CA2500113A1 - Therapeutic piperazine compounds - Google Patents

Therapeutic piperazine compounds Download PDF

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CA2500113A1
CA2500113A1 CA002500113A CA2500113A CA2500113A1 CA 2500113 A1 CA2500113 A1 CA 2500113A1 CA 002500113 A CA002500113 A CA 002500113A CA 2500113 A CA2500113 A CA 2500113A CA 2500113 A1 CA2500113 A1 CA 2500113A1
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halo
phenyl
alkyl
membered
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CA2500113C (en
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Qun Sun
Xiaoming Zhou
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Euro Celtique SA
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Abstract

A compound of formula: wherein Ar, Ar1, Ar2, R3-R6, R13, m, and t are disclosed herein, or a pharmaceutically acceptable salt thereof (a "Hydroxyiminopiperazine Compound"); compositions comprising an effective amount of a Hydroxyiminopiperazine Compound; and methods for treating or preventing pain and other conditions in an animal comprising administering to an animal in need thereof an effective amount of a Hydroxyiminopiperazine Compound are disclosed.

Claims (133)

What is claimed is:
1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein;
R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, NO2, -O(C1-C6)alkyl, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
each R3 is independently:
(a) -halo, -CN, -OH, NO2, -O(C1-C6)alkyl, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
R4 is -H, -(C1-C10)alkyl, -C(O)R9, or -C(O)NHR9;

R5 is -H or -(C1-C10)alkyl;
R6 is:
(a) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (b) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
each R7 and R8 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R10)2, -CH=NR10, -NR10OH,-OR10, -COR10, -C(O)OR10, -OC(O)R10, -OC(O)OR10, -SR10, -S(O)R10, or -S(O)2Ri10;
each R9 is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -OH, -N(R10)2, -CH=NR10, -NR10OH, -OR10, or -SR10;
each R10 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, or -CH2(halo);
each halo is independently -F, -C1, -Br, or -I;
n is an integer ranging from 0 to 2; and m is an integer ranging from 0 to 2.
2. The compound of claim 1, wherein:
n is 0;
m is 0; and R6 is phenyl.
3. The compound of claim 2, wherein the R6 phenyl is unsubstituted.
4. The compound of claim 2, wherein the R6 phenyl is substituted at the para-position.
5. The compound of claim 4, wherein the R6 phenyl is substituted with a -(C1-C6) alkyl group.
6. The compound of claim 5, wherein the -(Cl-C6) alkyl group is a tert-butyl group.
7. The compound of claim 5, wherein the -(C1-C6) alkyl group is an iso-propyl group.
8. The compound of claim 4, wherein the phenyl is substituted with a -CF3 group.
9. The compound of claim 1, wherein:
n is 0;
m is 1;
R3 is methyl; and R6 is phenyl.
10. The compound of claim 9, wherein the R6 phenyl is unsubstituted.
11. The compound of claim 9, wherein the R6 phenyl is substituted at the para-position.
12. The compound of claim 11, wherein the R6 phenyl is substituted with a -(C1-C6) alkyl group.
13. The compound of claim 12, wherein the -(C1-C6) alkyl group is a tert-butyl group.
14. The compound of claim 12, wherein the -(C1-C6) alkyl group is an iso-propyl group.
15. The compound of claim 11, wherein the R6 phenyl is substituted with a -CF3 group.
16. The compound of claim 1. wherein R4 is -H.
17. The compound of claim 1, wherein R4 is -(C2-C10)alkyl.
18. The compound of claim 1, wherein R4 is -C(O)R9.
19. The compound of claim 1, wherein R4 is -C(O)NHR9.
20. A compound of formula (II):

or a pharmaceutically acceptable salt thereof, wherein:

R1 is -halo, -CH3, -N02, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);

each R2 is independently:

(a) -halo, -CN, -OH, NO2, -O(C1-C6)alkyl, or -NH2;

(b) -(C1-C10)alkyl -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;

each R3 is independently:

(a) -halo, -CN, -OH, NO2, -O(C1-C6)alkyl, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalky, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups:
R4 is -H, -(C1-C10)alkyl, -C(O)R9, or -C(O)NHR9;
R5 is -H or -(C1-C10)alkyl;
R6 is:

(a) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicyC10alkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl,-(C8 C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10 membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (b) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
each R7 and R8 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered).heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R10)2, -CH=NR10, -NR10OH, -OR10, -COR10, -C(O)OR10, -OC(O)R10, -OC(O)OR10, -SR10, -S(O)R10, or -S(O)2R10;
each R9 is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -OH, -N(R10)2, -CH=NR10, -NR10OH, -OR10, or -SR10;
each R10 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, - (C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, CH(halo)2, or -CH2(halo);
each halo is independently -F, -C1, -Br, or -I;
p is an integer ranging from 0 to 2; and m is an integer ranging from 0 to 2.
21. The compound of claim 20, wherein:
p is 0;
m is 0; and R6 is phenyl.
22. The compound of claim 21, wherein the R6 phenyl is unsubstituted.
23. The compound of claim 21, wherein the R6 phenyl is substituted at the para-position.
24. The compound of claim 23, wherein the R6 phenyl is substituted with a -(C1-C6) alkyl group.
25. The compound of claim 24, wherein the -(C1-C6) alkyl group is a tert-butyl group.
26. The compound of claim 24, wherein the -(C1-C6) alkyl group is an iso-propyl group.
27. The compound of claim 23, wherein the R6 phenyl is substituted with a -CF3 group.
28. The compound of claim 20, wherein:

p is 0;

m is 1;

R3 is methyl; and R6 is phenyl.
29. The compound of claim 28, wherein the R6 phenyl is unsubstituted.
30. The compound of claim 28, wherein the R6 phenyl is substituted at the para-position.
31. The compound of claim 30, wherein the R6 phenyl is substituted with a -(C1-C5) alkyl group.
32. The compound of claim 31, wherein the -(C1-C6) alkyl group is a tert-butyl group.
33. The compound of claim 31, wherein the -(C1-C6) alkyl group is an iso-propyl group.
34. The compound of claim 30, wherein the R6 phenyl is substituted with a -CF3 group.
35. The compound of claim 20, wherein R4 is -H.
36. The compound of claim 20, wherein R4 is -(C1-C10)alkyl.
37. The compound of claim 20 wherein R4 is -C(O)R9.
38. The compound of claim 20, wherein R4 is -C(O)NHR9.
39. A compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, NO2, -O(C1-C6)alkyl, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloatkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-.membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
each R3 is independently:
(a) -halo, -CN, -OH, NO2, -O(C1-C6)alkyl, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
R4 is -H, -(C1-C10)alkyl, -C(O)R9, or -C(O)NHR9;
R5 is -H or -(C1-C10)alkyl;
R6 is:

(a) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (b) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
each R7 and R8 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R10)2, -CH=NR10, -NR10OH, -OR10, -COR10, -C(O)OR10, -OC(O)R10, -OC(O)OR10, -SR10, -S(O)R10, or -S(O)2R10;
each R9 is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -OH, -N(R10)2; -CH=NR10, -NR10OH, -OR10, or -SR10;
each R10 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, or -CH2(halo);
each halo is independently -F, -Cl, -Br, or -I;
p is an integer ranging from 0 to 2; and m is an integer ranging from 0 to 2.
40. The compound of claim 39, wherein:
p is 0;
m is 0; and R5 is phenyl.
41. The compound of claim 40, wherein the R6 phenyl is unsubstituted.
42. The compound of claim 40, wherein the R6 phenyl is substituted at the para-position.
43. The compound of claim 42, wherein the R6 phenyl is substituted with a -(C1-C6) alkyl group.
44. The compound of claim 43, wherein the -(C1-C5) alkyl group is a tert-butyl group.
45. The compound of claim 43, wherein the -(C1-C6) alkyl group is an iso-propyl group.
46. The compound of claim 42, wherein the R6 phenyl is substituted with a -CF3 group.
47. The compound of claim 39, wherein:
p is 0;
m is 1;
R3 is methyl; and R6 is phenyl.
48. The compound of claim 47, wherein the R6 phenyl is unsubstituted.
49. The compound of claim 47, wherein the R6 phenyl is substituted at the para-position.
50. The compound of claim 49, wherein the R6 phenyl is substituted with a -(C1-C6) alkyl group.
51. The compound of claim 50, wherein the -(C1-C6) alkyl group is a tert-butyl group.
52. The compound of claim 50, wherein the -(C1-C6) alkyl group is an iso-propyl group.
53. The compound of claim 49, wherein the R6 phenyl is substituted with a -CF3 group.
54. The compound of claim 39, wherein R4 is -H.
55. The compound of claim 39, wherein R4 is -(C1-C10)alkyl.
56. The compound of claim 39, wherein R4 is -C(O)R9.
57. The compound of claim 39, wherein R4 is -C(O)NHR9.
58. A compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein:
R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, =NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, NO2, -O(C1-C6)alkyl, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
each R3 is independently:
(a) -halo, -CN, -OH, NO2, -O(C1-C6)alkyl, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
R4 is -H, -(C1-C10)alkyl, -C(O)R9, or -C(O)NHR9;
R5 is -H or -(C1-C10)alkyl;
R6 is:

(a) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (b) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
each R7 and R8 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, =halo, -N3, -NO2, -N(R10)2, -CH=NR10, -NR10OH, -OR10, -COR10, -C(O)OR10, -OC(O)R10, -OC(O)OR10, -SR10, -S(O)R10, or -S(O)2R10;
each R9 is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -OH, -N(R10)2, -CH=NR10, -NR10OH, -OR10, or -SR10;
each R10 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-, C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, or -CH2(halo);
each halo is independently -F, -Cl, -Br, or -I;
p is an integer ranging from 0 to 2; and m is an integer ranging from 0 to 2.
59. The compound of claim 58, wherein:
p is 0;
m is 0; and R6 is phenyl.
60. The compound of claim 59, wherein the R6 phenyl is unsubstituted.
61. The compound of claim 59, wherein the R6 phenyl is substituted at the para-position.
62. The compound of claim 61, wherein the R6 phenyl is substituted with a -(C1-C6) alkyl group.
63. The compound of claim 62, wherein the -(C1-C6) alkyl group is a tert-butyl group.
64. The compound of claim 62, wherein the -(C1-C6) alkyl group is an iso-propyl group.
65. The compound of claim 61, wherein the R6 phenyl is substituted with a -CF3 group.
66. The compound of claim 58, wherein:
p is 0;
m is l;
R3 is methyl: and R6 is phenyl.
67. The compound of claim 66, wherein the R6 phenyl is unsubstituted.
68. The compound of claim 66, wherein the R6 phenyl is substituted at the para-, position.
69. The compound of claim 68; wherein the R6 phenyl is substituted with a -(C1-C6) alkyl group.
70. The compound of claim 69, wherein the -(C1-C6) alkyl group is a tert-butyl group.
71. The compound of claim 69, wherein the -(C1-C6) alkyl group is an iso-propyl group.
72. The compound of claim 68, wherein the R6 phenyl is substituted wits a -CF3 group.
73. The compound of claim 58, wherein R4 is -H.
74. The compound of claim 58, wherein R4 is -(C1-C10)alkyl.
75. The compound of claim 58, wherein R4 is -C(O)R9.
76. The compound of claim 58, wherein R4 is -C(O)NHR9.
77. A compound of formula (V):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -C.H(halo)2, or -CH2(halo);
each R3 is independently:
(a) -halo, -CN, -OH, NO2, or -NH2;
(b) -(C1-C10)alkyl -(C2-C10)alkenyl, -(C2-C10)alkynyl,-(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C2-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted dr substituted with one or.
more R7 goups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
R4 is -H, -(C1-C10)alkyl, -C(O)R9, or -C(O)NHR9;
R5 is -H or -(C1-C10)alkyl;
R6 is:
(a) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl,-(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 goups; or (b) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 goups;
each R7 and R8 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R10)2, -CH=NR10, -NR10OH, -OR10, -COR10, -C(O)OR10, -OC(O)R10, -OC(O)OR1, -SR10, -S(O)R10, or -S(O)2R10;
each R9 is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -OH, -N(R10)2, -CH=NR10, -NR10OH, -OR10, or -SR10;
each R10 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, or -CH2(halo);
each halo is independently -F, -Cl, -Br, or -I; and m is an integer ranging from 0 to 2.
78. The compound of claim 77, wherein:
m is 0; and R6 is phenyl.
79. The compound of claim 78, wherein the R6 phenyl is unsubstituted.
8). The compound of claim 78, wherein the R6 phenyl is substituted at the para-position.
81. The compound of claim 80, wherein the R6 phenyl is substituted with a -(C1-C6) alkyl group.
82. The compound of claim 81, wherein the -(C1-C6) alkyl group is a tert-butyl group.
83. The compound of claim 81, wherein the -(C1-C6) alkyl group is an iso-propyl group.
84. The compound of claim 80, wherein the R6 phenyl is substituted with a -CF3 group.
85. The compound of claim 77, wherein:
m is 1;
R3 is methyl; and R6 is phenyl.
86. The compound of claim 85, wherein the R6 phenyl is unsubstituted.
87. The compound of claim 85, wherein the R6 phenyl is substituted at the para-position.
88. The compound of claim 87, wherein the R6 phenyl is substituted with a -(C1-C6) alkyl group.
89. The compound of claim 88, wherein the -(C1-C6) alkyl group is a tert-butyl group.
90. The compound of claim 88, wherein the -(C1-C6) alkyl group is an iso-propyl group.
91. The compound of claim 87, wherein the R6 phenyl is substituted with a -CF3 group.
92. The compound of claim 77, wherein R4 is -H.
93. The compound of claim 77, wherein R4 is -(C1-C10)alkyl.
94. The compound of claim 77, wherein R4 is -C(O)R9.
95. The compound of claim 77, wherein R4 is -C(O)NHR9.
96. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
97. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 20 and a pharmaceutically acceptable carrier or excipient.
98. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 39 and a pharmaceutically acceptable carrier or excipient.
99. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 58 and a pharmaceutically acceptable carrier or excipient.
100. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 77 and a pharmaceutically acceptable carrier or excipient.
101. A method for treating pain, 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.
102. A method for treating pain, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 20.
103. A method for treating pain, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 39.
104. A method for treating pain, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 58.
105. A method for treating pain, comprising administering to an animal in.
need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 77.
106. A method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 1.
107. A method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 20.
108. A method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 39.
109. A method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 58.
110. A method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 77.
111. The compound of claim 1, wherein m is 1 and R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the -C(=N-OR4)-NR5R6 group.
112. The compound of claim 111, wherein the carbon atom to which R3 is attached is in the (R) configuration.
113. The compound of claim 112, wherein R3 is -CH3, -CF3, or -CH2CH3.
114. The compound of claim 20, wherein m is 1 and R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the -C(=N-OR4)-NR5R6 group.
115. The compound of claim 114, wherein the carbon atom to which R3 is attached is in the (R) configuration.
116. The compound of claim 115, wherein R3 is -CH3, -CF3, or -CH2CH3.
117. The compound of claim 39, wherein m is 1 and R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the -C(=N-OR4)-NR5R6 group.
118. The compound of claim 117, wherein the carbon atom to which R3 is attached is in the (R) configuration.
119. The compound of claim 118, wherein R3 is -CH3, -CF3, or -CH2CH2.
120. The compound of claim 58, wherein m is 1 and R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the -C(=N-OR4)-NR5R6 group.
121. The compound of claim 120, wherein the carbon atom to which R3 is attached is in the (R) configuration.
122. The compound of claim 121. wherein R3 is -CH3, -CF3, or -CH2CH3.
123. The compound of claim 77, wherein m is 1 and R3 is attached to a carbon atom adjacent to the nitrogen atom attached to the -C(=N-OR4)-NR5R6 group.
124. The compound of claim 123, wherein the carbon atom to which R3 is attached is in the (R) configuration.
125. The compound of claim 124, wherein R3 is -CH3, -CF3, or -CH2CH3.
126. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is Ar2 is R1 is -H, -halo, -GH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, NO2, -O(C1-C6)alkyl, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
each R3 is independently:
(a) -halo, -CN, -OH, NO2, -O(C1-C6)alkyl, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
R4 is -H, -(C1-C10)alkyl, -C(O)R9, or -C(O)NHR9;
R5 is -H or -(C1-C10)alkyl;
each R7 and R8 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(CZ-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R10)2, -CH=NR10, -NR10OH, -OR10, -COR10, -C(O)OR10, -OC(O)R10, -OC(O)OR10, -SR10, -S(O)R10, or -S(O)2R10;
each R9 is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -OH, -N(R10)2, -CH=NR10, -NR10OH, -OR10, or -SR10;
each R10 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R11 and R12 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3 -NO2, -N(R7)2, -CH=NR7, -NR7OH, -OR7, -COR7, -C(O)OR7, -OC(O)R7, -OC(O)OR7, -SR7, -S(O)R7, or -S(O)2R7;
each R13 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, CH2(halo), or -halo;
each halo is independently -F, -Cl, -Br, or -I;
s is an integer ranging from 0 to 4;
o is an integer ranging from 0 to 4;
q is an integer ranging from 0 to 6;
r is an integer ranging from 0 to 5;
t is an integer ranging from 0 to 2;
p is are integer ranging from 0 to 2;
n is an integer ranging from 0 to 3; and m is an integer ranging from 0 to 2.
127. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein:
Ar1 is Ar2 is R1 is -H, -halo, -CH3, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, NO2, -O(C1-C6)alkyl, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
each R3 is independently:
(a) -halo, -CN, -OH, NO2, -O(C1-C6)alkyl, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl, -(C8-C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, -(3- to 7-membered)heterocycle, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R7 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R8 groups;
R4 is -H, -(C1-C10)alkyl, -C(O)R9, or -C(O)NHR9;
R5 is -H or -(C1-C10)alkyl;
each R7 and R8 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R10)2, -CH=NR10, -NR10OH, -OR10, -COR10, -C(O)OR10, -OC(O)R10, -OC(O)OR10, -SR10, -S(O)R10, or -S(O)2R10;
each R9 is -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, -CH2(halo), -OH, -N(R10)2, -CH=NR10, -NR10OH, -OR10, or -SR10;
each R10 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C5)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R11 and R12 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -C(halo)3, -CH(halo)2, -CH2(halo), -CN, -OH, -halo, -N3, -NO2, -N(R7)2, -CH=NR7, -NR7OH, -OR7, -COR7, -C(O)OR7, -OC(O)R7, -OC(O)CR7, -SR7, -S(O)R7, or -S(O)2R7;
each R13 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(3- to 5-membered)heterocycle, -C(halo)3, -CH(halo)2, CH2(halo), or -halo;
each halo is independently -F, -Cl, -Br, or -I;
s is an integer ranging from 0 to 4;
o is an integer ranging from 0 to 4;
q is an integer ranging from 0 to 6;
r is an integer ranging from 0 to 5;
t is an integer ranging from 0 to 2;
p is an integer ranging from 0 to 2;
n is an integer ranging from 0 to 3; and m is an integer ranging from 0 to 2.
128. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 126 and a pharmaceutically acceptable carrier or excipient.
129. A composition comprising an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 127 and a pharmaceutically acceptable carrier or excipient.
130. A method for treating pain, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 126.
131. A method for treating pain, comprising administering to an animal in need thereof an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 127.
132. A method for inhibiting VR1 function in. a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of. the compound or a pharmaceutically acceptable salt of the compound of claim 126.
133. A method for inhibiting VR1 function in a cell, comprising contacting a cell capable of expressing VR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of claim 127.
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