Antagonists of the TRPV1 receptor and uses thereof

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

L 1 is a bond;

Y 1 is —N(R b )—;

Y 2 is ═O, ═S or ═N—CN;

Y 3 is —N(R c )—;

Ar 1 is 1,2,3,4-tetrahydro-quinolin-2-yl, 1,2,3,4-tetrahydro-quinolin-3-yl, or 1 ,2,3,4-tetrahydro-quinolin-4-yl;

wherein each Ar 1 is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R w , two R w that are attached to the same carbon atom of the monocyclic heterocycle, together with the carbon atom to which they are attached, optionally form a monocyclic cycloalkyl ring wherein said monocyclic cycloalkyl ring is optionally substituted with 1, 2, or 3 substituents selected from the group consisting of oxo, alkyl, and haloalkyl;

R 1 is hydrogen, hydroxy or alkoxy;

R w , R 2 , R 3 , R 4 , and R 5 , are each independently hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, nitro, R e OS(O) 2 —, R f R g N—, (R f R g N)alkyl, (R j R k N)carbonyl, (R j R k N)carbonylalkyl or (R j R k N)sulfonyl;

R b and R c are each independently hydrogen or alkyl;

R e is alkyl, haloalkyl, aryl, or arylalkyl;

R f and R g , at each occurrence, are each independently hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, arylalkyl, arylcarbonyl, carboxyalkyl, cycloalkylalkyl, haloalkyl, heteroarylalkyl, or heteroarylcarbonyl; or

R f and R g taken together with the nitrogen atom to which they are attached form a heterocyclic ring; and

R j and R k , at each occurrence, are each independently hydrogen, alkenyl, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylcarbonylalkyl, carboxyalkyl, cycloalkylalkyl, haloalkyl, or hydroxyalkyl.

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

Y 2 is ═O.

3. The compound, or pharmaceutically acceptable salt thereof, according to claim 2 , wherein

R 1 is hydroxy; and

R 2 is hydrogen.

4. The compound, or pharmaceutically acceptable salt thereof, according to claim 2 wherein

R 1 is hydroxy; and

R 2 , R 3 , R 4 , and R 5 are hydrogen.

5. The compound, or pharmaceutically acceptable salt thereof, according to claim 2 , wherein

R 1 is hydroxy;

R 2 is hydrogen; and

Ar 1 is 1,2,3,4-tetrahydroquinolin-4-yl.

6. The compound, or pharmaceutically acceptable salt thereof, according to claim 5 wherein Ar 1 is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R w and each R w is independently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, or R f R g N— wherein R f and R g are each independently hydrogen, alkyl, or haloalkyl.

7. The compound, or pharmaceutically acceptable salt thereof, according to claim 2 , wherein

R 1 is hydroxy;

R 2 is hydrogen; and

Ar 1 is 1,2,3,4-tetrahydroquinolin-3-yl.

8. The compound, or pharmaceutically acceptable salt thereof, according to claim 7 wherein Ar 1 is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R w and each R w is independently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, or R f R g N— wherein R f and R g are each independently hydrogen, alkyl, or haloalkyl.

9. The compound, or pharmaceutically acceptable salt thereof, according to claim 2 , wherein

R 1 is hydroxy;

R 2 is hydrogen; and

Ar 1 is 1,2,3,4-tetrahydroquinolin-2-yl.

10. The compound, or pharmaceutically acceptable salt thereof, according to claim 4 , wherein

Ar 1 is 1,2,3,4-tetrahydroquinolin-4-yl.

11. The compound, or pharmaceutically acceptable salt thereof, according to claim 10 wherein Ar 1 is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R w and each R w is independently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, or R f R g N— wherein R f and R g are each independently hydrogen, alkyl, or haloalkyl.

12. The compound according to claim 4 , wherein

Ar 1 is 1,2,3,4-tetrahydro-quinolin-3-yl.

13. The compound, or pharmaceutically acceptable salt thereof, according to claim 12 wherein Ar 1 is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R w and each R w is independently alkoxy, alkyl, arylalkyl, halogen, haloalkyl, or R f R g N— wherein R f and R g are each independently hydrogen, alkyl, or haloalkyl.

14. The compound, or pharmaceutically acceptable salt thereof, according to claim 1 selected from the group consisting of:

N-(8-tert-butyl-1 -methyl-1 ,2,3,4-tetrahydroquinolin-4-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;

N-(1 -benzyl-1,2,3,4-tetrahydroquinolin-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;

N-[1 -benzyl-7-(trifluoromethyl)-1 ,2,3,4-tetrahydroquinolin-3-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;

N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1 -yl)-N′-(1 -methyl-1,2,3,4-tetrahydroquinolin-4-yl)urea;

N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1 -yl)-N′-[1 -methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl]urea;

N-(1 -benzyl-1,2,3,4-tetrahydroquinolin-3-yl)-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;

N-[1 -benzyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]-N′-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)urea;

N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-(1-methyl-1,2,3,4-tetrahydroquinolin-3-yl)urea;

N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-N′-[1-methyl-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-3-yl]urea; and pharmaceutically acceptable salts thereof.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), or pharmaceutically acceptable salt thereof, according to claim 1 .

16. The pharmaceutical composition according to claim 15 further including a non-toxic pharmaceutically acceptable carrier and diluent.