein R 8 is halo.

21. The compound of claim 8 , wherein Ar 1 is

Ar 2 is

22. The compound of claim 21 , wherein n is 1 and R 2 is —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.

23. The compound of claim 21 , wherein R 1 is —F, —Cl, —Br, or —I; n is 0; r is 1 and R 8 is -halo.

24. The compound of claim 21 , wherein R 1 is —F, —Cl, —Br, or —I; n is 0; r is 1 and R 8 is —CF 3 .

25. The compound of claim 21 , wherein R 1 is —F, —Cl, —Br, or —I; n is 0; r is 1 and R 8 is -tert-butyl.

26. The compound of claim 21 , wherein R 1 is —CF 3; n is 0; r is 1 and R 8 is -tert-butyl.

27. The compound of claim 21 , wherein R 1 is —CH 3 ; n is 0; r is 1 and R 8 is -halo.

28. The compound of claim 21 , wherein R 1 is —CF 3 ; n is 0; r is 1 and R 8 is -halo.

29. The compound of claim 21 , wherein R 1 is —CF 3 ; n is 0; r is 1 and R 8 is —CH 3 .

30. The compound of claim 21 , wherein n is 0; m is 0; R 1 is —CH 3 ; r is 1 and R 8 is —CF 3 .

31. The compound of claim 21 , wherein R 1 is —CF 3 ; n is 0; r is 1 and R 8 is —CF 3 .

32. The compound of claim 21 , wherein R 1 is —CH 3; n is 0; r is 1 and R 8 is -tert-butyl.

33. The compound of claim 1 , wherein m is 0; n is 0, Ar 1 is

and R 1 is —Cl or —CH 3 .

34. The compound of claim 33 , wherein R 1 is —Cl.

35. The compound of claim 34 , wherein Ar 2 is

36. The compound of claim 35 , wherein r is 1 and R 8 is -halo or a —(C 1 -C 6 )alkyl.

37. The compound of claim 36 , wherein the Ar 2 is substituted in the 4-position.

38. The compound of claim 37 , wherein the —(C 1 -C 6 )alkyl group is a tert-butyl group.

39. The compound of claim 37 , wherein R 8 is -halo.

40. The compound of claim 39 , wherein R 8 is —F.

41. The compound of claim 8 , wherein Ar 1 is

Ar 2 is

wherein r is 1, n is zero, m is zero, R 1 is H, halo, CH 3 , CF 3 , CHF 2 , OH, NO 2 , or CN; R 8 is H, Cl, Br, I, CH 3 , C 3-4 alkyl, C 3-4 alkoxy, cyclohexyl, CF 3 , CH 2 CF 3 , or OCF 3 ; and R 8 is connected at the 4-position of the phenyl ring.

42. The compound of claim 8 , wherein Ar 1 is

and Ar 2 is

43. The compound of claim 42 , wherein n is 1 and R 2 is —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —(C 3 -C 10 )cycloalkyl, —(C 8 -C 14 )bicycloalkyl, —(C 8 -C 14 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 8 -C 14 )bicycloalkenyl, —(C 8 -C 14 )tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R 5 groups.

44. The compound of claim 42 , wherein R 1 is —F, —Cl, —Br, or —I; n is 0; s is 1 and R 8 is -halo.

45. The compound of claim 42 , wherein R 1 is —CH 3 ; n is 0; s is 1 and R 8 is -halo.

46. The compound of claim 42 , wherein R 1 is —CF 3 ; n is 0; s is 1 and R 8 is -halo.

47. The compound of claim 42 , wherein R 1 is —F, —Cl, —Br, or —I; n is 0; s is 1 and R 1 is —CH 3 .

48. The compound of claim 42 , wherein R 1 is —CH 3 ; n is 0; s is 1 and R is —CH 3 .

49. The compound of claim 42 , wherein R 1 is —CF 3 ; n is 0; s is 1 and R 8 is —CH 3 .

50. The compound of claim 42 , wherein R 1 is —F, —Cl, —Br, or —I; n is 0; s is 1 and R 8 is —CF 3 .

51. The compound of claim 42 , wherein R 1 is —CH 3 ; n is 0; s is 1 and R 8 is —CF 3 .

52. The compound of claim 42 , wherein R 1 is —CF 3 ; n is 0; s is 1 and R 8 is —CF 3 .

53. The compound of claim 42 , wherein R 1 is —F, —Cl, —Br, or —I; n is 0; s is 1 and R 8 is —CH 2 CF 3 .

54. The compound of claim 42 , wherein R 1 is —CH 3 ; n is 0; s is 1 and R 8 is —CH 2 CF 3 .

55. The compound of claim 42 , wherein R 1 is —CF 3 ; n is 0; s is 1 and R 8 is —CH 2 CF 3 .

56. The compound of claim 42 , wherein R 1 is —F, —Cl, —Br, or —I; n is 0; s is 1 and R 8 is -tert-butyl.

57. The compound of claim 42 , wherein R 1 is —CF 3 ; n is 0; s is 1 and R 8 is -tert-butyl.

58. The compound of claim 10 , wherein Ar 2 is

59. The compound of claim 58 , wherein R 1 is —F, —Cl, —Br, or —I; s is 1 and R 8 is -halo.

60. The compound of claim 58 , wherein R 1 is —F, —Cl, —Br, or —I; s is 1 and R 8 is —CF 3 .

61. The compound of claim 58 , wherein R 1 is —F, —Cl, —Br, or —I; and R 8 is -tert-butyl.

62. The compound of claim 58 , wherein R 1 is —CF 3 ; s is 1 and R 8 is -halo.

63. The compound of claim 58 , wherein R 1 is —CF 3 ; s is 1 and R 8 is —CF 3 .

64. The compound of claim 58 , wherein R 1 is —CF 3 ; s is 1 and R 8 is -tert-butyl.

65. The compound of claim 58 , wherein R 1 is —CH 3 ; s is 1 and R 8 is -halo.

66. The compound of claim 58 , wherein R 1 is —CF 3 ; s is 1 and R 8 is —CH 3 .

67. The compound of claim 58 , wherein R 1 is —CH 3 ; s is 1 and R 8 is —CF 3 .

68. The compound of claim 58 , wherein R 1 is —CH 3 ; s is 1 and R 8 is -tert-butyl.

69. The compound of claim 8 , wherein Ar 1 is

Ar 2 is

wherein r is 1, p is zero, R 1 is H, halo, CH 3 , CF 3 , CHF 2 , OH, NO 2 , or CN; R 8 is H, Cl, Br, I, CH 3 , C 3-4 alkyl, C 3-4 alkoxy, cyclohexyl, CF 3 , CH 2 CF 3 , or OCF 3 ; and R 8 is connected at the 4-position of the phenyl ring.

70. The compound of claim 1 , wherein m is 0.

71. The compound of claim 1 , wherein Ar 1 is a pyridyl group.

72. The compound of claim 1 , wherein Ar 2 is

73. The compound of claim 72 , wherein s is 0 or 1.

74. The compound of claim 1 , wherein Ar 2 is

75. The compound of claim 74 , wherein r is 0 or 1.

76. The compound of claim 1 , wherein Ar 2 is

77. The compound of claim 76 , wherein each R 8 is independently —H, halo, —(C 1 -C 6 )alkyl, —O(C 1 -C 6 )alkyl, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo).

78. The compound of claim 77 , wherein s is 0, 1 or 2.

79. A composition comprising the compound or a pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.

80. A method for treating pain in an animal, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1 .

81. A method for making the cyclo(hetero)alkenyl compound of claim 6 , comprising allowing a 1-heteroaromatic-1,2,3,6-tetrahydro-pyridine-4-carboxylic acid compound to react with a compound of formula Ar 2 —NHR 4 to provide the cyclo(hetero)alkenyl compound.

82. A method for making the cyclo(hetero)alkenyl compound of claim 6 , comprising allowing a 1,2,3,6-tetrahydro-pyridine-4-carboxylic acid amide compound to react with a compound of formula Ar 1 —Z to provide the cyclo(hetero)alkenyl compound; wherein Z is Cl, Br or I.