CA2511509A1 - Benzoazolylpiperazine derivatives having vr1 antagonist activity - Google Patents

Benzoazolylpiperazine derivatives having vr1 antagonist activity Download PDF

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CA2511509A1
CA2511509A1 CA002511509A CA2511509A CA2511509A1 CA 2511509 A1 CA2511509 A1 CA 2511509A1 CA 002511509 A CA002511509 A CA 002511509A CA 2511509 A CA2511509 A CA 2511509A CA 2511509 A1 CA2511509 A1 CA 2511509A1
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compound
halo
animal
effective amount
alkyl
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Qun Sun
Laykea Tafesse
Sam Victory
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Euro Celtique SA
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Abstract

A compound of formula (I) wherein Ar1, A, R3, x, and m are as disclosed herein and Ar2 is a benzothiazolyl, benzooxazolyl, or benzoimidazolyl group or a pharmaceutically acceptable salt thereof (a ~Benzoazolylpiperazine Compound~), compositions comprising a Benzoazolylpiperazine Compound, and methods for treating or preventing pain, UI, an ulcer, IBD, IBS, an addictive disorder, Parkinson~s disease, parkinsonism, anxiety, epilepsy, stroke, a seizure, a pruritic condition, psychosis, a cognitive disorder, a memory deficit, retricted brain function, Huntington~s chorea, amyotrophic lateral sclerosis, dementia, retinopathy, a muscle spasm, a migraine, vomiting, dyskinesia, or depression in an animal comprising administering to an animal in need thereof an effective amount of Benzoazolylpiperazine Compound are disclosed.

Claims (239)

1. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein R1 is -Cl, -Br, -I, -(C1-C6)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, or -NH2;

(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkyl, -(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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
each R3 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, 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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R4 is -H or -(C1-C6)alkyl;
each R5 is independently -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 R6 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -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 R7 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2;

R8 and R9 are each independently -H, -(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, -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 -halo is -F, -Cl, -Br,- or -I;
n is an integer ranging from 0 to 3;
p is an integer ranging from 0 to 2;
m is 0 or 1; and x is 0 or 1.
2. The compound of claim 1, wherein Ar1 is a pyridyl group.
3. The compound of claim 1, wherein x is 1 and A is -C(O)N(R4)-.
4. The compound of claim 1, wherein Ar1 is a pyridyl group, x is 1, and A is -C(O)N(R4)-.
5. The compound of claim 1, wherein Ar1 is a pyridyl group, x is 1, and A is -C(S)N(R4)-.
6. The compound of claim 1, wherein n or p is 0.
7. The compound of claim 1, wherein n or p is 1.
8. The compound of claim 1, wherein x is 0.
9. The compound of claim 1, wherein Ar1 is a pyrimidinyl group
10. The compound of claim 1, wherein Ar1 is a pyrimidinyl group, x is 1, and A
is -C(O)N(R4)-.
11. The compound of claim 1, wherein Ar1 is a pyrimidinyl group, x is 1, and A
is -C(S)N(R4)-.
12. The compound of claim 1, wherein:
R1 is -CH3, CF3, -Cl, -Br, or -I;
m is 0;
n or p is 0;
x is 1;
A is -C(O)-N(R4)-;
R4 is -H;
R8 is -H; and R9 is -CH3, CF3, -OCH2CH3, tert-butyl, Cl, -Br-, or -F.
13. The compound of claim 12, wherein Ar1 is a pyridyl group.
14. The compound of claim 13, wherein R1 is -CH3 and R9 is -Cl.
15. The compound of claim 13, wherein R1 is -CH3 and R9 is -Br.
16. The compound of claim 13, wherein R1 is -CH3 and R9 is -F.
17. The compound of claim 13, wherein R1 is -Cl and R9 is -Cl.
18. The compound of claim 13, wherein R1 is -Cl and R9 is -Br.
19. The compound of claim 13, wherein R1 is -Cl and R9 is -Cl.
20. The compound of claim 1, wherein:
R1 is -CH3, CF3, -Cl, -Br, or -I;
m is 1;
R3 is -(C1-C10)alkyl;
n or p is 0;
x is 1;
A is -C(O)-N(R4)-;
R4 is -H;
R8 is -H; and R9 is -CH3, CF3, -OCH2CH3, tert-butyl, Cl, -Br-, or -F.
21. The compound of claim 20, wherein R3 is -CH3.
22. The compound of claim 20, wherein the carbon to which R3 is attached is in the (R) configuration.
23. The compound of claim 20, wherein R3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -C(O)-N(R4)-group.
24. The compound of claim 20, wherein Ar1 is a pyridyl group.
25. The compound of claim 24, wherein R1 is -CH3 and R9 is -Cl.
26. The compound of claim 25, wherein the carbon to which R3 is attached is in the (R) configuration.
27. The compound of claim 24, wherein R1 is -CH3 and R9 is -Br.
28. The compound of claim 27, wherein the carbon to which R3 is attached is in the (R) configuration.
29. The compound of claim 24, wherein R1 is -CH3 and R9 is -F.
30. The compound of claim 29, wherein the carbon to which R3 is attached is in the (R) configuration.
31. The compound of claim 24, wherein R1 is -Cl and R9 is -Cl.
32. The compound of claim 31, wherein the carbon to which R3 is attached is in the (R) configuration.
33. The compound of claim 24, wherein R1 is -Cl and R9 is -Br.
34. The compound of claim 33, wherein the carbon to which R3 is attached is in the (R) configuration.
35. The compound of claim 24, wherein R1 is -Cl and R9 is -Cl.
36. The compound of claim 35, wherein the carbon to which R3 is attached is in the (R) configuration.
37. The compound of claim 1, wherein m is 1 and the carbon to which R3 is attached is in the (R) configuration.
38. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein R1 is -H, -halo, -(C1-C6)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, or -NH2;
-(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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
each R3 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, 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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R4 is -H or -(C1-C6)alkyl;
each R5 is independently -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 R6 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -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 R7 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2;
R8 and R9 are each independently -H, -(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, -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 -halo is -F, -Cl, -Br,- or -I;
p is an integer ranging from 0 to 2;
m is 0 or 1; and x is 0 or 1.
39. The compound of claim 38, wherein x is 1 and A is -C(O)N(R4)-.
40. The compound of claim 38, wherein Ar1 is a pyrazinyl group.
41. The compound of claim 38, wherein Ar1 is a pyridazinyl group.
42. The compound of claim 38, wherein Ar1 is a thiazanyl group.
43. The compound of claim 38, wherein Ar1 is a pyrazinyl group, x is 1, and A
is -C(O)N(R4)-.
44. The compound of claim 38, wherein Ar1 is a pyrazinyl group, x is 1, and A
is -C(S)N(R4)-.
45. The compound of claim 38, wherein Ar1 is a pyridazinyl group, x is 1, and A is -C(O)N(R4)-.
46. The compound of claim 38, wherein Ar1 is a pyridazinyl group, x is 1, and A is -C(S)N(R4)-.
47. The compound of claim 38, wherein Ar1 is a thiazanyl group, x is 1, and A
is -C(O)N(R4)-.
48. The compound of claim 38, wherein Ar1 is a thiazanyl group, x is 1, and A
is -C(S)N(R4)-.
49. The compound of claim 38, wherein p is 0.
50. The compound of claim 38, wherein p is 1.
51. The compound of claim 38, wherein x is 0.
52. The compound of claim 38, wherein:
R1 is -CH3, CF3, -Cl, -Br, or -I;
m is 0;
p is 0;
x is 1;
A is -C(O)-N(R4)-;
R4 is -H;
R8 is -H; and R9 is -CH3, CF3, -OCH2CH3, tert-butyl, Cl, -Br-, or -F.
53. The compound of claim 52, wherein R1 is -CH3 and R9 is -Cl.
54. The compound of claim 52, wherein R1 is -CH3 and R9 is -Br.
55. The compound of claim 52, wherein R1 is -CH3 and R9 is -F.
56. The compound of claim 52, wherein R1 is -Cl and R9 is -Cl.
57. The compound of claim 52, wherein R1 is -Cl and R9 is -Br.
58. The compound of claim 52, wherein R1 is -Cl and R9 is -Cl.
59. The compound of claim 38, wherein:
R1 is -CH3, CF3, -Cl, -Br, or -I;
m is 1;
R3 is -(C1-C10)alkyl;
p is 0;
x is 1;
A is -C(O)-N(R4)-;
R4 is -H;
R8 is -H; and R9 is -CH3, CF3, -OCH2CH3, tert-butyl, Cl, -Br-, or -F.
60. The compound of claim 59, wherein R3 is -CH3.
61. The compound of claim 59, wherein the carbon to which R3 is attached is in the (R) configuration.
62. The compound of claim 59, wherein R3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -C(O)-N(R4)-group.
63. The compound of claim 59, wherein R1 is -CH3 and R9 is -Cl.
64. The compound of claim 63, wherein the carbon to which R3 is attached is in the (R) configuration.
65. The compound of claim 59, wherein R1 is -CH3 and R9 is -Br.
66. The compound of claim 65, wherein the carbon to which R3 is attached is in the (R) configuration.
67. The compound of claim 59, wherein R1 is -CH3 and R9 is -F.
68. The compound of claim 67, wherein the carbon to which R3 is attached is in the (R) configuration.
69. The compound of claim 59, wherein R1 is -Cl and R9 is -Cl.
70. The compound of claim 69, wherein the carbon to which R3 is attached is in the (R) configuration.
71. The compound of claim 59, wherein R1 is -Cl and R9 is -Br.
72. The compound of claim 71, wherein the carbon to which R3 is attached is in the (R) configuration.
73. The compound of claim 59, wherein R1 is -Cl and R9 is -Cl.
74. The compound of claim 73, wherein the carbon to which R3 is attached is in the (R) configuration.
75. The compound of claim 38, wherein m is 1 and.the carbon to which R3 is attached is in the (R) configuration.
76. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein R1 is -Cl, -Br, -I, -(C1-C6)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, 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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
each R3 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkynyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl,-(C3-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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
each R5 is independently -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 R6 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -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 R7, is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2;
R8 and R9 are each independently -H, -(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, -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;
R10 is -H or -(C1-C4)alkyl;
each -halo is -F, -Cl, -Br,- or -I;
n is an integer ranging from 0 to 3;
p is an integer ranging from 0 to 2; and m is 0 or 1.
77. The compound of claim 76, wherein Ar1 is a pyridyl group.
78. The compound of claim 76, wherein Ar1 is a pyrimidinyl group.
79. The compound of claim 76, wherein Ar1 is a pyrazinyl group.
80. The compound of claim 76, wherein n or p is 0.
81. The compound of claim 76, wherein n or p is 1.
82. The compound of claim 76, wherein:
R1 is -CH3, CF3, -Cl, -Br, or -I;
m is 0;
n or p is 0;
R8 is -H; and R9 is -CH3, CF3, -OCH2CH3, tert-butyl, Cl, -Br-, or -F.
83. The compound of claim 82, wherein Ar1 is a pyridyl group.
84. The compound of claim 76, wherein:
R1 is -CH3, CF3, -Cl, -Br, or -I;
m is 1;
R3 is -(C1-C10)alkyl;
n or p is 0;
R8 is -H; and R9 is -CH3, CF3, -OCH2CH3, tert-butyl, Cl, -Br-, or -F.
85. The compound of claim 84, wherein R3 is -CH3.
86. The compound of claim 84, wherein the carbon to which R3 is attached is in the (R) configuration.
87. The compound of claim 76, wherein the carbon to which R3 is attached is in the (R) configuration.
88. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein R1 is -H, -halo, -(C1-C6)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, 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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
each R3 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkyl, -(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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R4 is -H or -(C1-C6)alkyl;
each R5 is independently -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 R6 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -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 R7 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2;
R8 and R9 are each independently -H, -(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, -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;
R10 is -H or -(C1-C4)alkyl;
each -halo is -F, -Cl, -Br,- or -I;
p is an integer ranging from 0 to 2;
m is 0 or 1; and x is 0 or 1.
89. The compound of claim 88, wherein Ar1 is a pyridazinyl group.
90. The compound of claim 88, wherein Ar1 is a thiazanyl group.
91. The compound of claim 88, wherein x is 1 and A is -C(O)N(R4)-.
92. The compound of claim 88, wherein Ar1 is a pyridazinyl group, x is 1, and A is -C(O)N(R4)-.
93. The compound of claim 88, wherein Ar1 is a pyridazinyl group, x is 1, and A is -C(S)N(R4)-.
94. The compound of claim 88, wherein p is 0.
95. The compound of claim 88, wherein p is 1.
96. The compound of claim 88, wherein x is 0.
97. The compound of claim 88, wherein Ar1 is a thiazanyl group.
98. The compound of claim 88, wherein Ar1 is a thiazanyl group, x is 1, and A
is -C(O)N(R4)-.
99. The compound of claim 88, wherein Ar1 is a thiazanyl group, x is 1, and A
is -C(S)N(R4)-.
100. The compound of claim 88, wherein:
R1 is -CH3, CF3, -Cl, -Br, or -I;
m is 0;

p is 0;
x is 1;
A is -C(O)-N(R4)-;
R4 is -H;
R8 is -H; and R9 is -CH3, CF3, -OCH2CH3, tert-butyl, Cl, -Br-, or -F.
101. The compound of claim 88, wherein:
R1 is -CH3, CF3, -Cl, -Br, or -I;
m is 1;
R3 is -(C1-C10)alkyl;
p is 0;
x is 1;
A is -C(O)-N(R4)-;
R4 is -H;
R8 is -H; and R9 is -CH3, CF3, -OCH2CH3, tert-butyl, Cl, -Br-, or -F.
102. The compound of claim 101, wherein R3 is -CH3.
103. The compound of claim 101, wherein the carbon to which R3 is attached is in the (R) configuration.
104. The compound of claim 101, wherein R3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -C(O)-N(R4)-group.
105. The compound of claim 88, wherein m is 1 and the carbon to which R3 is attached is in the (R) configuration.
106. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein Ar1 is A is R1 is -Cl, -Br, -I, -(C1-C6)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, or -NH2;

(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkyl, -(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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
each R3 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, 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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R4 is -H or -(C1-C6)alkyl;
each R5 is independently -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 R7 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -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 R7 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2;
R8 and R9 are each independently -H, -(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, -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 -halo is -F, -Cl, -Br,- or -I;
n is an integer ranging from 0 to 3;
p is an integer ranging from 0 to 2;
m is 0 or 1; and x is 0 or 1.
107. The compound of claim 106, wherein Ar1 is a pyridyl group.
108. The compound of claim 106, wherein x is 1 and A is -C(O)N(R4)-.
109. The compound of claim 106, wherein Ar1 is a pyridyl group, x is 1, and A
is -C(O)N(R4)-.
110. The compound of claim 106, wherein Ar1 is a pyridyl group, x is 1, and A
is -C(S)N(R4)-.
111. The compound of claim 106, wherein n or p is 0.
112. The compound of claim 106, wherein n or p is 1.
113. The compound of claim 106, wherein x is 0.
114. The compound of claim 106, wherein Ar1 is a pyrimidinyl group
115. The compound of claim 106, wherein Ar1 is a pyrimidinyl group, x is 1, and A
is -C(O)N(R4)-.
116. The compound of claim 106, wherein Ar1 is a pyrimidinyl group, x is 1, and A
is -C(S)N(R4)-.
117. The compound of claim 106, wherein:
R1 is -CH3, CF3, -Cl, -Br, or -I;
m is 0;
n or p is 0;
x is 1;
A is -C(O)-N(R4)-;
R4 is -H;
R8 is -H; and R9 is -CH3, CF3, -OCH2CH3, tert-butyl, Cl, -Br-, or -F.
118. The compound of claim 106, wherein:
R1 is -CH3, CF3, -Cl, -Br, or -I;
m is 1;
R3 is -(C1-C10)alkyl;
n or p is 0;
x is 1;
A is -C(O)-N(R4)-;
R4 is -H;
R8 is -H; and R9 is -CH3, CF3, -OCH2CH3, tert-butyl, Cl, -Br-, or -F.
119. The compound of claim 118, wherein R3 is -CH3.
120. The compound of claim 118, wherein the carbon to which R3 is attached is in the (R) configuration.
121. The compound of claim 118, wherein R3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -C(O)-N(R4)-group.
122. The compound of claim 106, wherein m is 1 and the carbon to which R3 is attached is in the (R) configuration.
123. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein Ar1 is R1 is -H, -halo, -(C1-C6)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkyl, -(C3-C10)cycloalkyl, -(C8-C14)bicycloalkyl, -(C8-C14)tricycloalkyl, -(C5-C10)cycloalkenyl,-(C8 C14)bicycloalkenyl, -(C8-C14)tricycloalkenyl, or -(7- to 10-membered)bicycloheterocycle, each of which is unsubstituted or substituted with one or more R5 groups; or (c) -phenyl, -naphthyl, or-(C14)aryl each of which is unsubstituted or substituted with one or more R6 groups;
each R3 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, 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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R4 is -H or -(C1-C6)alkyl;
each R5 is independently -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 R6 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -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 R7 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2;
R8 and R9 are each independently -H, -(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, -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 -halo is -F, -Cl, -Br,- or -I;
p is an integer ranging from 0 to 2;
m is 0 or 1; and x is 0 or 1.
124. The compound of claim 123, wherein Ar1 is a pyrazinyl group.
125. The compound of claim 123, wherein x is 1 and A is -C(O)N(R4)-.
126. The compound of claim 123, wherein Ar1 is a pyrazinyl group, x is 1, and A is -C(O)N(R4)-.
127. The compound of claim 123, wherein Ar1 is a pyrazinyl group, x is 1, and A is -C(S)N(R4)-.
128. The compound of claim 123, wherein p is 0.
129. The compound of claim 123, wherein p is 1.
130. The compound of claim 123, wherein x is 0.
131. The compound of claim 123, wherein Ar1 is a pyridazinyl group
132. The compound of claim 123, wherein Ar1 is a pyridazinyl group, x is 1, and A
is -C(O)N(R4)-.
133. The compound of claim 123, wherein Ar1 is a pyridazinyl group, x is 1, and A
is -C(S)N(R4)-.
134. The compound of claim 123, wherein Ar1 is a thiazanyl group.
135. The compound of claim 123, wherein Ar1 is a thiazanyl group, x is 1, and A is -C(O)N(R4)-.
136. The compound of claim 123, wherein Ar1 is a thiazanyl group, x is 1, and A is -C(S)N(R4)-.
137. The compound of claim 123, wherein:
R1 is -CH3, CF3, -Cl, -Br, or -I;
m is 0;
p is 0;
x is 1;
A is -C(O)-N(R4)-;
R4 is -H;
R8 is -H; and R9 is -CH3, CF3, -OCH2CH3, tert-butyl, Cl, -Br-, or -F.
138. The compound of claim 123, wherein:
R1 is -CH3, CF3, -Cl, -Br, or -I;
m is 1;
R3 is -(C1-C10)alkyl;
p is 0;
x is 1;
A is -C(O)-N(R4)-;
R4 is -H;
R8 is -H; and R9 is -CH3, CF3, -OCH2CH3, tert-butyl, Cl, -Br-, or -F.
139. The compound of claim 138, wherein R3 is -CH3.
140. The compound of claim 138, wherein the carbon to which R3 is attached is in the (R) configuration.
141. The compound of claim 138, wherein R3 is attached to a carbon atom adjacent to a nitrogen atom attached to the -C(O)-N(R4)-group.
142. The compound of claim 123, wherein m is 1 and the carbon to which R3 is attached is in the (R) configuration.
143. A composition comprising the compound or a pharmaceutically acceptable salt of the compound of any one of claims 1, 38, 76, 88, 106, or 123 and a pharmaceutically acceptable vehicle.
144. A method for treating or preventing 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 any one of claims 1, 38, 76, 88, 106, or 123.
145. A method for treating or preventing urinary incontinence 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 any one of claims 1, 38, 76, 88, 106, or 123.
146. A method for treating or preventing an ulcer 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 any one of claims 1, 38, 76, 88, 106, or 123.
147. A method for treating or preventing irritable-bowel syndrome 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 any one of claims 1, 38, 76, 88, 106, or 123.
148. A method for treating or preventing inflammatory-bowel disease 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 any one of claims 1, 38, 76, 88, 106, or 123.
149. A method for treating or preventing an addictive disorder 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 any one of claims 1, 38, 76, 88, 106, or 123.
150. A method for treating or preventing Parkinson's disease 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 any one of claims 1, 38, 76, 88, 106, or 123.
151. A method for treating or preventing parkinsonism 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 any one of claims 1, 38, 76, 88, 106, or 123.
152. A method for treating or preventing anxiety 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 any one of claims 1, 38, 76, 88, 106, or 123.
153. A method for treating or preventing epilepsy 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 any one of claims 1, 38, 76, 88, 106, or 123.
154. A method for treating or preventing stroke 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 any one of claims 1, 38, 76, 88, 106, or 123.
155. A method for treating or preventing a seizure 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 any one of claims 1, 38, 76, 88, 106, or 123.
156. A method for treating or preventing a pruritic condition 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 any one of claims 1, 38, 76, 88, 106, or 123.
157. A method for treating or preventing psychosis 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 any one of claims 1, 38, 76, 88, 106, or 123.
158. A method for treating or preventing a cognitive disorder 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 any one of claims 1, 38, 76, 88, 106, or 123.
159. A method for treating or preventing a memory deficit 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 any one of claims 1, 38, 76, 88, 106, or 123.
160. A method for treating or preventing restricted brain function 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 any one of claims 1, 38, 76, 88, 106, or 123.
161. A method for treating or preventing Huntington's chorea 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 any one of claims 1, 38, 76, 88, 106, or 123.
162. A method for treating or preventing amyotrophic lateral sclerosis 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 any one of claims 1, 38, 76, 88, 106, or 123.
163. A method for treating or preventing retinopathy 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 any one of claims 1, 38, 76, 88, 106, or 123.
164. A method for treating or preventing a muscle spasm 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 any one of claims 1, 38, 76, 88, 106, or 123.
165. A method for treating or preventing a migraine 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 any one of claims 1, 38, 76, 88, 106, or 123.
166. A method for treating or preventing vomiting 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 any one of claims 1, 38, 76, 88, 106, or 123.
167. A method for treating or preventing dyskinesia 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 any one of claims 1, 38, 76, 88, 106, or 123.
168. A method for treating or preventing depression 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 any one of claims 1, 38, 76, 88, 106, or 123.
169. 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 any one of claims 1, 38, 76, 88, 106, or 123.
170. A method for inhibiting mGluR5 function in a cell comprising contacting a cell capable of expressing mGluR5 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of any one of claims 1, 38, 76, 88, 106, or 123.
171. A method for inhibiting mGluR1 function in a cell comprising contacting a cell capable of expressing mGluR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of any one of claims 1, 38, 76, 88, 106, or 123.
172. A kit comprising a container containing an effective amount of the compound or a pharmaceutically acceptable salt of the compound of any one of claims 1, 38, 76, 88, 106, or 123.
173. A method for preparing a composition comprising the step of admixing a compound or a pharmaceutically acceptable salt of the compound of any one of claims 1, 38, 76, 88, 106, or 123 and a pharmaceutically acceptable vehicle.
174. A compound selected from the group consisting of and pharmaceutically acceptable salts thereof.
175. A compound selected from the group consisting of and pharmaceutically acceptable salts thereof.
176. A compound selected from the group consisting of and pharmaceutically acceptable salts thereof.
177. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein Ar1 is R1 is -halo, -(C1-C6)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, 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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R3 is -H or -CH3:
each R5 is independently -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 R6 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -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 R7 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2;
R8 and R9 are each independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -C(halo)3, -CH(halo)2, -CH2(halo), -OC(halo)3, -OCH(halo)2, -OCH2(halo), -CN, -OH, -halo, -N3, -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 -halo is -F, -Cl, -Br,- or -I;
n is an integer ranging from 0 to 3; and p is an integer ranging from 0 to 2.
178. A compound of formula:

or a pharmaceutically acceptable salt thereof, wherein R1 is -halo, -(C1-C6)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, or -NH2;
(b) -(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkyl, -(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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R3 is -CH3;
R4 is -H or -(C1-C6)alkyl;
each R5 is independently -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 R6 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -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 R7 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2;
R8 and R9 are each independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -C(halo)3, -CH(halo)2, -CH2(halo), -OC(halo)3, -OCH(halo)2, -OCH2(halo), -CN, -OH, -halo, -N3, -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 -halo is -F, -Cl, -Br,- or -I;
n is an integer ranging from 0 to 3;
p is an integer ranging from 0 to 2; and x is 0 or 1.
179. A composition comprising the compound or a pharmaceutically acceptable salt of the compound of any one of claims 177 or 178 and a pharmaceutically acceptable vehicle.
180. A method for treating or preventing 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 any one of claims 177 or 178.
181. A method for treating or preventing urinary incontinence 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 any one of claims 177 or 178.
182. A method for treating or preventing an ulcer 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 any one of claims 177 or 178.
183. A method for treating or preventing irritable-bowel syndrome 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 any one of claims 177 or 178.
184. A method for treating or preventing inflammatory-bowel disease 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 any one of claims 177 or 178.
185. A method for treating or preventing an addictive disorder 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 any one of claims 177 or 178.
186. A method for treating or preventing Parkinson's disease 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 any one of claims 177 or 178.
187. A method for treating or preventing parkinsonism 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 any one of claims 177 or 178.
188. A method for treating or preventing anxiety 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 any one of claims 177 or 178.
189. A method for treating or preventing epilepsy 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 any one of claims 177 or 178.
190. A method for treating or preventing stroke 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 any one of claims 177 or 178.
191. A method for treating or preventing a seizure 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 any one of claims 177 or 178.
192. A method for treating or preventing a pruritic condition 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 any one of claims 177 or 178.
193. A method for treating or preventing psychosis 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 any one of claims 177 or 178.
194. A method for treating or preventing a cognitive disorder 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 any one of claims 177 or 178.
195. A method for treating or preventing a memory deficit 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 any one of claims 177 or 178.
196. A method for treating or preventing restricted brain function 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 any one of claims 177 or 178.
197. A method for treating or preventing Huntington's chorea 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 any one of claims 177 or 178.
198. A method for treating or preventing amyotrophic lateral sclerosis 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 any one of claims 177 or 178.
199. A method for treating or preventing retinopathy 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 any one of claims 177 or 178.
200. A method for treating or preventing a muscle spasm 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 any one of claims 177 or 178.
201. A method for treating or preventing a migraine 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 any one of claims 177 or 178.
202. A method for treating or preventing vomiting 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 any one of claims 177 or 178.
203. A method for treating or preventing dyskinesia 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 any one of claims 177 or 178.
204. A method for treating or preventing depression 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 any one of claims 177 or 178.
205. 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 any one of claims 177 or 178.
206. A method for inhibiting mGluR5 function in a cell comprising contacting a cell capable of expressing mGluR5 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of any one of claims 177 or 178.
207. A method for inhibiting mGluR1 function in a cell comprising contacting a cell capable of expressing mGluR1 with an effective amount of the compound or a pharmaceutically acceptable salt of the compound of any one of claims 177 or 178.
208. A kit comprising a container containing an effective amount of the compound or a pharmaceutically acceptable salt of the compound of any one of claims 177 or 178.
209. A method for preparing a composition comprising the step of admixing a compound or a pharmaceutically acceptable salt of the compound of any one of claims 177 or 178 and a pharmaceutically acceptable vehicle.
210. A composition comprising:
(i) an effective amount of a compound of formula:

or a pharmaceutically acceptable salt thereof, wherein Ar1 is Ar2 is R1 is -halo, -(C1-C6)alkyl, -NO2, -CN, -OH, -OCH3, -NH2, -C(halo)3, -CH(halo)2, or -CH2(halo);
each R2 is independently:
(a) -halo, -CN, -OH, -O(C1-C6)alkyl, -NO2, or -NH2;
-(C1-C10)alkyl, -(C2-C10)alkenyl, -(C2-C10)alkyl, -(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 R5 groups; or (c) -phenyl, -naphthyl, -(C14)aryl, or -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with one or more R6 groups;
R3 is -H or -CH3:
each R5 is independently -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 R6 is independently -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -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 R7 is independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -(C3-C5)heterocycle, -C(halo)3, -CH2(halo), or -CH(halo)2;

R8 and R9 are each independently -H, -(C1-C6)alkyl, -(C2-C6)alkenyl, -(C2-C6)alkynyl, -(C3-C8)cycloalkyl, -(C5-C8)cycloalkenyl, -phenyl, -C(halo)3, -CH(halo)2, -CH2(halo), -OC(halo)3, -OCH(halo)2, -OCH2(halo), -CN, -OH, -halo, -N3, -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 -halo is -F, -Cl, -Br,- or -I;
n is an integer ranging from 0 to 3; and p is an integer ranging from 0 to 2; and (ii) a pharmaceutically acceptable carrier or excipient.
211. A method for treating or preventing pain in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
212. A method for treating or preventing urinary incontinence in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
213. A method for treating or preventing an ulcer in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
214. A method for treating or preventing irritable-bowel syndrome in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
215. A method for treating or preventing inflammatory-bowel disease in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
216. A method for treating or, preventing an addictive disorder in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
217. A method for treating or preventing Parkinson's disease in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
218. A method for treating or preventing parkinsonism in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
219. A method for treating or preventing anxiety in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
220. A method for treating or preventing epilepsy in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
221. A method for treating or preventing stroke in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
222. A method for treating or preventing a seizure in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
223. A method for treating or preventing a pruritic condition in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
224. A method for treating or preventing psychosis in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
225. A method for treating or preventing a cognitive disorder in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
226. A method for treating or preventing a memory deficit in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
227. A method for treating or preventing restricted brain function in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
228. A method for treating or preventing Huntington's chorea in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
229. A method for treating or preventing amyotrophic lateral sclerosis in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
230. A method for treating or preventing retinopathy in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
231. A method for treating or preventing a muscle spasm in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
232. A method for treating or preventing a migraine in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
233. A method for treating or preventing vomiting in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
234. A method for treating or preventing dyskinesia in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
235. A method for treating or preventing depression in an animal, comprising administering to an animal in need thereof an effective amount of the composition of claim 210.
236. A method for inhibiting VR1 function in a cell comprising contacting a cell capable of expressing VR1 with an effective amount of the composition of claim 210.
237. A method for inhibiting mGluR5 function in a cell comprising contacting a cell capable of expressing mGluR5 with an effective amount of the composition of claim 210.
238. A method for inhibiting mGluR1 function in a cell comprising contacting a cell capable of expressing mGluR1 with an effective amount of the composition of claim 210.
239. A kit comprising a container containing an effective amount of the composition of claim 210.
CA2511509A 2002-12-24 2003-12-22 Benzoazolylpiperazine derivatives having vr1 antagonist activity Expired - Fee Related CA2511509C (en)

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US47385603P 2003-05-29 2003-05-29
US60/473,856 2003-05-29
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