Heteroaryl substituted urea modulators of fatty acid amide hydrolase

Abstract

Certain heteroaryl-substituted piperidinyl and piperazinyl urea compounds are described, which are useful as FAAH inhibitors. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by fatty acid amide hydrolase (FAAH) activity, such as anxiety, pain, inflammation, sleep disorders, eating disorders, insulin resistance, diabetes, osteoporosis, and movement disorders (e.g., multiple sclerosis).

What is claimed is: 
     
         1 . A chemical entity selected from compounds of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         Ar 1  is mono- or fused bicyclic heteroaryl group consisting of 5-10 ring atoms and having one heteroatom selected from the group consisting of N, O and S, with a carbon atom as point of ring attachment, and optionally having up to four additional carbon ring atoms replaced with nitrogen, said heteroaryl group having not more than five heteroatoms, each heteroaryl group independently unsubstituted or substituted with halo, —C 1-4 alkyl, —OC 1-4 alkyl, —OCF 3 , —CN, or —CF 3 ; 
         Ar 2  is
 (i) phenyl unsubstituted or substituted with one or two R a  moieties;
 where each R a  moiety is independently —C 1-8 alkyl, —OC 1-8 alkyl, halo, —CF 3 , —OCF 3 , —OCH 2 CF 3 , —S(O) 0-2 C 1-8 alkyl, —S(O) 0-2 CF 3 , —CO 2 H, —N(R b )R c , —SO 2 NR b R c , —NR b SO 2 R c , —C(O)NR b R c , or —NO 2 ; 
 or two adjacent R a  moieties taken together form —O(CH 2 ) 1-2 O— or —OCF 2 O—; 
 where R b  and R c  are each independently —H or —C 1-8 alkyl, or optionally R b  and R c  taken together with the atoms of attachment form a 4-8 membered ring; 
 
 (ii) phenyl substituted at the 3- or 4-position with -L-Ar 3 , unsubstituted or substituted with one or two R a  moieties, wherein:
 L is a linker selected from the group consisting of —(CH 2 ) 1-6 —, —CH═CH—, —O—, —C 1-6 alkyl-O—C 1-6 alkyl-, —C 1-6 alkyl-N(C 1-6 alkyl)-C 1-6 alkyl-, —C 1-6 alkyl-S(O) 0-2 C 1-6 alkyl-, —C≡C—, —C(O)—, or a covalent bond; 
 Ar 3  is:
 (a) phenyl unsubstituted or substituted with one or two R a  moieties; 
 (b) a monocyclic heteroaryl group unsubstituted or substituted with one or two R a  moieties; or 
 (c) a 9- or 10-membered fused bicyclic heteroaryl group unsubstituted or substituted with one or two R a  moieties; or 
 
 
 (iii) a 9- or 10-membered fused bicyclic heteroaryl having one heteroatom selected from the group consisting of N, O, and S, and optionally having up to four additional carbon ring atoms replaced with nitrogen, said fused bicyclic heteroaryl having not more than five heteroatoms, and unsubstituted or substituted with one, two or three R a  moieties; 
 
         and pharmaceutically acceptable salts of compounds of Formula (I), 
         pharmaceutically acceptable prodrugs of compounds of Formula (I), and 
         pharmaceutically active metabolites of compounds of Formula (I). 
       
     
     
         2 . A chemical entity as in  claim 1 , wherein Ar 1  is isoxazolo[5,4-c]pyridin-3-yl, isoxazolo[4,5-c]pyridin-3-yl, isoxazolo[4,5-b]pyridin-3-yl, isoxazolo[5,4-b]pyridin-3-yl, imidazo[1,2-a]pyridin-8-yl, imidazo[1,2-a]pyridin-7-yl, imidazo[1,2-a]pyridin-6-yl, imidazo[1,2-a]pyridin-5-yl, imidazo[1,2-b]pyridazin-3-yl, imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-2-yl, imidazo[1,2-a]pyrimidin-7-yl, imidazo[1,2-a]pyrimidin-5-yl, imidazo[1,2-c]pyrimidin-7-yl, benzooxazol-6-yl, 1H-indazol-7-yl, quinolin-8-yl, isoquinolin-5-yl, isoquinolin-4-yl, 1,1-dioxo-1H-1A 6 -benzo[d]isothiazol-3-yl, 1H-pyrrolo[2,3-b]pyridin-5-yl, 1H-pyrrolo[2,3-b]pyridin-4-yl, 1H-pyrrolo[3,2-b]pyridin-6-yl, 2-methyl-benzothiazol-6-yl, 1-isopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 2-methyl-benzooxazol-5-yl, 1H-indazol-7-yl, 1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-5-yl, 2-methyl-2H-indazol-4-yl, benzooxazole-2-yl group, 6-[1,2,3]triazol-1-yl-pyridin-3-yl, 6-[1,2,4]triazol-4-yl-pyridin-3-yl, 6-[1,2,4]triazol-1-yl-pyridin-3-yl, 6-[1,2,3]triazol-2-yl-pyridin-3-yl, 4-[1,2,3]triazol-2-yl-phenyl, 4-[1,2,3]triazol-1-yl-phenyl, 5-methyl-[1,3,4]oxadiazol-2-yl, 2-phenyl-pyrimidin-5-yl, 3-pyridyl, benzisoxazol-3-yl, pyrimidin-4-yl, isoxazol-3-yl, 6-fluorobenzo[d]isoxazol-3-yl, 3-phenyl-[1,2,4]thiadiazol-5-yl, 1H-tetrazol-5-yl, benzo[1,2,5]thiadiazol-4-yl, benzo[1,2,5]oxadiazol-4-yl, thiophen-2-yl, thiophen-3-yl, 6-chloro-pyridazin-3-yl, pyrazin-2-yl, 1H-benzotriazol-5-yl, [1,5]naphthyridin-2-yl, benzothiazol-6-yl, or 1H-pyrazol-3-yl. 
     
     
         3 . A chemical entity as in  claim 1 , wherein Ar 1  is pyrimidine, isoxazole, benzisoxazole, or pyridine, each group optionally substituted with one or two R a . 
     
     
         4 . A chemical entity as in  claim 1 , wherein Ar 2  is phenyl substituted with one or two R a  moieties. 
     
     
         5 . A chemical entity as in  claim 4 , wherein each R a  moiety is independently selected from the group consisting of: chloro, cyano, isobutyl, methylsulfanyl, methanesulfonyl, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, fluoro, methyl, methoxy, tert-butyl, bromo, methoxycarbonyl, cyanomethyl, methoxycarbonylmethyl, trifluoromethanesulfonyl, trifluoromethanesulfanyl, and butyl; or two adjacent R a  moieties taken together form —OCH 2 O— or —OCF 2 O—. 
     
     
         6 . A chemical entity as in  claim 4 , wherein each R a  moiety is independently selected from the group consisting of: F, Cl, Br, CF 3 , or two adjacent R a  moieties taken together form —OCF 2 O—. 
     
     
         7 . A chemical entity as in  claim 1 , wherein Ar 2  is phenyl substituted at the 3- or 4-position with -L-Ar 3 , unsubstituted or substituted with one or two R a  moieties. 
     
     
         8 . A chemical entity as in  claim 7 , wherein L is —CH 2 CH 2 —, —O—, —OCH 2 —, or —CδC—. 
     
     
         9 . A chemical entity as in  claim 7 , wherein L is —O—. 
     
     
         10 . A chemical entity as in  claim 7 , wherein Ar 3  is phenyl, unsubstituted or substituted with one or two R a  moieties. 
     
     
         11 . A chemical entity as in  claim 10 , wherein each R a  moiety is independently selected from the group consisting of: chloro, cyano, isobutyl, methylsulfanyl, methanesulfonyl, trifluoromethyl, trifluoromethoxy, 2,2,2-trifluoroethoxy, fluoro, methyl, methoxy, tert-butyl, bromo, methoxycarbonyl, cyanomethyl, methoxycarbonylmethyl, trifluoromethanesulfonyl, trifluoromethanesulfanyl, and butyl; or two adjacent R a  moieties taken together form —OCH 2 O— or —OCF 2 O—. 
     
     
         12 . A chemical entity as in  claim 10 , wherein each R a  moiety is independently fluoro. 
     
     
         13 . A chemical entity selected from the group consisting of:
 3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic acid pyridin-3-ylamide;   N-pyrimidin-4-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxamide;   N-pyrimidin-4-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxamide;   3-[(4-fluorophenyl)methyl]-N-pyrimidin-4-ylpiperidine-1-carboxamide;   N-1,2-benzisoxazol-3-yl-3-{[4-(trifluoromethyl)-phenyl]-methyl}piperidine-1-carboxamide;   N-1,2-benzisoxazol-3-yl-3-{[3-(trifluoromethyl)-phenyl]-methyl}piperidine-1-carboxamide;   N-1,2-benzisoxazol-3-yl-3-[(4-fluorophenyl)methyl]piperidine-1-carboxamide;   N-isoxazol-3-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxamide;   N-isoxazol-3-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxamide;   3-[3-(4-fluorophenoxy)benzyl]-N-pyridin-3-ylpiperidine-1-carboxamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid (4-chloro-pyridin-3-yl)-amide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-b]pyridazin-3-ylamide;   (+)-3-[3-(4-chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid pyridin-3-ylamide;   (−)-3-[3-(4-chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid pyridin-3-ylamide;   3-[3-(4-trifluoromethoxy-phenoxy)-benzyl]-piperidine-1-carboxylic acid pyridine-3-ylamide;   3-quinolin-3-ylmethyl-piperidine-1-carboxylic acid pyridin-3-ylamide;   3-(3,4-dichloro-benzyl)-piperidine-1-carboxylic acid pyridin-3-ylamide;   3-(3-trifluoromethoxy-benzyl)piperidine-1-carboxylic acid pyridin-3-ylamide;   3-(4-trifluoromethoxy-benzyl)piperidine-1-carboxylic acid pyridin-3-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid (1H-pyrrolo[2,3-b]pyridin-4-yl)-amide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid isoxazolo[4,5-c]pyridin-3-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid isoxazolo[5,4-c]pyridin-3-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyridin-8-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyridin-7-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyridin-5-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyrimidin-7-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyrimidin-5-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-c]pyrimidin-7-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid (4-cyano-pyridin-3-yl)-amide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid quinolin-8-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid isoquinolin-5-ylamide;   3-[3-(4-trifluoromethyl-phenoxy)-benzyl]-piperidine-1-carboxylic acid pyridin-3-ylamide;   3-(4-chloro-3-trifluoromethoxy-benzyl)-piperidine-1-carboxylic acid pyridin-3-ylamide;   and pharmaceutically acceptable salts thereof.   
     
     
         14 . A pharmaceutical composition for treating a disease, disorder, or medical condition mediated by FAAH activity, comprising:
 (a) an effective amount of at least one chemical entity selected from compounds of Formula (I):   
       
         
           
           
               
               
           
         
         wherein: 
         Ar 1  is mono- or fused bicyclic heteroaryl group consisting of 5-10 ring atoms and having one heteroatom selected from the group consisting of N, O and S, with a carbon atom as point of ring attachment, and optionally having up to four additional carbon ring atoms replaced with nitrogen, said heteroaryl group having not more than five heteroatoms, each heteroaryl group independently unsubstituted or substituted with halo, —C 1-4 alkyl, —OC 1-4 alkyl, —OCF 3 , —CN, or —CF 3 ; 
         Ar 2  is
 (i) phenyl unsubstituted or substituted with one or two R a  moieties;
 where each R a  moiety is independently —C 1-8 alkyl, —OC 1-8 alkyl, halo, —CF 3 , —OCF 3 , —OCH 2 CF 3 , —S(O) 0-2 C 1-8 alkyl, —S(O) 0-2 CF 3 , —CO 2 H, —N(R b )R c , —SO 2 NR b R c , —NR b SO 2 R c , —C(O)NR b R c , or —NO 2 ; 
 or two adjacent R a  moieties taken together form —O(CH 2 ) 1-2 O— or —OCF 2 O—; 
 where R b  and R c  are each independently —H or —C 1-8 alkyl, or optionally R b  and R c  taken together with the atoms of attachment form a 4-8 membered ring; 
 
 (ii) phenyl substituted at the 3- or 4-position with -L-Ar 3 , unsubstituted or substituted with one or two R a  moieties, wherein:
 L is a linker selected from the group consisting of —(CH 2 ) 1-6 —, —CH═CH—, —O—, —C 1-6 alkyl-O—C 1-6 alkyl-, —C 1-6 alkyl-N(C 1-6 alkyl)-C 1-6 alkyl-, —C 1-6 alkyl-S(O) 0-2 C 1-6 alkyl-, —C≡C—, —C(O)—, or a covalent bond; 
 Ar 3  is:
 (a) phenyl unsubstituted or substituted with one or two R a  moieties; 
 (b) a monocyclic heteroaryl group unsubstituted or substituted with one or two R a  moieties; or 
 (c) a 9- or 10-membered fused bicyclic heteroaryl group unsubstituted or substituted with one or two R a  moieties; or 
 
 
 (iii) a 9- or 10-membered fused bicyclic heteroaryl having one heteroatom selected from the group consisting of N, O, and S, and optionally having up to four additional carbon ring atoms replaced with nitrogen, said fused bicyclic heteroaryl having not more than five heteroatoms, and unsubstituted or substituted with one, two or three R a  moieties; 
 
         and pharmaceutically acceptable salts of compounds of Formula (I), 
         pharmaceutically acceptable prodrugs of compounds of Formula (I), and 
         pharmaceutically active metabolites of compounds of Formula (I); and
 (b) a pharmaceutically acceptable excipient. 
 
       
     
     
         15 . A pharmaceutical composition according to  claim 14 , wherein said at least one chemical entity is selected from the group consisting of:
 3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic acid pyridin-3-ylamide;   N-pyrimidin-4-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxamide;   N-pyrimidin-4-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxamide;   3-[(4-fluorophenyl)methyl]-N-pyrimidin-4-ylpiperidine-1-carboxamide;   N-1,2-benzisoxazol-3-yl-3-{[4-(trifluoromethyl)-phenyl]-methyl}piperidine-1-carboxamide;   N-1,2-benzisoxazol-3-yl-3-{[3-(trifluoromethyl)-phenyl]-methyl}piperidine-1-carboxamide;   N-1,2-benzisoxazol-3-yl-3-[(4-fluorophenyl)methyl]piperidine-1-carboxamide;   N-isoxazol-3-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxamide;   N-isoxazol-3-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxamide;   3-[3-(4-fluorophenoxy)benzyl]-N-pyridin-3-ylpiperidine-1-carboxamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid (4-chloro-pyridin-3-yl)-amide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-b]pyridazin-3-ylamide;   (+)-3-[3-(4-chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid pyridin-3-ylamide;   (−)-3-[3-(4-chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid pyridin-3-ylamide;   3-[3-(4-trifluoromethoxy-phenoxy)-benzyl]-piperidine-1-carboxylic acid pyridine-3-ylamide;   3-quinolin-3-ylmethyl-piperidine-1-carboxylic acid pyridin-3-ylamide;   3-(3,4-dichloro-benzyl)-piperidine-1-carboxylic acid pyridin-3-ylamide;   3-(3-trifluoromethoxy-benzyl)-piperidine-1-carboxylic acid pyridin-3-ylamide;   3-(4-trifluoromethoxy-benzyl)-piperidine-1-carboxylic acid pyridin-3-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid (1H-pyrrolo[2,3-b]pyridin-4-yl)-amide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid isoxazolo[4,5-c]pyridin-3-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid isoxazolo[5,4-c]pyridin-3-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyridin-8-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyridin-7-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyridin-5-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyrimidin-7-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyrimidin-5-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-c]pyrimidin-7-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid (4-cyano-pyridin-3-yl)-amide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid quinolin-8-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid isoquinolin-5-ylamide;   3-[3-(4-trifluoromethyl-phenoxy)-benzyl]-piperidine-1-carboxylic acid pyridin-3-ylamide;   3-(4-chloro-3-trifluoromethoxy-benzyl)-piperidine-1-carboxylic acid pyridin-3-ylamide;   and pharmaceutically acceptable salts thereof.   
     
     
         16 . A pharmaceutical composition according to  claim 14 , further comprising: an analgesic selected from the group consisting of opioids and non-steroidal anti-inflammatory drugs. 
     
     
         17 . A pharmaceutical composition according to  claim 14 , further comprising: an additional active ingredient selected from the group consisting of aspirin, acetaminophen, opioids, ibuprofen, naproxen, COX-2 inhibitors, gabapentin, pregabalin, and tramadol. 
     
     
         18 . A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by FAAH activity, comprising administering to the subject in need of such treatment an effective amount of at least one chemical entity selected from compounds of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         Ar 1  is mono- or fused bicyclic heteroaryl group consisting of 5-10 ring atoms and having one heteroatom selected from the group consisting of N, O and S, with a carbon atom as point of ring attachment, and optionally having up to four additional carbon ring atoms replaced with nitrogen, said heteroaryl group having not more than five heteroatoms, each heteroaryl group independently unsubstituted or substituted with halo, —C 1-4 alkyl, —OC 1-4 alkyl, —OCF 3 , —CN, or —CF 3 ; 
         Ar 2  is
 (i) phenyl unsubstituted or substituted with one or two R a  moieties;
 where each R a  moiety is independently —C 1-8 alkyl, —OC 1-8 alkyl, halo, —CF 3 , —OCF 3 , —OCH 2 CF 3 , —S(O) 0-2 C 1-8 alkyl, —S(O) 0-2 CF 3 , —CO 2 H, —N(R b )R c , —SO 2 NR b R c , —NR b SO 2 R c , —C(O)NR b R c , or —NO 2 ;
 or two adjacent R a  moieties taken together form —O(CH 2 ) 1-2 O— or —OCF 2 O—; 
 where R b  and R c  are each independently —H or —C 1-8 alkyl, or optionally R b  and R c  taken together with the atoms of attachment form a 4-8 membered ring; 
 
 
 (ii) phenyl substituted at the 3- or 4-position with -L-Ar 3 , unsubstituted or substituted with one or two R a  moieties, wherein:
 L is a linker selected from the group consisting of —(CH 2 ) 1-6 —, —CH═CH—, —O—, —C 1-6 alkyl-O—C 1-6 alkyl-, —C 1-6 alkyl-N(C 1-6 alkyl)-C 1-6 alkyl-, —C 1-6 alkyl-S(O) 0-2 C 1-6 alkyl-, —C≡C—, —C(O)—, or a covalent bond; 
 Ar 3  is:
 (a) phenyl unsubstituted or substituted with one or two R a  moieties; 
 (b) a monocyclic heteroaryl group unsubstituted or substituted with one or two R a  moieties; or 
 (c) a 9- or 10-membered fused bicyclic heteroaryl group unsubstituted or substituted with one or two R a  moieties; or 
 
 
 (iii) a 9- or 10-membered fused bicyclic heteroaryl having one heteroatom selected from the group consisting of N, O, and S, and optionally having up to four additional carbon ring atoms replaced with nitrogen, said fused bicyclic heteroaryl having not more than five heteroatoms, and unsubstituted or substituted with one, two or three R a  moieties; 
 
         and pharmaceutically acceptable salts of compounds of Formula (I), 
         pharmaceutically acceptable prodrugs of compounds of Formula (I), and 
         pharmaceutically active metabolites of compounds of Formula (I). 
       
     
     
         19 . A method according to  claim 18 , wherein said at least one chemical entity is selected from the group consisting of:
 3-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperidine-1-carboxylic acid pyridin-3-ylamide;   N-pyrimidin-4-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxamide;   N-pyrimidin-4-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxamide;   3-[(4-fluorophenyl)methyl]-N-pyrimidin-4-ylpiperidine-1-carboxamide;   N-1,2-benzisoxazol-3-yl-3-{[4-(trifluoromethyl)-phenyl]-methyl}-piperidine-1-carboxamide;   N-1,2-benzisoxazol-3-yl-3-{[3-(trifluoromethyl)-phenyl]-methyl}-piperidine-1-carboxamide;   N-1,2-benzisoxazol-3-yl-3-[(4-fluorophenyl)methyl]piperidine-1-carboxamide;   N-isoxazol-3-yl-3-{[4-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxamide;   N-isoxazol-3-yl-3-{[3-(trifluoromethyl)phenyl]methyl}piperidine-1-carboxamide;   3-[3-(4-fluorophenoxy)benzyl]-N-pyridin-3-ylpiperidine-1-carboxamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid (4-chloro-pyridin-3-yl)-amide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-b]pyridazin-3-ylamide;   (+)-3-[3-(4-chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid pyridin-3-ylamide;   (−)-3-[3-(4-chloro-phenoxy)-benzyl]-piperidine-1-carboxylic acid pyridin-3-ylamide;   3-[3-(4-trifluoromethoxy-phenoxy)-benzyl]-piperidine-1-carboxylic acid pyridine-3-ylamide;   3-quinolin-3-ylmethyl-piperidine-1-carboxylic acid pyridin-3-ylamide;   3-(3,4-dichloro-benzyl)piperidine-1-carboxylic acid pyridin-3-ylamide;   3-(3-trifluoromethoxy-benzyl)piperidine-1-carboxylic acid pyridin-3-ylamide;   3-(4-trifluoromethoxy-benzyl)piperidine-1-carboxylic acid pyridin-3-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid (1H-pyrrolo[2,3-b]pyridin-4-yl)-amide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid isoxazolo[4,5-c]pyridin-3-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid isoxazolo[5,4-c]pyridin-3-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyridin-8-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyridin-7-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyridin-5-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyrimidin-7-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-a]pyrimidin-5-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid imidazo[1,2-c]pyrimidin-7-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid (4-cyano-pyridin-3-yl)-amide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid quinolin-8-ylamide;   3-[3-(4-fluoro-phenoxy)-benzyl]-piperidine-1-carboxylic acid isoquinolin-5-ylamide;   3-[3-(4-trifluoromethyl-phenoxy)-benzyl]-piperidine-1-carboxylic acid pyridin-3-ylamide;   3-(4-chloro-3-trifluoromethoxy-benzyl)-piperidine-1-carboxylic acid pyridin-3-ylamide;   and pharmaceutically acceptable salts thereof.   
     
     
         20 . A method according to  claim 18 , wherein the disease, disorder, or medical condition is selected from the group consisting of: anxiety, depression, pain, sleep disorders, eating disorders, inflammation, movement disorders, HIV wasting syndrome, closed head injury, stroke, learning and memory disorders, Alzheimer's disease, epilepsy, Tourette's syndrome, Niemann-Pick disease, Parkinson's disease, Huntington's chorea, optic neuritis, autoimmune uveitis, drug withdrawal, nausea, emesis, sexual dysfunction, post-traumatic stress disorder, cerebral vasospasm, glaucoma, irritable bowel syndrome, inflammatory bowel disease, immunosuppression, gastroesophageal reflux disease, paralytic ileus, secretory diarrhea, gastric ulcer, rheumatoid arthritis, unwanted pregnancy, hypertension, cancer, hepatitis, allergic airway disease, autoimmune diabetes, intractable pruritis, and neuroinflammation. 
     
     
         21 . A method according to  claim 18 , wherein the disease, disorder, or medical condition is pain or inflammation. 
     
     
         22 . A method according to  claim 18 , wherein the disease, disorder, or medical condition is anxiety, a sleep disorder, an eating disorder, or a movement disorder. 
     
     
         23 . A method according to  claim 18 , wherein the disease, disorder, or medical condition is multiple sclerosis. 
     
     
         24 . A method according to  claim 18 , wherein the disease, disorder, or medical condition is energy metabolism or bone homeostasis.