Heterocyclic compounds

1. A compound of Formula I:

or a pharmaceutically acceptable derivative thereof, wherein

Ar 1 is

Y is

Ar 2 is

Ar 3 is oxadiazole, isoxazole, oxazole, furan or pyrazole, each of which is unsubstituted or substituted with 1 or 2 independently selected R 6 groups;

Z is

(a) —(C 1 -C 6 )alkyl which is unsubstituted or substituted with 1 or 2 —OR 12 groups,

(b) —(C 2 -C 6 )alkenyl which is unsubstituted or substituted with 1 or 2 —OR 12 groups,

(c) —OR 12 , or

(d) —C(O)OR 7 ;

L 1 and L 2 are each independently a bond;

R 1 is —H, -halo, —NO 2 , —CN, —OR 7 , —N(R 7 ) 2 , —(C 1 -C 4 )alkyl, —C(halo) 3 , —CH(halo) 2 , CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , or —OC H2 (halo);

each R 2 is independently -halo, —OR 7 , —CN, —NO 2 , —N(R 7 ) 2 , —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, or -phenyl;

X is 0;

each R 3 is independently:

(a) —(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-OR13, —C(O)R 13 , —C(O)OR 13 , —N(R 13 )C(O)R 13 , or —C(O)N(R 13 ) 2 ;

(b) two R 3 groups together form ═O;

(c) two R 3 groups together form a (C 2 -C 6 ) bridge, which is unsubstituted or substituted with 1, 2 or 3 independently selected R 13 groups, and which bridge optionally contains —HC═CH— within the (C 2 -C 6 ) bridge; or

(d) two R 3 groups together form

R 4 is —H -halo, —(C 1 -C 6 )alkyl, —CH 2 OR 7 , —CH 2 (halo), —CH(halo) 2 , —C(halo) 3 , —OC(halo) 3 , —OR 7 , —SR 7 , —C(O)OR 7 , —C(O)R 7 , —OC(O)R 7 , —OC(O)N(R 8 ) 2 , —NR 7 C(O)R 13 , —C(O)N(R 8 ) 2 , —S(O) 2 R 7 , or —NO 2 ;

R 5 is —H, —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, —(C 1 -C 6 )alkyl-OC(O)R 7 , —C(O)R 7 , or —C(O)N(R 8 ) 2 ;

each R 6 is independently —(C 1 -C 6 )alkyl or two R 6 groups together form ═O;

each R 7 is independently —H or —(C 1 -C 6 )alkyl;

each R 8 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, or phenyl;

each R 9 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 7-membered)heterocycle, —(C 1 -C 6 )haloalkyl, —(C 2 -C 6 )haloalkenyl, —(C 2 -C 6 )haloalkynyl, —(C 1 -C 6 )hydroxyalkyl, —(C 2 -C 6 )hydroxyalkenyl, —(C 2 -C 6 )hydroxyalkynyl, —(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkoxy(C 2 -C 6 )alkenyl, —(C 1 -C 6 )alkoxy(C 2 -C 6 )alkynyl, —CN, -halo, —N 3 , —NO 2 , —CH═NR 13 , —N(R 13 ) 2 , —NR 13 OR 13 , —OR 13 , —SR 13 , —O(CH 2 ) b OR 13 , —O(CH 2 ) b SR 13 , —O(CH 2 ) b N(R 13 ) 2 , —N(R 13 )(CH 2 ) b OR 13 , —N(R 13 )(CH 2 ) b SR 13 , —N(R 13 )(CH 2 ) b N(R 13 ) 2 , —N(R 13 )C(O)R 13 , —C(O)R 13 , —C(O)OR 13 , —OC(O)R 13 , —OC(O)OR 13 , —S(O)R 13 , —S(O) 2 R 13 , —S(O) 2 N(R 13 ) 2 , —S(O) 2 -(3- to 7-membered)heterocycle, —C(O) 2 N(R 13 ) 2 , —(C 1 -C 6 )alkyl-C═N—OR 13 , —(C 1 -C 6 )alkyl-C(O)N(R 13 ) 2 , —(C 1 -C 6 )alkyl-NHS(O) 2 N(R 13 ) 2 , or —(C 1 -C 6 )alkylC(═NH)—N(R 13 ) 2 , each of which -phenyl, -(3- to 7-membered)heterocycle, or —(C 3 -C 6 )cycloalkyl is unsubstituted or substituted with 1, 2 or 3 independently selected R 13 groups;

each R 10 is independently:

(a) —(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, or -phenyl, each of which is unsubstituted or substituted with 1 or 2 —OH groups;

(b) —CH 2 CH 2 (halo), —CH 2 CH(halo) 2 , —CH 2 C(halo) 3 , —C(halo) 3 , —CH(halo) 2 , —CH2(halo), —CN, -halo, —N 3 , —NO 2 , —CH═NR 13 , —N(R 13 ) 2 —NR 13 OR 13 , —OR 13 , —C(O)R 13 , —C(O)OR 13 , —OC(O)R 13 , —OC(O)OR 13 , —SR 13 , —S(O)R 13 , or —S(O) 2 R 13 ; or

(c) two R 10 groups on adjacent carbon atoms together form a (C 1 -C 2 )alkylenedioxy bridge, which is unsubstituted or substituted 1, 2 or 3 independently selected R 13 groups;

each R 12 is independently —H, —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, —C(O)R 13 , C(O)OR 13 , or —C(O)N(R 13 ) 2 ;

each R 13 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, -benzyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )hydroxyalkyl, —(C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl, —(C 1 -C 6 )alkyl-N(R 8 ) 2 or —C(O)N(R 8 ) 2 ;

R a is —H, —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, —CH 2 —C(O)R c , —(CH 2 )—C(O)OR c , (CH 2 )—C(O)N(R c ) 2 , —(CH 2 ) 2 —OR c , —(CH 2 ) 2 —S(O) 2 N(R c ) 2 , or —(CH 2 ) 2 —N(R c )S(O) 2 R c ;

Rb is

(a) —H, —(C 1 -C 6 )alkyl, —(C 3 -C 8 )cycloalkyl, -(3- to 7-membered)heterocycle, —N(R c ) 2 , —N(R c )—(C 3 -C 8 )cycloalkyl, or —N(R c )-(3- to 7 membered)heterocycle, each of which -(3- to 7-membered)heterocycle or —(C 3 -C 8 )cycloalkyl is unsubstituted or substituted with 1, 2 or 3 independently selected R 13 groups; or

(b) -phenyl, -(5- or 6-membered)heteroaryl, —N(R c )-phenyl, or —N(R c )-(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2 or 3 independently selected R 13 groups;

each R c is independently —H or —(C 1 -C 4 )alkyl

each R 14 is independently —H, —(C 1 -C 6 )alkyl, —C(O)R 13 , —S(O)R 13 , —S(O) 2 R 13 ,

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

n is the integer 0, 1, or 2;

m is the integer 0, 1, or 2;

q is the integer 0, 1, 2, 3, or 4;

s is the integer 0, 1, 2, 3, 4, or 5;

u is the integer 0, 1, 2 or 3;

v is the integer 0, 1, 2 or 3;

b is the integer 1 or 2; and

provided that when Ar 1 is

then Ar 2 is not

2. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein

Z is

(a) —(C 1 -C 3 )alkyl substituted with 1 or 2 —OH groups, or

(c) —OH; and

V is 1, 2 or 3.

3. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein

Z is —(C 1 -C 3 )alkyl substituted with 1 or 2 —OH groups,

V is 1, 2 or 3, and

Ar 1 is

4. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein Ar 1 is

Y is

L 1 and L 2 are each independently a bond.

5. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein

Ar 1 is

Y is

Ar 3 is oxadiazole, isoxazole, oxazole, furan or pyrazole, each of which is unsubstituted or substituted with 1 or 2 independently selected R 6 groups;

Z is

(a) —(C 1 -C 2 )alkyl substituted with 1 or 2 —OH groups, or

(c) —OH

V is 1, 2 or 3; and

L 1 and L 2 are each independently a bond.

6. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein

Ar 1 is

Y is

Ar 2 is

Ar 3 is oxadiazole, isoxazole, oxazole, furan or pyrazole, each of which is unsubstituted or substituted with 1 or 2 independently selected R 6 groups;

Z is

(a) —(C 1 -C 6 )alkyl substituted with 1 or 2 —OH groups, or

(c) —OH

v is 1, 2 or 3;

L 1 is a bond;

L 2 is a bond; and

X is O.

7. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein

Ar 1 is

8. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein

Y is

9. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein

Y is

10. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein

Y is

11. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein Z is —OH, —(C 1 -C 3 )alkyl substituted with 1 or 2 —OH groups, or —(C 2 -C 4 )alkenyl substituted with 1 or 2 —OH groups; and v is 1 or 2.

12. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein Z is —OH or —(C 1 -C 3 )alkyl substituted with 1 or 2 —OH groups; and v is 1 or 2.

13. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein Z is —(C 2 -C 3 )alkyl substituted with 2 —OH groups; and v is 1 or 2.

14. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein Z is —OH and v is 1 or 2.

15. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein Z is CH 2 OH and v is 1 or 2.

16. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein Z is —CH 2 CH 2 OH and v is 1 or 2.

17. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein Z is —CH(OH)CH(OH) and v is 1 or 2.

18. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein Z is —OH or —(C 1 -C 3 )alkyl substituted with 1 or 2 —OH groups; and v is 1 or 2.

19. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein R 1 is -methyl, -halo or —C(halo) 3 .

20. The compound according to claim tor a pharmaceutically acceptable derivative thereof, wherein R 4 is —H or -halo.

21. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein each R 9 is independently selected from -halo, —C(halo) 3 ,)alkyl, —(C 1 -C 6 )alkoxy, —OC(halo) 3 , and S(O) 2 C(halo) 3 .

22. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein Ar 2 is

R 9a is —C(halo) 3 or —OC(halo) 3 ; and

R 9b is —H, -halo, -methyl, or —OCH 3 .

23. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein Ar 2 is

R 9a is —C(halo) 3 or —OC(halo) 3 .

24. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein n or p=0.

25. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof, wherein m=0.

26. The compound according to claim 1 or a pharmaceutically acceptable derivative thereof wherein the pharmaceutically acceptable derivative is a pharmaceutically acceptable salt.

27. A composition comprising a compound of claim 1 or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or excipient.

28. A composition for treating pain, UI, IBD, or BS in an animal comprising a compound of claim 1 or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or excipient.

29. A composition for inhibiting TRPV1 function comprising a compound of claim 1 or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier or excipient.

30. A method for treating pain, UI, an ulcer, IBD, or IBS in an animal, comprising administering to an animal in need thereof, an effective amount of a compound of claim 1 or a pharmaceutically acceptable derivative thereof.

31. A method of inhibiting TRPVI function in a cell comprising contacting a cell capable of expressing TRPV 1 with an effective amount of a compound of claim 1 or a pharmaceutically acceptable derivative thereof.