Thiazole and thiadiazole compounds for inflammation and immune-related uses

Abstract

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

1 - 137 . (canceled) 
     
     
         138 . A compound represented by formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         Y is an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted alkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, or an optionally substituted heteroaryl; 
         R′ 1  is an optionally substituted aryl or an optionally substituted heteroaryl, provided that R′ 1  is not a pyrazolyl; 
         X and X′ are each independently CH, CZ, or N; provided that at least one of X or X′ is N; 
         L is a linker; and 
         Z is a substituent. 
       
     
     
         139 . The compound of  claim 138 , wherein the compound is represented by formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate thereof, wherein: 
         Y′ is an optionally substituted aryl or an optionally substituted heteroaryl; 
         L′ is —NRCH 2 —, —CH 2 NR—, —C(O)—, —NR—C(O)—, —C(O)—NR—, C(S)—, —NR—C(S)—, —C(S)—NR—, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)CH 2 —, —NRC(O)CH═CH—, —NRC(O)NR—, —NRC(NR)NR—, —NRC(S)NR—, NRS(O) 2 NR—, —NR—CH 2 —NR—, —CH═CH—, —C≡C—, NRN═CR 6 —, —C(NR)—, or —CR 6 ═NNR—; 
         R, for each occurrence, is independently —H, alkyl, —C(O)—R 7 , or —C(O)OR 7 ; 
         R 6 , for each occurrence, is —H or alkyl; 
         R 7 , for each occurrence, is independently —H, 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 aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; 
         R 8 , for each occurrence, is independently —H, lower alkyl, —CH 2 CH 2 OH, or (CH 2 ) 3 NMe; 
         Z 1  is —H, halo, or a lower alkyl which is optionally substituted with halo, —NH 2 , lower alkyl amino, lower dialkyl amino, or cycloalkyl; 
         Z 3  is a substituent, provided that Z 3  is not —S(O) 2 CH 3 , —S(O) 2 Cl or S(O) 2 NR 8 R 8 ; 
         t is an integer 1-5; and 
         provided that when Z 3  is methoxy, Y′ is not a substituted naphthalene; 
         provided that when Z 3  is chloro, Y′ is not [(pyrazinyloxy)methyl]fluorophenyl; 
         provided that when Z 3  is chloro, Y′ is not cyanobenzoic acid; and 
         provided that when L′ is —N(CH 2 CH 2 CH 3 )—CH 2 —, Z 3  is not methoxy. 
       
     
     
         140 . The compound of  claim 139 , wherein the compound is represented by formula (IV): 
       
         
           
           
               
               
           
         
         wherein, 
         Z 5  and Z 6  are each independently 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 aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a haloalkyl, —C(O)NR 1 R 2 , —NR 4 C(O)R 5 , halo, —OR 4 , cyano, nitro, haloalkoxy, —C(O)R 4 , —NR 1 R 2 , —SR 4 , —C(O)OR 4 , —OC(O)R 4 , —NR 4 C(O)NR 1 R 2 , —OC(O)NR 1 R 2 , —NR 4 C(O)OR 5 , —S(O) p R 4 , or —S(O) p NR 1 R 2 ; 
         R 1  and R 2 , for each occurrence are, independently, H, 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 aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R 1  and R 2  taken together with the nitrogen to which they are attached is optionally substituted heterocyclyl or optionally substituted heteroaryl; 
         R 4  and R 5 , for each occurrence are, independently, H, 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 aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; and 
         p is 0, 1, or 2. 
       
     
     
         141 . The compound of  claim 140 , wherein Y′ is an optionally substituted phenyl or an optionally substituted pyridinyl. 
     
     
         142 . The compound of  claim 141 , wherein Y′ is substituted with one to two substituents. 
     
     
         143 . The compound of  claim 142 , wherein the one to two substituents are each independently a lower alkyl or a halo. 
     
     
         144 . The compound of  claim 143 , wherein Y′ is 2,6-difluorophenyl. 
     
     
         145 . The compound of  claim 140 , wherein L′ is —NRCH 2 —, —CH 2 NR—, —C(O)—, —NR—C(O)—, —C(O)—NR—, —OC(O)—, —C(O)O—, —C(S)—, —NR—C(S)—, or —C(S)—NR—. 
     
     
         146 . The compound of  claim 145 , wherein L′ is —NH—C(O)—. 
     
     
         147 . The compound of  claim 140 , wherein L′ is —NRS(O) 2 —, —S(O) 2 NR—, —NRS(O) 2 NR—, —NRC(O)CH 2 —, —NRC(O)CH═CH—, —NRC(O)NR—, —NRC(NR)NR—, —NRC(S)NR—, —NRCH 2 NR—, —NRN═CR 6 —, —C(NR)—, —CR 6 ═NNR—; —CH═CH— or —C≡C—. 
     
     
         148 . The compound of  claim 140 , wherein Z 1  is lower alkyl. 
     
     
         149 . The compound of  claim 140 , wherein Z 1  is —H. 
     
     
         150 . The compound of  claim 140 , wherein
 Y′ is a phenyl substituted with one to two substituents or a pyridinyl substituted with one to two substituents, wherein the one to two substituents are each independently a lower alkyl or a halo;   L′ is —NR—C(O)—;   Z 1  is lower alkyl or —H; and   Z 5  and Z 6  are each independently chloro, bromo, fluoro, cyano, trifluoromethyl, —C(O)CH 3 , 2-methyl-2H-tetrazolyl, methoxy, nitro, dimethylamino, thiazol-2-yl, oxazol-2-yl, or methyl.   
     
     
         151 . The compound of  claim 139 , wherein the compound is represented by formula (V): 
       
         
           
           
               
               
           
         
         wherein: 
         Z 6 , Z 7  and Z 8  are each independently a substituent. 
       
     
     
         152 . The compound of  claim 139 , wherein the compound is represented by formula (VI): 
       
         
           
           
               
               
           
         
         wherein Z 5 , Z 6 , Z 7  and Z 8  are each independently a substituent. 
       
     
     
         153 . The compound of  claim 138 , wherein the compound is selected from the group consisting of:
 N-[4-(2,4-Dichloro-phenyl)-thiazol-2-yl]-2,6-difluoro-benzamide;   N-[4-(2,5-Dimethoxy-phenyl)-thiazol-2-yl]-2,6-difluoro-benzamide;   N-[5-(2,5-Dimethoxy-phenyl)-thiazol-2-yl]-2,6-difluoro-benzamide;   N-[5-(2-Chloro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-2,6-difluoro-benzamide;   2,6-difluoro-N-(5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   N-[5-(3-Cyano-phenyl)-thiazol-2-yl]-2,6-difluoro-benzamide;   2,6-Difluoro-N-{5-[3-(2-methyl-2H-tetrazol-5-yl)-phenyl]-thiazol-2-yl}-benzamide;   3-[2-(2,6-Difluoro-benzoylamino)-4-methyl-thiazol-5-yl]-benzoic acid methyl ester;   2,6-Difluoro-N-[4-methyl-5-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-benzamide;   3-Fluoro-N-[4-methyl-5-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-isonicotinamide;   3-Methyl-N-[4-methyl-5-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-isonicotinamide;   4-Methyl-[1,2,3]thiadiazole-5-carboxylic acid [4-methyl-5-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-amide;   N-[5-(3-Cyano-phenyl)-4-methyl-thiazol-2-yl]-2,6-difluoro-benzamide;   2,6-Difluoro-N-[4-methyl-5-(4-nitro-phenyl)-thiazol-2-yl]-benzamide;   3-Methyl-N-[4-methyl-5-(4-nitro-phenyl)-thiazol-2-yl]-isonicotinamide;   2,6-Difluoro-N-(4-methyl-5-pyridin-3-yl-thiazol-2-yl)-benzamide;   2,6-Difluoro-N-(4-methyl-5-pyridin-4-yl-thiazol-2-yl)-benzamide; 3-Methyl-N-(4-methyl-5-pyridin-4-yl-thiazol-2-yl)-isonicotinamide;   2,6-Difluoro-N-{4-methyl-5-[3-(2-methyl-2H-tetrazol-5-yl)-phenyl]-thiazol-2-yl}-benzamide;   N-(5-(4-(dimethylamino)phenyl)-4-methylthiazol-2-yl)-2,6-difluorobenzamide;   N-[5-(4-Dimethylamino-phenyl)-4-methyl-thiazol-2-yl]-3-methyl-isonicotinamide;   N-(5-(2-bromo-5-methoxyphenyl)-4-methylthiazol-2-yl)-2,6-difluorobenzamide;   N-(5-(2-bromo-4,5-dimethoxyphenyl)-4-methylthiazol-2-yl)-2,6-difluorobenzamide;   2,6-difluoro-N-(5-(3-methoxyphenyl)-4-methylthiazol-2-yl)benzamide;   N-(5-(3,4-dimethoxyphenyl)-4-methylthiazol-2-yl)-2,6-difluorobenzamide;   2,6-difluoro-N-(4-methyl-5-(2-methyl-5-(oxazol-2-yl)phenyl)thiazol-2-yl)benzamide;   N-[5-(2-Bromo-pyridin-4-yl)-4-methyl-thiazol-2-yl]-2,6-difluoro-benzamide;   2,6-difluoro-N-(4-methyl-5-(2-methylpyridin-4-yl)thiazol-2-yl)benzamide;   3-Methyl-N-(4-methyl-5-(2-methylpyridin-4-yl)thiazol-2-yl)isonicotinamide;   N-(5-(4-chloropyridin-2-yl)-4-methylthiazol-2-yl)-2,6-difluorobenzamide;   N-(5-(4-chloropyridin-2-yl)-4-methylthiazol-2-yl)-3-methylisonicotinamide hydrochloride;   N-[5-(2-Cyano-pyridin-4-yl)-4-methyl-thiazol-2-yl]-2,6-difluoro-benzamide;   2,6-Difluoro-N-[4-methyl-5-(2-morpholin-4-yl-pyridin-4-yl)-thiazol-2-yl]-benzamide;   N-[4-Ethyl-5-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-2,6-difluoro-benzamide;   Methyl 2-(2,6-difluorobenzamido)-5-(3-(trifluoromethyl)phenyl)thiazole-4-carboxylate;   Methyl 2-(3-methylisonicotinamido)-5-(3-(trifluoromethyl)phenyl) thiazole-4-carboxylate;   Methyl 2-(2,6-difluorobenzamido)-5-(3-fluorophenyl)thiazole-4-carboxylate;   Methyl 5-(3-fluorophenyl)-2-(3-methylisonicotinamido)thiazole-4-carboxylate;   2,6-difluoro-N-(4-(hydroxymethyl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   2,6-difluoro-N-(4-(hydroxymethyl)-5-(3-(fluoro)phenyl)thiazol-2-yl)benzamide;   N-[4-(2,5-Dimethoxy-phenyl)-thiazol-2-yl]-2,6-difluoro-benzamide;   N-(5-(2,5-dimethylcyclohex-1-enyl)thiazol-2-yl)-3-methylisonicotinamide;   5-(2-Chloro-5-trifluoromethyl-phenyl)-thiazole-2-carboxylic acid(3-methyl-pyridin-4-yl)-amide;   2-(2-Chloro-5-trifluoromethyl-phenyl)-4-methyl-thiazole-5-carboxylic acid (2,6-difluoro-phenyl)-amide;   Sodium (2,6-difluorobenzoyl)(4-methyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)amide;   Sodium (4-methyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)(3-methyl isonicotinoyl)amide;   2-Fluoro-N-(4-methyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)nicotinamide;   2-Methyl-N-(4-methyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)nicotinamide;   N-(4-Cyclopropyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   N-(4-cyclopropyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-3-methylisonicotinamide;   2,6-Difluoro-N-(4-methyl-5-(pyridin-4-yl)thiazol-2-yl)benzamide hydrobromide;   N-(5-(2,5-Dimethoxyphenyl)-4-methylthiazol-2-yl)-2,6-difluorobenzamide;   N-(5-(7-Bromobenzo[d][1,3]dioxol-5-yl)-4-methylthiazol-2-yl)-2,6-difluorobenzamide;   N-(5-(Benzo[d][1,3]dioxol-5-yl)-4-methylthiazol-2-yl)-2,6-difluorobenzamide;   N-(5-(7-Cyanobenzo[d][1,3]dioxol-5-yl)-4-methylthiazol-2-yl)-2,6-difluorobenzamide;   N-(5-(5-Bromothiophen-2-yl)-4-methylthiazol-2-yl)-2,6-difluorobenzamide;   2,6-Difluoro-N-(4-methyl-5-(thiophen-2-yl)thiazol-2-yl)benzamide;   N-(5-(2,5-Dibromothiophen-3-yl)-4-methylthiazol-2-yl)-2,6-difluorobenzamide;   2,6-Difluoro-N-(4-methyl-5-(thiophen-3-yl)thiazol-2-yl)benzamide;   Methyl 5-(2-(allyloxy)-5-(trifluoromethyl)phenyl)-2-(2,6-difluorobenzamido)thiazole-4-carboxylate;   N-(5-(2-(Allyloxy)-5-(trifluoromethyl)phenyl)-4-(prop-1-en-2-yl)thiazol-2-yl)-2,6-difluorobenzamide;   N-(5-(2-(Allyloxy)-5-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   2-(2,6-difluorobenzamido)-5-(3-(trifluoromethyl)phenyl)thiazole-4-carboxylic acid;   2,6-Difluoro-N-(4-formyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   2,6-Difluoro-N-(4-(2-hydroxypropan-2-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   2,6-difluoro-N-(4-(prop-1-en-2-yl)-5-(3-(trifluoromethyl)phenyl) thiazol-2-yl)benzamide;   2,6-Difluoro-N-(4-isopropyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   N-(4-(Chloromethyl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   N-(4-((Dimethylamino)methyl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   (Z)-2,6-difluoro-N-(4-((hydroxyimino)methyl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   N-(4-Cyano-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   2,6-Difluoro-N-(4-(1-hydroxyethyl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   2,6-Difluoro-N-(5-(3-(trifluoromethyl)phenyl)-4-vinylthiazol-2-yl)benzamide;   2,6-Difluoro-N-(4-(oxazol-5-yl)-5-(3-(trifluoromethyl)phenyl) thiazol-2-yl)benzamide;   N-(4-(4,5-Dihydro-1H-imidazol-2-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   N-(4-(1H-Imidazol-2-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluoro benzamide hydrochloride;   2,6-Difluoro-N-(4-(4-methyloxazol-5-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   2,6-Difluoro-N-(4-(1-methyl-1H-imidazol-5-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   N-(4-(2,4-dimethyloxazol-5-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   2,6-Difluoro-N-(4-(5-methyl-1,2,4-oxadiazol-3-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   2,6-difluoro-N-(4-(hydroxyl(pyridin-2-yl)methyl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   N-(4-Acetyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   N-(4-(2-Bromoacetyl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   2,6-Difluoro-N-(2′-methyl-5-(3-(trifluoromethyl)phenyl)-4,4′-bithiazol-2-yl)benzamide;   N-(2′-amino-5-(3-(trifluoromethyl)phenyl)-4,4′-bithiazol-2-yl)-2,6-difluorobenzamide;   Ethyl 2′-(2,6-difluorobenzamido)-5′-(3-(trifluoromethyl)phenyl)-4,4′-bithiazole-2-carboxylate;   N-(4-(4,5-dihydrooxazol-2-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide   N-(4-(1,3,4-oxadiazol-2-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   2,6-difluoro-N-(4-(oxazol-2-yl)-5-(3-(trifluoromethyl)phenyl) thiazol-2-yl)benzamide;   2,6-difluoro-N-(4-(3-methyl-1,2,4-oxadiazol-5-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   2-(2,6-difluorobenzamido)-N-methoxy-N-methyl-5-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;   2,6-difluoro-N-(4-propionyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   N-(2′,5′-dimethyl-5-(3-(trifluoromethyl)phenyl)-4,4′-bithiazol-2-yl)-2,6-difluorobenzamide;   Ethyl 2′-(2,6-difluorobenzamido)-5-methyl-5′-(3-(trifluoromethyl) phenyl)-4,4′-bithiazole-2-carboxylate;   2-(2,6-Difluorobenzamido)-5-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;   N-(2,2-diethoxyethyl)-2-(2,6-difluorobenzamido)-5-(3-(trifluoromethyl)phenyl)thiazole-4-carboxamide;   2,6-Difluoro-N-(4-propioloyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   N-(4-(1H-Pyrazol-3-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   2,6-Difluoro-N-(4-(1-methyl-1H-pyrazol-3-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   N-(4-amino-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   N-(4-Chloro-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   N-(4-ethynyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   2,6-Difluoro-N-(5-(3-(trifluoromethyl)phenyl)-4-(5-(trimethylsilyl)isoxazol-3-yl)thiazol-2-yl)benzamide;   2,6-Difluoro-N-(4-(isoxazol-3-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   2,6-Difluoro-N-(4-(pyridin-2-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   2,6-Difluoro-N-(4-(6-methylpyridin-2-yl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)benzamide;   N-(4-(3,4-Dimethoxyphenyl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   N-(4-(4-(Dimethylamino)phenyl)-5-(3-(trifluoromethyl)phenyl)thiazol-2-yl)-2,6-difluorobenzamide;   2-(3-methylisonicotinamido)-5-(3-(trifluoromethyl)phenyl)thiazole-4-carboxylate hydrochloride;   2-(3-Methylisonicotinamido)-5-(3-(trifluoromethyl)phenyl)thiazole-4-carboxylic acid;   Methyl 2-(2,6-difluorobenzamido)-5-(3-methoxyphenyl)thiazole-4-carboxylate;   Methyl 2-(2,6-difluorobenzamido)-5-(3-(methoxycarbonyl)phenyl) thiazole-4-carboxylate;   Ethyl 2′-(2,6-difluorobenzamido)-4′-methyl-4,5′-bithiazole-2-carboxylate;   N-(2,4′-Dimethyl-4,5′-bithiazol-2′-yl)-2,6-difluorobenzamide;   N-(2,6-Difluorobenzyl)-4-methyl-5-(3-(trifluoromethyl)phenyl)thiazol-2-amine;   N-(2,6-difluorophenyl)-4-methyl-5-(3-(oxazol-2-yl)phenyl)thiazole-2-carboxamide;   methyl 3-(2-(2,6-difluorophenylcarbamoyl)-4-methylthiazol-5-yl)benzoate;   5-(3-(1,3,4-oxadiazol-2-yl)phenyl)-N-(2,6-difluorophenyl)-4-methylthiazole-2-carboxamide;   5-(2-chloro-5-(trifluoromethyl)phenyl)-N-(2,6-difluorophenyl)-4-methylthiazole-2-carboxamide;   4-methyl-N-(3-methylpyridin-4-yl)-5-(3-(trifluoromethyl)phenyl)thiazole-2-carboxamide;   N-(2,6-difluorophenyl)-5-(3-(trifluoromethyl)phenyl)thiazole-2-carboxamide;   N-(2,6-difluorophenyl)-5-(3-(oxazol-2-yl)phenyl)thiazole-2-carboxamide;   5-(2-methyl-5-(oxazol-2-yl)phenyl)-N-(3-methylpyridin-4-yl)thiazole-2-carboxamide; or   5-(2-methyl-5-(thiazol-2-yl)phenyl)-N-(3-methylpyridin-4-yl)thiazole-2-carboxamide;   or a pharmaceutically acceptable salt thereof.   
     
     
         154 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of  claim 138 . 
     
     
         155 . The pharmaceutical composition of  claim 154 , further comprising one or more additional therapeutic agents. 
     
     
         156 . The pharmaceutical composition according to  claim 155 , wherein the additional therapeutic agent is selected from the group consisting of immunosuppressive agents, anti-inflammatory agents, steroids, non-steroidal anti-inflammatory agents, antihistamines, analgesics, and suitable mixtures thereof.