Vinyl-phenyl derivatives for inflammation and immune-related uses

Abstract

The invention relates to compounds of structural formula (Ia): or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein X 1 , X 2 , X 3 , X 4 , X 6 , X 10 , R 1 , Y, Z, L, and n are defined herein. These compounds are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

We claim: 
     
         1 . A compound of structural formula (Ia): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         X 1  and X 2  are, independently, CH, CZ, or N; 
         X 3 , X 6  and X 10  are each, independently, CH 2 , CHR 2 , C(R 2 ) 2 , or NR 2 ; 
         X 4  is CH 2 , CHR 2 , C(R 2 ) 2 , or CH R 4 , provided that when X 3  is NR 2 , X 4  is CHR 4 , and provided that not more than one of X 3 , X 6  or X 10  is NR 2 , 
         L 1  is a linker selected from the group consisting of —NRC(R) 2 —, —C(R) 2 NR—, —C(O)—, —NR—C(O)—, —C(O)—NR—, —C(S)—, —C(NR 8 )—, —NR—C(S)—, —C(S)—NR—, —NR—C(NR 8 )—, —C(NR 8 )—NR—, —NRC(O)NR—, —NRC(S)NR—, —NRC(NR 8 )NR—, —S(O) 2 NR—, —NRS(O) 2 —, —NRS(O) 2 NR—, —NRC(R) 2 NR—, —CR═CR—, —C≡C—, —N═CR—, —CR═N—, —NR—N═CR—, or —CR═N—NR—; 
         Y is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted monocyclic aryl, or an optionally substituted heteroaryl; 
         each Z is independently selected from the group consisting of a lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower alkyl sulfanyl, cyano, nitro, or lower haloalkoxy; 
         R is H or a lower alkyl; 
         R 1  is H or a substituent, provided that when R 1  is H, X 4  is CH R 4 , and X 3  is NR 2 ; 
         R 2 , for each occurrence is, independently, a substituent, provided that R 2  is not ═O or ═C(R 28 ) 2 ; 
         R 4  is a substituent; 
         R 8 , for each occurrence, is independently —H, a halo, an alkyl, —OR 5 , —NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , or —C(O)NR 6 R 7 ; 
         wherein R 28 , for each occurrence is, independently, H or a substituent; 
         n is 0, 1 or 2; and 
         q is 0, 1 or 2, 
         provided that when q is 0 or 1, Y is not an optionally substituted alkyl; 
         provided that when q is 1, Y is not a substituent represented by the following formula: 
       
       
         
           
           
               
               
           
         
         and 
         provided that the compound is not a compound represented by the following structural formula: 
       
       
         
           
           
               
               
           
         
         wherein R 29  is —NO 2  or —NHC(O)CH 2 CN; and 
         t is 0 or 1. 
       
     
     
         2 . The compound of  claim 1 , wherein the compound is represented by structural formula (VII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein m is 0, 1, 2, 3, or 4. 
       
     
     
         3 . The compound of  claim 2 , wherein the compound is represented by structural formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. 
       
     
     
         4 . The compound of  claim 3 , wherein Y is selected from the group consisting of an optionally substituted phenyl, an optionally substituted pyridyl, an optionally substituted furyl, an optionally substituted thienyl, an optionally substituted pyrrolyl, an optionally substituted oxazolyl, an optionally substituted imidazolyl, an optionally substituted indolizinyl, an optionally substituted thiazolyl, an optionally substituted isoxazolyl, an optionally substituted pyrazolyl, an optionally substituted isothiazolyl, an optionally substituted pyridazinyl, an optionally substituted pyrimidinyl, an optionally substituted pyrazinyl, an optionally substituted triazinyl, an optionally substituted triazolyl, an optionally substituted thiadiazolyl, an optionally substituted pyrazinyl, an optionally substituted quinolinyl, an optionally substituted isoquinolinyl, an optionally substituted indazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzofuryl, an optionally substituted benzothiazolyl, an optionally substituted indolizinyl, an optionally substituted imidazopyridinyl, an optionally substituted isothiazolyl, an optionally substituted tetrazolyl, an optionally substituted benzoxazolyl, an optionally substituted benzothiazolyl, an optionally substituted benzothiadiazolyl, an optionally substituted benzoxadiazolyl, an optionally substituted indolyl, an optionally substituted tetrahydroindolyl, an optionally substituted azaindolyl, an optionally substituted imidazopyridyl, an optionally substituted quinazolinyl, an optionally substituted purinyl, an optionally substituted pyrrolo[2,3]pyrimidyl, an optionally substituted pyridopyrimidyl, an optionally substituted pyrazolo[3,4]pyrimidyl or an optionally substituted benzo(b)thienyl. 
     
     
         5 . The compound of  claim 1 , wherein the compound is represented by structural formula (III): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. 
       
     
     
         6 . The compound of  claim 5 , wherein the compound is represented by formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         X 5  is CH or N; 
         R 12  is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy; and 
         R 13  is H, a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy. 
       
     
     
         7 . The compound of  claim 6 , wherein
 R 1  is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, a lower haloalkoxy, or an optionally substituted heteroaryl; and   R 2  is an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, —C(O)NR 6 R 7 , —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(S)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(NR 8 )NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —S(O) p R 5 , —S(O) p NR 6 R 7 , —P(O)(OR 5 ) 2 , —P(S)(OR 5 ) 2 , —P(O)(OR 5 )(SR 5 ), —P(S)(OR 5 )(SR 5 ), —P(O)(SR 5 ) 2 , or —P(S)(SR 5 ) 2 .   
     
     
         8 . The compound of  claim 3 , wherein the compound is represented by structural formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. 
       
     
     
         9 . The compound of  claim 8 , wherein the compound is represented by structural formula (VI): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         X 5  is CH or N; 
         R 12  is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy; and 
         R 13  is H, a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy. 
       
     
     
         10 . The compound of  claim 1 , wherein the compound is represented by formula (XVI): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. 
       
     
     
         11 . The compound of  claim 10 , wherein the compound is represented by formula (XVII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         X 5  is CH or N; 
         R 12  is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy; and 
         R 13  is H, a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy. 
       
     
     
         12 . The compound of  claim 1 , wherein the compound is represented by formula (XVIII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein m is 0, 1, 2, 3, or 4. 
       
     
     
         13 . The compound of  claim 12 , wherein the compound is represented by formula (XIX): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. 
       
     
     
         14 . The compound of  claim 13 , wherein the compound is represented by formula (XX): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         X 5  is CH or N; 
         R 12  is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy; and 
         R 13  is H, a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy. 
       
     
     
         15 . The compound of  claim 12 , wherein the compound is represented by formula (XXI): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. 
       
     
     
         16 . The compound of  claim 15 , wherein the compound is represented by formula (XXII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         X 5  is CH or N; 
         R 12  is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy; and 
         R 13  is H, a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy. 
       
     
     
         17 . The compound of  claim 1 , wherein the compound is represented by formula (XXIII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein m is 0, 1, 2, 3, or 4. 
       
     
     
         18 . The compound of  claim 17 , wherein the compound is represented by formula (XXIV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         X 5  is CH or N; 
         R 12  is a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy; and 
         R 13  is H, a halo, a lower alkyl, a lower alkoxy, a haloalkyl, or a lower haloalkoxy. 
       
     
     
         19 . The compound of  claim 1 , wherein the compound is selected from the group consisting of:
 3-Fluoro-N-[4-(2-methyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;   3-Methyl-N-[4-(2-methyl-5(R)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;   3-Methyl-N-[4-(2-methyl-5(S)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;   3-Fluoro-N-[4-(2-methyl-5(R)-isopropenyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;   3-Fluoro-N-[4-(2-methyl-5(S)-isopropenyl-cyclohex-1-enyl)-pyridin-2-yl]-isonicotinamide;   3-Methyl-N-[4-(2-methyl-5(R)-acetyl-cyclohex-1-enyl)-phenyl]-isonicotinamide;   N-[4-(1,4-dimethyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-2,6-difluoro-benzamide;   5-[4-(2,6-difluoro-benzoylamino)-phenyl]-4-methyl-2,4-dihydro-2H-pyridine-1-carboxylic acid ethyl ester;   N-(4-((S)-5-((R)-1,2-dihydroxypropan-2-yl)-2-methylcyclohex-1-enyl)phenyl)-3-methylisonicotinamide;   N-(4-(1,4-dimethyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-2,6-difluorobenzamide;   N-(4-(1-benzyl-4-methyl-1,2,5,6-tetrahydropyridin-3-yl)phenyl)-2,6-difluorobenzamide;   Ethyl 3-(4-(2,6-difluorobenzamido)phenyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate;   N-(4-(1,5-Dimethyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2,6-difluorobenzamide;   Ethyl 4-(4-(2,6-difluorobenzamido)phenyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate;   2,6-Difluoro-N-(4-(5-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)benzamide;   N-(4-Cyclohexenylphenyl)-3-fluoroisonicotinamide;   N-(4-(1-benzyl-5-methyl-1,2,3,6-tetrahydropyridin-4-yl)phenyl)-2,6-difluorobenzamide;   N-(4-cyclohexenylphenyl)-3-fluoroisonicotinamide;   N-[4-(2-chloro-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;   N-[4-(2-hydroxymethyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;   N-[4-(2-oxazol-5-yl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;   N-[4-(2-oxazol-5-yl-cyclohexen-1-yl)-phenyl]-3-fluoroisonicotinamide;   N-[4-(2-methyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;   5-Methyl-pyrimidine-4-carboxylic acid [4-(2-methyl-cyclohex-1-enyl)-phenyl]-amide;   4-Methyl-pyrimidine-5-carboxylic acid [4-(2-methyl-cyclohex-1-enyl)-phenyl]-amide;   4-Chloro-thiazole-5-carboxylic acid [4-(2-methyl-cyclohex-1-enyl)-phenyl]-amide;   N-[4-(2-ethyl-cyclohex-1-enyl)-phenyl]-2,6-difluoro-benzamide;   2-[4-(2,6-Difluoro-benzoylamino)phenyl]-cyclopent-1-enecarboxylic acid ethyl ester;   2,6-Difluoro-N-[4-(2-hydroxymethyl-cyclopent-1-enyl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(2-formyl-cyclopent-1-enyl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(2-vinyl-cyclopent-1-enyl)-phenyl]benzamide;   2,6-Difluoro-N-[4-(2-oxazol-5-yl-cyclopent-1-enyl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(2-methoxycarbonyl-cyclohept-1-enyl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(2-hydroxymethyl-cyclohept-1-enyl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(2-formyl-cyclohept-1-enyl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(2-oxazol-5-yl-cyclohept-1-enyl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(1-methoxycarbonyl-5-ethoxycarbonyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(1-methoxycarbonyl-5-vinyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-thiazol-2-yl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-isopropyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;   N-[4-(4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;   2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;   N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;   N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid [4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amide;   N-[4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;   2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;   N-[4-(1-ethoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide, hydrochloride;   N-[4-(1-benzyloxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;   N-{4-[1-(4-nitro-phenyloxycarbonyl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;   N-[4-(1-allyloxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;   2,6-Difluoro-N-[4-(1-allyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(1-phenyloxycarbonyl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(1-cyano-3-ethoxycarbonyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;   N-[4-(1-cyano-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;   2,6-Difluoro-N-[4-(1-cyano-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;   N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;   N-[4-(1-ethanesulfonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;   N-[4-(1-phenylsulfonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-methyl-isonicotinamide;   2,6-Difluoro-N-[4-(1-acetyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(1-cyclopropylcarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;   2,6-Difluoro-N-{4-[1-(pyridine-3-carbonyl)-cyclopropanecarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;   N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;   N-[4-(1-pyridin-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;   N-[4-(1-benzooxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;   2,6-Difluoro-N-[4-(1-benzooxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;   N-[4-(1-cyclopropylmethyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;   2,6-Difluoro-N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;   N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;   2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyridin-2-yl]-benzamide, hydrochloride;   2,6-Difluoro-N-[4-(1-thiocarbamoyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;   N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide, dihydrochloride;   2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide, hydrochloride;   2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;   5-Methyl-pyrimidine-4-carboxylic acid [4-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-amide;   2,6-Difluoro-N-[4-(1-thiazol-2-yl-4-formyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;   2,6-Difluoro-N-[4-(1-oxazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide, hydrochloride;   2,6-Difluoro-N-{4-[1-(4-methyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;   5-Methyl-pyrimidine-4-carboxylic acid {4-[1-(4,5-dimethyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-amide;   2,6-Difluoro-N-{4-[1-(4,5-dimethyl-oxazol-2-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;   2,6-Difluoro-N-[4-(1-pyrimidin-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide;   N-{4-[1-(1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;   N-{4-[1-(1-methyl-1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;   N-{4-[1-(2-methyl-2H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-3-fluoro-isonicotinamide;   2,6-Difluoro-N-{4-[1-(2-methyl-2H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;   2,6-Difluoro-N-{4-[1-(1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;   2,6-Difluoro-N-{4-[1-(1-methyl-1H-tetrazol-5-yl)-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl]-phenyl}-benzamide;   N-[4-(1-pyrimidin-5-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-3-fluoro-isonicotinamide;   2,6-Difluoro-N-[4-(1-thiazol-2-yl-3-methyl-1,2,5,6-tetrahydro-pyridin-4-yl)-phenyl]-benzamide;   2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyrimidin-2-yl]-benzamide;   2,6-Difluoro-N-[5-(1-thiazol-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-pyrimidin-2-yl]-benzamide;   or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.   
     
     
         20 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of  claim 1 .