TRPV1 antagonists

1. A compound having formula (I) or pharmaceutically acceptable salt, solvate, or a combination thereof

wherein

one of X 1 , X 2 , X 3 , and X 4 is C, and the others are C(R a ); wherein each R a is the same or different, and is independently hydrogen, —CN, NO 2 , alkyl, halogen, haloalkyl, OR x , or N(R x ) 2 ;

J is CR 3J ;

K is N;

L is NR 3L ;

is a double bond;

R 3L is hydrogen, alkyl, or haloalkyl;

R 3J is hydrogen, alkyl, halogen, haloalkyl, OR x , or N(R x ) 2 ;

X 5 -X 6 is CR 3a R 3b , C(R 3 R 4 )C(R 5 R 6 ), CR 7 ═CR 8 , or C(R 9 R 10 )C(R 11 R 12 )C(R 13 R 14 );

R 4 , R 6 , R 7 , R 8 , R 10 , R 12 , and R 14 , are the same or different, and are each independently hydrogen, alkyl, or haloalkyl;

R 3a and R 3b are each independently hydrogen, alkyl, halogen, or haloalkyl;

R 3 , R 5 , R 9 , R 11 , and R 13 , are the same or different, and are each independently hydrogen, —CN, alkyl, halogen, haloalkyl, OR x , or N(R x ) 2 ;

R 3 and R 5 , together with the carbon atoms to which they are attached, optionally form a C 3 -C 6 cycloalkyl that is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl, halogen, and haloalkyl;

m is 0, 1, 2, 3, or 4;

each R b is an optional substituent and at each occurrence, is independently —CN, alkyl, halogen, haloalkyl, OR x , or N(R x ) 2 ;

each R x is independently hydrogen, alkyl, or haloalkyl;

ring G 2 is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, oxo, haloalkyl, CN, NO 2 , —OR f , —OC(O)R e , —OC(O)N(R f )(R g ), —SR f , —S(O) 2 R e , —S(O) 2 N(R f )(R g ), —C(O)R f , —C(O)OR f , —C(O)N(R f )(R g ), —N(R f )(R g ), —N(R g )C(O)R e , —N(R g )S(O) 2 R e , —N(R g )C(O)O(R e ), —N(R g )C(O)N(R f )(R g ), G a , —(C 1 -C 6 alkylenyl)-OR f , —(C 1 -C 6 alkylenyl)-OC(O)R e , —(C 1 -C 6 alkylenyl)-OC(O)N(R f )(R g ), —(C 1 -C 6 alkylenyl)-S(O) 2 R e , —(C 1 -C 6 alkylenyl)-S(O) 2 N(R f )(R g ), —(C 1 -C 6 alkylenyl)-C(O)R f , —(C 1 -C 6 alkylenyl)-C(O)OR f , —(C 1 -C 6 alkylenyl)-C(O)N(R f )(R g ), —(C 1 -C 6 alkylenyl)-N(R f )(R g ), —(C 1 -C 6 alkylenyl)-N(R g )C(O)R e , —(C 1 -C 6 alkylenyl)-N(R g )S(O) 2 R e , —(C 1 -C 6 alkylenyl)-N(R g )C(O)O(R e ), —(C 1 -C 6 alkylenyl)-N(R g )C(O)N(R f )(R g ), —(C 1 -C 6 alkylenyl)-CN, and —(C 1 -C 6 alkylenyl)-G a ;

R e , at each occurrence, is independently alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, G a , or —(C 1 -C 6 alkylenyl)-G a ;

R f , at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, G a , or —(C 1 -C 6 alkylenyl)-G a ;

R g , at each occurrence, is independently hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, benzyl, or monocyclic cycloalkyl;

G a , at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, —CN, oxo, —OR h , —OC(O)R i , —OC(O)N(R h ) 2 , —SR h , —S(O) 2 R i , —S(O) 2 N(R h ) 2 , —C(O)R h , —C(O)OR h , —C(O)N(R h ) 2 , —N(R h ) 2 , —N(R h )C(O)R i , —N(R h )S(O) 2 R i , —N(R h )C(O)O(R i ), —N(R h )C(O)N(R h ) 2 , —(C 1 -C 6 alkylenyl)-OR f , —(C 1 -C 6 alkylenyl)-OC(O)R i , —(C 1 -C 6 alkylenyl)-OC(O)N(R h ) 2 , —(C 1 -C 6 alkylenyl)-S(O) 2 R i , —(C 1 -C 6 alkylenyl)-S(O) 2 N(R h ) 2 , —(C 1 -C 6 alkylenyl)-C(O)R h , —(C 1 -C 6 alkylenyl)-C(O)OR h , —(C 1 -C 6 alkylenyl)-C(O)N(R h ) 2 , —(C 1 -C 6 alkylenyl)-N(R h ) 2 , —(C 1 -C 6 alkylenyl)-N(R h )C(O)R i , —(C 1 -C 6 alkylenyl)-N(R h )S(O) 2 R i , —(C 1 -C 6 alkylenyl)-N(R h )C(O)O(R i ), —(C 1 -C 6 alkylenyl)-N(R h )C(O)N(R h ) 2 , and —(C 1 -C 6 alkylenyl)-CN;

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

R i , at each occurrence, is independently alkyl or haloalkyl.

2. The compound of claim 1 of formula (I) or a pharmaceutically acceptable salt, solvate, or a combination thereof wherein

one of X 1 , X 2 , X 3 , and X 4 is C, and the others are C(R a ); and

each R a is the same or different, and are each independently hydrogen or halogen.

3. The compound of claim 2 of formula (I) or a pharmaceutically acceptable salt, solvate, or a combination thereof wherein

X 5 -X 6 is C(R 3 R 4 )C(R 5 R 6 ); and

G 2 is optionally substituted aryl.

4. The compound of claim 1 of formula (I-i) or a pharmaceutically acceptable salt, solvate, or a combination thereof

5. The compound of claim 4 or a pharmaceutically acceptable salt, solvate, or a combination thereof, wherein

X 5 -X 6 is CR 3a R 3b , C(R 3 R 4 )C(R 5 R 6 ), or C(R 9 R 10 )C(R 11 R 12 )C(R 13 R 14 ).

6. The compound of claim 4 or a pharmaceutically acceptable salt, solvate, or a combination thereof, wherein

X 5 -X 6 is C(R 3 R 4 )C(R 5 R 6 ); and

G 2 is aryl, heteroaryl, or cycloalkyl, each of which is optionally substituted.

7. The compound of claim 6 or a pharmaceutically acceptable salt, solvate, or a combination thereof, wherein

G 2 is optionally substituted phenyl.

8. The compound of claim 1 of formula (I-iii) or a pharmaceutically acceptable salt, solvate, or a combination thereof

9. The compound according to claim 1 , or a pharmaceutically acceptable salt, solvate, or a combination thereof, wherein the compound is selected from the group consisting of

1-(1-methyl-1H-indazol-4-yl)-3-[(1R,3S)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1R,3S)-3-phenylcyclopentyl]urea;

1-(1-methyl-1H-indazol-4-yl)-3-[(1S,3S)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1S,3S)-3-phenylcyclopentyl]urea;

1-(1-methyl-1H-indazol-4-yl)-3-[(1R,3R)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1R,3R)-3-phenylcyclopentyl]urea;

1-(1-methyl-1H-indazol-4-yl)-3-[(1S,3R)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1S,3R)-3-phenylcyclopentyl]urea;

1-[3-(4-tert-butylphenyl)cyclohexyl]-3-(1H-indazol-4-yl)urea;

1-(1H-indazol-4-yl)-3-{3-[4-(trifluoromethyl)phenyl]cyclohexyl}urea;

1-(1H-indazol-4-yl)-3-{(1R,3R)-3-[4-(trifluoromethyl)phenyl]cyclohexyl}urea;

1-(1H-indazol-4-yl)-3-{(1S,3S)-3-[4-(trifluoromethyl)phenyl]cyclohexyl}urea;

1-(1H-indazol-4-yl)-3-{(1S,3R)-3-[4-(trifluoromethyl)phenyl]cyclohexyl}urea;

1-(1H-indazol-4-yl)-3-{(1R,3S)-3-[4-(trifluoromethyl)phenyl]cyclohexyl}urea;

1-(1H-indazol-4-yl)-3-[(1S,3S)-3-phenylcyclohexyl]urea;

1-(1H-indazol-4-yl)-3-[(1R,3S)-3-phenylcyclohexyl]urea;

1-[3-(4-tert-butylphenyl)cyclopentyl]-3-(1H-indazol-4-yl)urea;

1-(1H-indazol-4-yl)-3-[cis-3-(pyridin-2-yl)cyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[trans-3-(pyridin-2-yl)cyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[3-(4-methoxyphenyl)cyclopentyl]urea;

1-(1H-indazol-4-yl)-3-{(1S,3S)-3-[4-(trifluoromethyl)phenyl]cyclopentyl}urea;

1-(1H-indazol-4-yl)-3-{(1R,3S)-3-[4-(trifluoromethyl)phenyl]cyclopentyl}urea;

1-(1H-indazol-4-yl)-3-{(1S,3R)-3-[4-(trifluoromethyl)phenyl]cyclopentyl}urea;

1-(1H-indazol-4-yl)-3-{(1R,3R)-3-[4-(trifluoromethyl)phenyl]cyclopentyl}urea;

1-[(3S)-3-(4-fluorophenyl)cyclopentyl]-3-(1H-indazol-4-yl)urea;

1-(1H-indazol-4-yl)-3-{(3S)-3-[4-(methylsulfanyl)phenyl]cyclopentyl}urea;

1-{(3S)-3-[4-(dimethylamino)phenyl]cyclopentyl}-3-(1H-indazol-4-yl)urea;

1-(1H-indazol-4-yl)-3-[(1S,4R)-4-phenylcyclopent-2-en-1-yl]urea;

1-((1S,3R)-3-cyclohexylcyclopentyl)-3-(1H-indazol-4-yl)urea;

1-[(1S,2S,3R,4S)-2,3-dihydroxy-4-phenylcyclopentyl]-3-(1H-indazol-4-yl)urea;

1-[(1S,2R,3S,4S)-2,3-dihydroxy-4-phenylcyclopentyl]-3-(1H-indazol-4-yl)urea;

1-[(1R,2R,4S,5R)-6,6-difluoro-4-phenylbicyclo[3.1.0]hex-2-yl]-3-(1H-indazol-4-yl)urea;

1-(1H-indazol-4-yl)-3-[(1S,2R,4S,5S)-4-phenylbicyclo[3.1.0]hex-2-yl]urea;

1-(1H-indazol-4-yl)-3-(cis-3-phenylcyclobutyl)urea;

1-(1H-indazol-4-yl)-3-(trans-3-phenylcyclobutyl)urea;

1-[(trans)-3-hydroxy-3-phenylcyclopentyl]-3-(1H-indazol-4-yl)urea;

1-[(1R,3S)-3-(2-fluorophenyl)cyclopentyl]-3-(1H-indazol-4-yl)urea;

1-[(1S,3S)-3-(2-fluorophenyl)cyclopentyl]-3-(1H-indazol-4-yl)urea;

1-(1H-indazol-4-yl)-3-[(1R,4S)-4-phenylcyclopent-2-en-1-yl]urea;

1-[(1S,3S)-3-(3-fluorophenyl)cyclopentyl]-3-(1H-indazol-4-yl)urea;

1-[(1R,3S)-3-(3-fluorophenyl)cyclopentyl]-3-(1H-indazol-4-yl)urea;

1-[(1R,3R)-3-(2-fluorophenyl)cyclopentyl]-3-(1H-indazol-4-yl)urea;

1-[(1S,3R)-3-(2-fluorophenyl)cyclopentyl]-3-(1H-indazol-4-yl)urea;

1-[(1R,3R)-3-(3-fluorophenyl)cyclopentyl]-3-(1H-indazol-4-yl)urea;

1-[(1S,3R)-3-(3-fluorophenyl)cyclopentyl]-3-(1H-indazol-4-yl)urea;

1-(1H-indazol-4-yl)-3-[(1S,3R)-3-methyl-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1R,3R)-3-methyl-3-phenylcyclopentyl]urea;

1-[(1R,3R)-3-(3-fluorophenyl)cyclopentyl]-3-(1-methyl-1H-indazol-4-yl)urea;

1-[(1S,3R)-3-(3-fluorophenyl)cyclopentyl]-3-(1-methyl-1H-indazol-4-yl)urea;

1-[(1R,3R)-3-(2-fluorophenyl)cyclopentyl]-3-(1-methyl-1H-indazol-4-yl)urea;

1-[(1S,3R)-3-(2-fluorophenyl)cyclopentyl]-3-(1-methyl-1H-indazol-4-yl)urea;

1-(1H-indazol-4-yl)-3-[(trans)-3-(4-methyl-1,3-thiazol-2-yl)cyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1S,3R)-3-(4-methyl-1,3-thiazol-2-yl)cyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1R,3S)-3-(4-methyl-1,3-thiazol-2-yl)cyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1S,3R)-3-(4-methyl-1,3-oxazol-2-yl)cyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1R,3S)-3-(4-methyl-1,3-oxazol-2-yl)cyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1S,3R)-3-(5-methyl-1,3-oxazol-2-yl)cyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1R,3S)-3-(5-methyl-1,3-oxazol-2-yl)cyclopentyl]urea;

1-(1H-indazol-4-yl)-3-{(1R*,3R*)-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]cyclopentyl}urea;

1-(1H-indazol-4-yl)-3-{(1R*,3S*)-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]cyclopentyl}urea; and

1-(1H-indazol-4-yl)-3-{(1R)-3-[4-(trifluoromethyl)-1,3-thiazol-2-yl]cyclopentyl}urea.

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

11. The pharmaceutical composition according to claim 10 further comprising an analgesic or a nonsteroidal anti-inflammatory drug, or a combination thereof.

12. A method for treating pain comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, solvate, or a combination thereof, to a subject in need thereof, with or without a pharmaceutically acceptable carrier.

13. The method according to claim 12 further comprising the step of co-administering with an analgesic or a nonsteroidal anti-inflammatory drug, or a combination thereof.

14. The method according to claim 13 wherein the nonsteroidal anti-inflammatory drug is ibuprofen.

15. The compound of formula 1 according to claim 1 or pharmaceutical acceptable salt or solvate thereof wherein said compound exhibits less than about a 25% increase in response latency of noxious thermosensation in a tail immersion model relative to vehicle control.

16. The compound according to claim 15 or pharmaceutical acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of

1-(1-methyl-1H-indazol-4-yl)-3-[(1R,3S)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1R,3S)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1S,3S)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1R,3R)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1S,3R)-3-phenylcyclopentyl]urea; and

1-(1H-indazol-4-yl)-3-[(1S,4R)-4-phenylcyclopent-2-en-1-yl]urea.

17. The compound of formula 1 according to claim 1 , or pharmaceutical acceptable salt or solvate thereof wherein said compound exhibits less than about a 10% increase in response latency of noxious thermosensation in a tail immersion model relative to vehicle control.

18. The compound according to claim 17 or pharmaceutical acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of

1-(1-methyl-1H-indazol-4-yl)-3-[(1R,3S)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1R,3S)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1S,3S)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1S,3R)-3-phenylcyclopentyl]urea; and

1-(1H-indazol-4-yl)-3-[(1S,4R)-4-phenylcyclopent-2-en-1-yl]urea.

19. The compound of formula 1, according to claim 1 , or pharmaceutical acceptable salt or solvate thereof wherein said compound blocks about 75% or less calcium flux caused by activation of human TRPV1 at about a pH of 5.0, and exhibits less than about a 25% increase in response latency of noxious thermosensation in a tail immersion model relative to vehicle control.

20. The compound according to claim 19 or pharmaceutical acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of

1-(1H-indazol-4-yl)-3-[(1R,3S)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1S,3S)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1S,3R)-3-phenylcyclopentyl]urea; and

1-(1H-indazol-4-yl)-3-[(1S,4R)-4-phenylcyclopent-2-en-1-yl]urea.

21. The compound of formula 1 according to claim 1 , or pharmaceutical acceptable salt or solvate thereof wherein said compound blocks about 75% or less calcium flux caused by activation of human TRPV1 at about a pH of 5.0, and exhibits less than about a 10% increase in response latency of noxious thermosensation in a tail immersion model relative to vehicle control.

22. The compound according to claim 21 or pharmaceutical acceptable salt or solvate thereof, wherein the compound is selected from the group consisting of

1-(1H-indazol-4-yl)-3-[(1R,3S)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1S,3S)-3-phenylcyclopentyl]urea;

1-(1H-indazol-4-yl)-3-[(1S,3R)-3-phenylcyclopentyl]urea; and

1-(1H-indazol-4-yl)-3-[(1S,4R)-4-phenylcyclopent-2-en-1-yl]urea.

23. The compound or salt according to claim 1 that is 1-(1H-indazol-4-yl)-3-[(1S,3R)-3-phenylcyclopentyl]urea, or a pharmaceutically acceptable salt thereof.

24. The pharmaceutical composition according to claim 10 , wherein the composition comprises 1-(1H-indazol-4-yl)-3-[(1S,3R)-3-phenylcyclopentyl]urea, or a pharmaceutically acceptable salt thereof.

25. The method for treating pain according to claim 12 , wherein the method comprises administering a therapeutically effective amount of 1-(1H-indazol-4-yl)-3-[(1S,3R)-3-phenylcyclopentyl]urea, or a pharmaceutically acceptable salt thereof, to the subject in need thereof.