TRPV1 antagonists

1. A compound of formula (I)

or a pharmaceutically acceptable salt, thereof, wherein

W is CH 2 or O;

R 1 is phenyl, a monocyclic heteroaryl, or a monocyclic cycloalkenyl, a monocyclic cycloalkyl, each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents as represented by R 3 , wherein each R 3 is independently alkyl, alkenyl, alkynyl, —NO 2 , —CN, halogen, —OR a , —OC(O)R a , —SR a , —SF 5 , —S(O)R b , —S(O) 2 R b , —S(O) 2 N(R a )(R c ), —N(R a )(R c ), —N(R c )C(O)R a , —N(R c )S(O) 2 R b , —N(R c )C(O)N(R a )(R c ), —N(R c )S(O) 2 N(R a )(R c ), —C(O)R a , —C(O)O(R a ), —C(O)N(R a )(R c ), —(CR e R f ) m —CN, haloalkyl, or a monocyclic cycloalkyl that is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl, haloalkyl and halogen;

R a , at each occurrence, is independently hydrogen, alkyl, or haloalkyl;

R b , at each occurrence, is independently alkyl or haloalkyl;

R c , at each occurrence, is independently hydrogen, alkyl, or haloalkyl;

R e and R f are each independently hydrogen, alkyl, or haloalkyl;

m is 1, 2, or 3;

R 2 is hydrogen or alkyl; and

R 4 is methyl, ethyl, C 1 -C 2 haloalkyl, or —CN.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is hydrogen.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally substituted phenyl.

4. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is optionally substituted heteroaryl.

5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the phenyl is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyl, alkenyl, —CN, halogen, —OR a , —SF 5 , —S(O) 2 R b , haloalkyl, —(CR e R f ) m —CN, and an optionally substituted monocyclic cycloalkyl.

6. The compound according to claim 1 of formula (Ia) or a pharmaceutically acceptable salt thereof

wherein W, R 2 , R 3 , and R 4 are as set forth in claim 1 .

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof wherein R 2 is hydrogen.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof wherein each R 3 is independently selected from the group consisting of alkyl, alkenyl, —CN, halogen, —OR a , —SF 5 , —S(O) 2 R b , haloalkyl, —(CR e R f ) m —CN, and an optionally substituted monocyclic cycloalkyl.

9. The compound according to claim 1 selected from the group consisting of

8-({5-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({5-[3,4-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({5-[2,4-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({5-[2-methoxy-4-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({5-[2-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({5-[2,3-difluoro-4-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-[(4-methyl-5-thien-3-yl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol;

8-[(4-methyl-5-thien-2-yl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({4-methyl-5-[4-(trifluoromethoxy)phenyl]-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[5-(4-tert-butylphenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[4-methyl-5-(4-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({4-methyl-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[5-(4-chlorophenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[5-(4-methoxyphenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

4-{2-[(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)amino]-4-methyl-1,3-oxazol-5-yl} benzonitrile;

8-{[5-(4-bromophenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[5-(3,4-dichlorophenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[5-(4-fluorophenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[5-(4-chloro-2-methylphenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[5-(4-bromo-2-fluorophenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

(2R)-8-({4-methyl-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

(2S)-8-({4-methyl-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({4-methyl-5-[6-(trifluoromethyl)pyridin-3-yl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

(2R)-8-({5-[2-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

(2S)-8-({5-[2-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[5-(4-bromo-3-fluorophenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[5-(3-fluoro-4-methylphenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({4-methyl-5-[5-(trifluoromethyl)-2-furyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({5-[(4R)-4-isopropenylcyclohex-1-en-1-yl]-4-methyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[5-(5-ethylthien-2-yl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

(2R)-8-({4-methyl-5-[5-(trifluoromethyl)pyridin-2-yl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

2-(4-{2-[(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)amino]-4-methyl-1,3-oxazol-5-yl}phenyl)-2-methylpropanenitrile;

8-{[5-(4-cyclopropyl-3-fluorophenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[5-(4-chloro-3-fluorophenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({5-[4-(difluoromethyl)phenyl]-4-methyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

(2R)-8-({5-[4-(difluoromethyl)phenyl]-4-methyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({4-methyl-5-[4-(pentafluoro-lambda˜6˜sulfanyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

(2R)-8-{[5-(4-chloro-3-fluorophenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

(2R)-8-{[5-(4-bromo-3-fluorophenyl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

(2R)-8-({4-ethyl-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[5-(5-bromopyridin-2-yl)-4-ethyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({5-[3-chloro-4-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-({4-ethyl-5-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

8-{[5-(4-bromophenyl)-4-ethyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

(2R)-8-({4-ethyl-5-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

(2S)-8-({4-ethyl-5-[2-fluoro-4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

(2S)-8-({4-ethyl-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

5-({4-methyl-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)chroman-3-ol;

(2S)-8-({4-(difluoromethyl)-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

(2R)-8-({4-(difluoromethyl)-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

(2R)-8-({5-[4-(difluoromethyl)phenyl]-4-ethyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

(2S)-8-({5-[4-(difluoromethyl)phenyl]-4-ethyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

2-{[(7R)-7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]amino}-5-[4-(trifluoromethyl)phenyl]-1,3-oxazole-4-carbonitrile;

(2R)-8-{[5-(5-bromopyridin-2-yl)-4-methyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;

(2R)-8-({5-[2,3-difluoro-4-(trifluoromethyl)phenyl]-4-methyl-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;

(2R)-8-{[5-(4-bromophenyl)-4-ethyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol; and

(2S)-8-{[5-(4-bromophenyl)-4-ethyl-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol; or

a pharmaceutically acceptable salt thereof.

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

11. The pharmaceutical composition according to claim 10 further comprising one or more analgesic agents selected from the group consisting of a nonsteroidal anti-inflammatory drug (NSAID) and acetaminophen, or a combination thereof.

12. The pharmaceutical composition of claim 11 wherein the nonsteroidal anti-inflammatory drug is ibuprofen.

13. A method for treating pain in a mammal in need of such treatment, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof.

14. The method according to claim 13 further comprising the step of co-administering with one or more analgesic agents selected from the group consisting of nonsteroidal anti-inflammatory drug (NSAID) and acetaminophen, or a combination thereof.

15. The method according to claim 14 wherein the nonsteroidal anti-inflammatory drug is ibuprofen.