TRPV3 modulators

1. A compound of formula (I)

or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof, wherein

X 1 and X 2 are each CH;

each R x is an optional substituent on any substitutable carbon atom, and is independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, CN, O(R 1a ), N(R 1a )(R 1b ), NO 2 , haloalkyl, —(C 1 -C 6 alkylenyl)-O(R 1a ), and —(C 1 -C 6 alkylenyl)-N(R 1a )(R 1b );

n is 0, 1, 2, or 3;

R 1 is a monocyclic cycloalkyl, a monocyclic heterocycle, or —CH 2 -(monocyclic cycloalkyl); wherein the monocyclic cycloalkyl, the monocyclic heterocycle, or the monocyclic cycloalkyl moiety of the —CH 2 -(monocyclic cycloalkyl), is substituent, with one substituent, R y , selected from the group consisting of OH, —(CH 2 )—OH, and —C(O)N(R 5 ) 2 , and is optionally further substituted with 1, 2, 3, 4, or 5 substituents, R z , selected from the group consisting of alkyl, halogen, haloalkyl, and oxo; or R 1 is

G 1 is OH or —C(O)N(R 5 ) 2 ;

m is 0, 1, or 2; with the proviso that m is 1 or 2 when G 1 is OH;

each R 3 is independently hydrogen, alkyl, halogen, haloalkyl, —C(O)R 3a , —C(O)OR 3a , —C(O)N(R 3a )(R 3b ), G 3a , —(C 1 -C 6 alkylenyl)-G 3a , hydroxyalkyl, alkoxyalkyl, or haloalkoxyalkyl; wherein G 3a is cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl; or two R 3 together with the carbon atom to which they are attached, form a 3-, 4-, 5-, or 6-membered monocyclic ring wherein said ring optionally contains 1, 2, or 3 heteroatoms selected from the group consisting of S, O, N, and NH, and optionally contains one double bond; said ring is unsubstituted or substituted on any substitutable ring atoms with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, halogen, haloalkyl, and oxo;

R 3a , at each occurrence, is independently hydrogen, alkyl, or haloalkyl;

R 3b is hydrogen, alkyl, haloalkyl, or aryl wherein the aryl is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, halogen, and haloalkyl;

each R 4 is independently hydrogen, alkyl, halogen, phenyl, or haloalkyl; two R 4 together with the carbon atom to which they are attached, optionally form a 3-, 4-, 5-, or 6-membered monocyclic ring, said ring optionally contains 1, 2, or 3 heteroatoms selected from the group consisting of S, O, N, and NH, and optionally contains one double bond; said ring is unsubstituted or substituted on any substitutable ring atoms with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, halogen, haloalkyl, and oxo;

each R 5 is independently hydrogen or alkyl, or two R 5 together with the nitrogen atom to which they are attached, form 3-, 4-, 5-, or 6-membered monocyclic heterocycle ring; wherein said ring optionally contains one additional heteroatom selected from the group consisting of N, NH, O, S, S(O), and S(O) 2 and optionally a double bond, and is optionally fused with a monocyclic ring selected from the group consisting of benzo, heteroaryl, heterocycle, cycloalkyl, and cycloalkenyl; said ring is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, oxo, halogen, and haloalkyl;

R 2 is G 2a ;

G 2a , at each occurrence, is independently heteroaryl, and is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, G a , NO 2 , CN, —OR f , —OC(O)R f , —OC(O)N(R f ) 2 , —Si(alkyl) 3 , —SF 5 , —SR f , —S(O) 2 R e , —S(O) 2 N(R f ) 2 , —C(O)R f , —C(O)OR f , —C(O)N(R f ) 2 , —N(R f ) 2 , —N(R f )C(O)R e , —N(R f )S(O) 2 R e , —N(R f )C(O)O(R e ), —N(R f )C(O)N(R f ) 2 , —(C 1 -C 6 alkylenyl)-G a , —(C 1 -C 6 alkylenyl)-OR f , —(C 1 -C 6 alkylenyl)-OC(O)R f , —(C 1 -C 6 alkylenyl)-OC(O)N(R f ) 2 , —(C 1 -C 6 alkylenyl)-S(O) 2 R e , —(C 1 -C 6 alkylenyl)-S(O) 2 N(R f ) 2 , —(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 ) 2 , —(C 1 -C 6 alkylenyl)-N(R f ) 2 —(C 1 -C 6 alkylenyl)-N(R f )C(O)R e , —(C 1 -C 6 alkylenyl)-N(R f )S(O) 2 R e , —(C 1 -C 6 alkylenyl)-N(R f )C(O)O(R e ), —(C 1 -C 6 alkylenyl)-N(R f )C(O)N(R f ) 2 , and —(C 1 -C 6 alkylenyl)-CN;

R f , at each occurrence, is independently hydrogen, alkyl, haloalkyl, —(C 1 -C 6 alkylenyl)-OR g , G a , or —(C 1 -C 6 alkylenyl)-G a ;

R e , at each occurrence, is independently alkyl, haloalkyl, —(C 1 -C 6 alkylenyl)-OR g , G a , or —(C 1 -C 6 alkylenyl)-G a ;

R g , at each occurrence, is independently hydrogen, alkyl, haloalkyl, monocyclic cycloalkyl, or —(C 1 -C 6 alkylenyl)-(monocyclic cycloalkyl); wherein the monocyclic cycloakyl, alone or as part of the group, is optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, haloalkyl, oxo, OH, and alkoxy;

G a , at each occurrence, is independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle;

G 3a and G a , are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, oxo, NO 2 , CN, —OR 1a , —OC(O)R 1c , —OC(O)N(R 1a )(R 1b ), —SR 1a , —S(O) 2 R 1a , —S(O) 2 N(R 1a )(R 1b ), —C(O)R 1a , —C(O)OR 1a , —C(O)N(R 1a )(R 1b ), —N(R 1a )(R 1b ), —N(R 1a )C(O)R 1c , —N(R 1a )S(O) 2 R 1c , —N(R 1a )C(O)O(R 1c ), —N(R 1a )C(O)N(R 1a )(R 1b ), —(C 1 -C 6 alkylenyl)-OR 1a —(C 1 -C 6 alkylenyl)-OC(O)R 1c , —(C 1 -C 6 alkylenyl)-OC(O)N(R 1a )(R 1b ), —(C 1 -C 6 alkylenyl)-S(O) 2 R 1a , —(C 1 -C 6 alkylenyl)-S(O) 2 N(R 1a )(R 1b ), —(C 1 -C 6 alkylenyl)-C(O)R 1a , —(C 1 -C 6 alkylenyl)-C(O)OR 1a , —(C 1 -C 6 alkylenyl)-C(O)N(R 1a )(R 1b ), —(C 1 -C 6 alkylenyl)-N(R 1a )(R 1b ), —(C 1 -C 6 alkylenyl)-N(R 1a )C(O)R 1c , —(C 1 -C 6 alkylenyl)-N(R 1a )S(O) 2 R 1c , —(C 1 -C 6 alkylenyl)-N(R 1a )C(O)O(R 1c ), —(C 1 -C 6 alkylenyl)-N(R 1a )C(O)N(R 1a )(R 1b ), and —(C 1 -C 6 alkylenyl)-CN;

R 1a and R 1b , at each occurrence, are each independently hydrogen, alkyl, or haloalkyl; and

R 1c , at each occurrence, is each independently alkyl or haloalkyl.

2. The compound of formula (I-a) according to claim 1 or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof,

wherein

G 2 is a C 3 -C 6 cycloalkyl wherein two non-adjacent atoms of the G 2 ring are optionally linked by an alkylenyl bridge of 1 or 2 carbon atoms;

R y is OH or —(CH 2 )—OH;

p is 0, 1, 2, 3, 4, or 5; and

R x , R 2 , n, and R z are as set forth in claim 1 .

3. The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof, wherein

R 1 is

 and

G 1 is OH.

4. The compound of formula (I) according to claim 3 or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof, wherein

each R 4 is independently hydrogen, alkyl, phenyl, or haloalkyl; two R 4 together with the carbon atom to which they are attached optionally form C 3 -C 6 cycloalkyl, oxetanyl, or tetrahydropyranyl, each of which is optionally substituted.

5. The compound of formula (I) according to claim 4 or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof, wherein

m is 1, and

each R 4 is independently hydrogen or C 1 -C 4 alkyl.

6. The compound of formula (I-b) according to claim 1 or a pharmaceutically acceptable salt, solvate, or salt of a solvate thereof,

wherein X 1 , X 2 , R x , R 2 , and n are as set forth in claim 1 .

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

(2R)-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[5-fluoro-2′-(trifluoromethyl)-2,4′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2S)-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-{[(5,5′-difluoro-2,2′-bipyridin-6-yl)methyl]amino}-3-methylbutan-1-ol;

(2R)-2-{[(6′-choloro-5-fluoro-2,3′-bipyridin-6-yl)methyl]amino}-3-methylbutan-1-ol;

(2R)-2-({[5-fluoro-2′-(morpholin-4-yl)-2,4′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[5-fluoro-6′-(propan-2-yloxy)-2,3′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[3-fluoro-6-(1-methyl-1H-indol-4-yl)pyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[3-fluoro-6-(1-methyl-1H-indol-6-yl)pyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[5-fluoro-6′-(2,2,2-trifluoroethoxy)-2,3′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-3-methyl-2-({[6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)butan-1-ol;

(2R)-2-({[3-fluoro-6-(quinolin-3-yl)pyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[5-fluoro-5′-(trifluoromethyl)-2,2′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-cyclopropyl-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-ethanol;

(2R)-2-cyclopropyl-2-({[5-fluoro-6′-(2,2,2-trifluoroethoxy)-2,3′-bipyridin-6-yl]methyl}-amino )ethanol;

(2R)-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)butan-1-ol;

(2R)-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)pentan-1-ol;

(2R)-2-cyclohexyl-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-ethanol;

(2R)-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-3,3-dimethylbutan-1-ol;

3-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)butan-2-ol;

(3R)-3-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-2,4-dimethylpentan-2-ol;

3-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-4-methylpentan-2-ol;

(2R)-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[5-chloro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-3-methyl-2-({[5-methyl-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)butan-1-ol;

(2R)-2-({[5-methoxy-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-[({3-fluoro-6-[2-(trifluoromethyl)pyrimidin-5-yl]pyridin-2-yl}methyl)amino]-3-methylbutan-1-ol;

(2R)-2-[({3-fluoro-6-[2-(2,2,2-trifluoroethoxy)pyrimidin-5-yl]pyridin-2-yl}methyl)amino]-3-methylbutan-1-ol;

(3R)-3-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)pentan-2-ol;

(R)-2-((5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl)methylamino)-3-methylbutanamide;

(2R)-2-({[4,6′-bis(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(S)-2-((5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl)methylamino)-3-methylbutanamide;

(2S,3R)-2-((5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl)methylamino)-3-hydroxybutanamide;

(2R,3R)-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)butane-1,3-diol;

(1S,2S)-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)cyclohexanol;

(1R,2S)-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)cyclohexanol;

N 2 -{[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}-N-naphthalen-2-yl-L-threoninamide;

(2R)-2-({[6-(1-benzothiophen-2-yl)-3-fluoropyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[6-(1,3-benzothiazol-5-yl)-3-fluoropyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[6-(5-chlorothiophen-2-yl)-3-fluoropyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[3-fluoro-6-(5-methylthiophen-2-yl)pyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[3-fluoro-6-(1-methyl-1H-indol-5-yl)pyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[3-fluoro-6-(1-methyl-1H-indol-2-yl)pyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-[({6-[1-(1,3-dioxolan-2-ylmethyl)-1H-pyrazol-4-yl]-3-fluoropyridin-2-yl}methyl)-amino]-3-methylbutan-1-ol;

(2R)-2-({[3-fluoro-6-(furan-3-yl)pyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[3-fluoro-6-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[5-fluoro-5′-methyl-6′-(morpholin-4-yl)-2,3′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[5-fluoro-6′-(4-methylpiperazin-1-yl)-2,3′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[6-(1-benzothiophen-5-yl)-3-fluoropyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[6-(1-benzofuran-5-yl)-3-fluoropyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

tert-butyl 4-(benzyloxy)-2-[5-fluoro-6-({[(2R)-1-hydroxy-3-methylbutan-2-yl]amino}methyl)pyridin-2-yl]-1H-indole-1-carboxylate;

(2R)-2-[({6-[2-(dimethylamino)pyrimidin-5-yl]-3-fluoropyridin-2-yl}methyl)amino]-3-methylbutan-1-ol;

tert-butyl 2-[5-fluoro-6-({[(2R)-1-hydroxy-3-methylbutan-2-yl]amino}methyl)pyridin-2-yl]-1H-indole-1-carboxylate;

(2R)-2-({[3-fluoro-6-(1H-indol-2-yl)pyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-{[(5′-chloro-5-fluoro-2,3′-bipyridin-6-yl)methyl]amino}-3-methylbutan-1-ol;

(2R)-2-({[3-fluoro-6-(4-methyl-2-phenyl-1,3-thiazol-5-yl)pyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-[({3-fluoro-6-[5-(trifluoromethyl)thiophen-2-yl]pyridin-2-yl}methyl)amino]-3-methylbutan-1-ol;

(2R)-2-[({3-fluoro-6-[1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]pyridin-2-yl}methyl)amino]-3-methylbutan-1-ol;

(2R)-2-({[5-fluoro-5′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[6-(1-benzyl-1H-pyrazol-4-yl)-3-fluoropyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[6′-(dimethylamino)-5-fluoro-2,3′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[6′-(cyclopropylmethoxy)-5-fluoro-2,3′-bipyridin-6-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[3-fluoro-6-(3-methylthiophen-2-yl)pyridin-2-yl]methyl}amino)-3-methylbutan-1-ol;

(2R)-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-2-phenylethanol;

N 2 -{[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}-L-leucinamide;

(2S)-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-4-methylpentan-1-ol ; and

(2S)-2-({[5-fluoro-6′-(trifluoromethyl)-2,3′-bipyridin-6-yl]methyl}amino)-2-phenylethanol.

8. 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 salt of a solvate thereof, in combination with a pharmaceutically acceptable carrier.

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