TRPV1 antagonists including dihydroxy substituent and uses thereof

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X is O, S, or N—OR 10 ;

L 1 and L 2 are each C(R 3 );

Ar 1 is:

Ar 2 is:

R 1 is -halo, —(C 1 -C 4 )alkyl, —NO 2 , —CN, —S(O) 2 N(R 20 ) 2 , —OH, —OCH 3 , —NH 2 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , or —OCH 2 (halo);

each R 2 is independently:

(a) -halo, —OH, —O(C 1 -C 4 )alkyl, —CN, —NO 2 , —NH 2 , —(C 1 -C 10 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —S(O) 2 (C 1 -C 6 )alkyl, —N(R 20 )S(O) 2 (C 1 -C 6 )alkyl, or -phenyl; or

(b) a group of formula Q, wherein Q is:

Z 1 is independently —H, —OR 20 , —N(R 20 ) 2 , —CH 2 OR 20 , or —CH 2 N(R 20 ) 2 ;

Z 2 is independently —H, —(C 1 -C 6 )alkyl, or —CH 2 OR 20 ;

each Z 3 is independently —H, —(C 1 -C 6 )alkyl, or —(C 3 -C 8 )cycloalkyl;

J is —OR 20 or —N(R 20 ) 2 ;

provided that at least one R 2 group is a group of formula Q;

each R 3 is independently —H, —OCF 3 , -halo, —(C 1 -C 6 )alkyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )alkoxy, —N(R 20 )S(O) 2 (C 1 -C 6 )alkyl, -(3- to 7-membered)heterocycle, —OR 23 , —SR 23 , —N(R 20 )(R 23 ), —C(O)OR 23 , —C(O)R 23 , —OC(O)R 23 , —OC(O)NHR 20 , —NHC(O)R 13 , —C(O)N(R 13 ) 2 , —S(O) 2 R 20 , —N(R 20 )S(O) 2 R 13 , or —CH 2 OR 7 ;

each R 7 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —(C 1 -C 6 )haloalkyl, —(C 1 -C 6 )hydroxyalkyl, —(C 1 -C 6 )alkoxy(C 2 -C 6 )alkyl, —(C 1 -C 6 )alkyl-N(R 20 ) 2 , or —C(O)N(R 20 ) 2 ;

each R 8 and R 9 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 optionally substituted with 1 or 2 —OH groups; or

(b) —H, —CH 2 C(halo) 3 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , —OCH 2 (halo), —SC(halo) 3 , —SCH(halo) 2 , —SCH 2 (halo), —CN, —O—CN, —OH, -halo, —N 3 , —NO 2 , —CH═NR 7 , —N(R 7 ) 2 , —NR 7 OH, —OR 7 , —C(O)R 7 , —C(O)OR 7 , —OC(O)R 7 , —OC(O)OR 7 , —SR 7 , —S(O)R 7 , or —S(O) 2 R 7 ;

R 10 is —H, —(C 1 -C 4 )alkyl, or —(C 3 -C 7 )cycloalkyl;

each R 13 is independently —H, —(C 1 -C 4 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 4 )alkynyl, -(3- to 7-membered)heterocycle, or -phenyl;

each R 20 is independently —H, —(C 1 -C 6 )alkyl, or —(C 3 -C 8 )cycloalkyl;

R 22 is —H, —(C 1 -C 6 )alkyl, or —(C 3 -C 8 )cycloalkyl;

each R 23 is independently —(C 1 -C 6 )alkyl or —(C 3 -C 8 )cycloalkyl;

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

m is the integer 0, 1, or 2; and

n is the integer 1, 2, or 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X is O.

3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein R 22 is —H.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is -halo, —(C 1 -C 4 )alkyl, or —C(halo) 3 .

5. The compound of claim 3 or a pharmaceutically acceptable salt thereof, wherein R 1 is —Cl, —F, —CF 3 , or —CH 3 .

6. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein m is 1.

7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently —H, —(C 1 -C 3 )alkyl, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo).

8. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein Ar 1 is:

9. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein Ar 1 is:

10. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein the R 3 of each L 1 and L 2 C(R 3 ) group is H.

11. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein:

Q is:

Z 2 is —H or —(C 1 -C 3 )alkyl; and

each Z 3 is independently —H or —(C 1 -C 3 )alkyl.

12. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein:

Ar 2 is:

and

each R 8 and R 9 is independently —H, —Cl, —Br, —F, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —CF 3 , —OCF 3 , -iso-propyl, -tert-butyl, —S(O) 2 CF 3 , —S(O) 2 CH 3 , or —S(O) 2 CH 2 CH 3 .

13. The compound of claim 12 or a pharmaceutically acceptable salt thereof, wherein R 14 is —CF 3 , —Cl, or —F.

14. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein:

Ar 2 is:

and

each R 8 and R 9 is independently —H, —Cl, —Br, —F, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —CF 3 , —OCF 3 , -iso-propyl, -tert-butyl, —S(O) 2 CF 3 , —S(O) 2 CH 3 , or —S(O) 2 CH 2 CH 3 .

15. The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein Ar 2 is:

16. The compound of claim 15 or a pharmaceutically acceptable salt thereof, wherein each R 8 and R 9 is independently —H, —F, —CH 3 , —OCH 3 , —OCH 2 CH 3 , or —CF 3 .

17. A compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein:

Ar 1 is:

Ar 2 is:

Z 3 is —H or —(C 1 -C 3 )alkyl;

R 1 is -halo, —(C 1 -C 4 )alkyl, —OCH 3 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —OC(halo) 3 , —OCH(halo) 2 , or —OCH 2 (halo);

each R 3 is independently —H, —OCF 3 , -halo, —(C 1 -C 3 )alkyl, —(C 1 -C 3 )haloalkyl, —(C 1 -C 6 )alkoxy, —N(R 20 )S(O) 2 (C 1 -C 3 )alkyl, —OR 23 , —N(R 20 )(R 23 ), —NHC(O)R 13 , —C(O)N(R 13 ) 2 , —S(O) 2 R 20 , —N(R 20 )S(O) 2 R 13 , or —CH 2 OR 7 ;

each R 7 is independently —H, —(C 1 -C 3 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 4 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, —(C 1 -C 3 )haloalkyl, —(C 1 -C 6 )hydroxyalkyl, —(C 1 -C 6 )alkoxy(C 2 -C 6 )alkyl, —(C 1 -C 3 )alkyl-N(R 20 ) 2 , or —C(O)N(R 20 ) 2 ;

each R 8 and R 9 is independently —H, —CI, —Br, —F, —CH 3 , —OCH 3 , —OCH 2 CH 3 , —CF 3 , —OCF 3 , -iso-propyl, -tert-butyl, —S(O) 2 CF 3 , —S(O) 2 CH 3 , or —S(O) 2 CH 2 CH 3 ;

each R 13 is independently —H, —(C 1 -C 4 )alkyl, —(C 2 -C 4 )alkenyl, —(C 2 -C 4 )alkynyl, -(3- to 7-membered)heterocycle, or -phenyl;

each R 20 is independently —H, —(C 1 -C 6 )alkyl, or —(C 3 -C 8 )cycloalkyl;

each R 23 is independently —(C 1 -C 6 )alkyl or —(C 3 -C 8 )cycloalkyl;

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

m is the integer 0, 1, or 2.

18. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein m is 1 and R 3 is —H, —OCF 3 , -halo, —(C 1 -C 3 )alkyl, or —(C 1 -C 3 )haloalkyl.

19. The compound of claim 18 or a pharmaceutically acceptable salt thereof, wherein R 3 is —H, —CH 3 , or —CF 3 .

20. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein Ar 2 is:

21. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein Z 3 is —H.

22. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein Z 3 is —CH 3 .

23. The compound of claim 17 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a hydrochloride-salt, a sodium-salt, a potassium-salt, or a para-toluenesulfonic acid-salt.

24. The compound of claim 17 or a pharmaceutically acceptable salt thereof, which comprises the Q group

and has an enantiomeric excess of at least about 60%.

25. A composition comprising a compound of claim 17 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

26. A method for preparing a composition comprising admixing a compound of claim 17 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or excipient.

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

28. A method of inhibiting TRPV1 function in a cell comprising contacting a cell capable of expressing TRPV1 with an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

29. A method for treating pain in an animal, comprising administering to an animal in need thereof, an effective amount of the compound of claim 17 or a pharmaceutically acceptable salt thereof.

30. A method of inhibiting TRPV1 function in a cell comprising contacting a cell capable of expressing TRPV1 with an effective amount of a compound of claim 17 or a pharmaceutically acceptable salt thereof.

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

32. A method for preparing a composition comprising admixing a compound of claim 1 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier or excipient.