Vinyl-aryl derivatives for inflammation and immune-related uses

Abstract

The invention relates to compounds that are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

1 . A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         X 1  and X 2  are, independently, CH or N; 
         one of X 3  or X 6  is NR 29 , and the other is CH 2 , CHR 2 , or C(R 2 ) 2 ; 
         L is a linker selected from the group consisting of —NHCH 2 —, —CH 2 NH—, —NR 5 —C(O)—, —C(O)—NR 5 —, —NR 5 —C(S)—, —C(S)—NR 5 —, —NR 5 —C(NR 8 )—, —C(NR 8 )—NR 5 —, —NR 5 C(S)NR 5 —, —NR 5 C(NR 8 )NR 5 —, and —NR 5 CR a R b NR 5 —; 
         Y is a substituted phenyl, provided that Y is not substituted with —NHC(O)R 30 ; 
         R 1  is H or a substituent; 
         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 a  and R b , 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, an optionally substituted heteraralkyl, cyano, nitro, halo, —OR 5 , —SR S , —NR 6 R 7 , —C(O)NR 6 R 7 , —NR 5 C(O)R 5 , —C(O)R 5 , —C(O)OR 5 , —OC(O)R 5 , —C(O)SR 5 , —SC(O)R 5 , —C(S)NR 6 R 7 , —NR 5 C(S)R 5 , —C(S)R 5 , —C(S)OR 5 , —OC(S)R 5 , —C(S)SR 5 , —SC(S)R 5 , —C(NR 8 )NR 6 R 7 , —NR 5 C(NR 8 )R 5 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —OC(NR 8 )R 5 , —C(NR 8 )SR 5 , —SC(NR 8 )R 5 , —OC(O)OR 5 , —OC(O)NR 6 R 7 , —NR 5 C(O)OR 5 , —NR 5 C(O)NR 6 R 7 , —SC(O)OR 5 , —SC(O)NR 6 R 7 , —SC(O)SR 5 , —NR 5 C(O)SR 5 , —OC(O)SR 5 , —OC(S)OR 5 , —OC(S)NR 6 R 7 , —NR 5 C(S)OR 5 , —NR 5 C(S)NR 6 R 7 , —SC(S)OR 5 , —SC(S)NR 6 R 7 , —SC(S)SR 5 , —NR 5 C(S)SR 5 , —OC(S)SR 5 , —OC(NR 8 )OR 5 , —OC(NR 8 )NR 6 R 7 , —NR 5 C(NR 8 )OR 5 , —NR 5 C(NR 8 )NR 6 R 7 , —SC(NR 8 )OR 5 , —SC(NR 8 )NR 6 R 7 , —SC(NR 8 )SR 5 , —NR 5 C(NR 8 )SR 5 , or —OC(NR 8 )SR 5 ; 
         R 5 , 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 6  and R 7 , 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 6  and R 7  taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl; 
         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 ; 
         R 28 , for each occurrence is, independently, H or a substituent; 
         R 29  is —C(O)R 30  or an optionally substituted N containing 6-membered aromatic ring; 
         R 30  is —H, —OR 5 , —SR S , —NR 6 R 7 , 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; 
         m is 0, 1, or 2; 
         n is 0, 1 or 2; and 
         with the proviso that the compound is not: 
         5-[4-(2,6-difluoro-benzoylamino)-phenyl]-4-methyl-2,4-dihydro-2H-pyridine-1-carboxylic acid ethyl ester; 
         Ethyl 3-(4-(2,6-difluorobenzamido)phenyl)-4-methyl-5,6-dihydropyridine-1(2H)-carboxylate; 
         Ethyl 4-(4-(2,6-difluorobenzamido)phenyl)-3-methyl-5,6-dihydropyridine-1(2H)-carboxylate; 
         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; 
         2,6-Difluoro-N-[4-(1-methoxycarbonyl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide; 
         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-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; or 
         2,6-Difluoro-N-[4-(1-pyrimidin-2-yl-4-methyl-1,2,5,6-tetrahydro-pyridin-3-yl)-phenyl]-benzamide. 
       
     
     
         2 . The compound of  claim 1 , wherein Y is substituted with one to two substituents. 
     
     
         3 . The compound of  claim 2 , wherein the one to two substituents are each independently a lower alkyl or a halo. 
     
     
         4 . The compound of  claim 3 , wherein Y is a difluorophenyl. 
     
     
         5 . The compound of  claim 4 , wherein Y is 2,6-difluorophenyl. 
     
     
         6 . The compound of  claim 1 , wherein L is —NHCH 2 —, —CH 2 NH—, —NH—C(O)—, or —C(O)—NH—. 
     
     
         7 . The compound of  claim 6 , wherein L is —NHC(O)—. 
     
     
         8 . The compound of  claim 1 , wherein R 1  is selected from the group consisting of a halo, 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, and an optionally substituted heteraralkyl. 
     
     
         9 . The compound of  claim 8 , wherein R 1  is selected from the group consisting of halo, and an optionally substituted lower alkyl. 
     
     
         10 . The compound of  claim 1 , wherein X 3  is CH 2  and X 6  is NR 29 . 
     
     
         11 . The compound of  claim 1 , wherein X 6  is CH 2  and X 3  is NR 29 . 
     
     
         12 . The compound of  claim 1 , wherein X 1  and X 2  are both CH or both N. 
     
     
         13 . (canceled) 
     
     
         14 . The compound of  claim 1 , wherein X 1  is N and X 2  is CH. 
     
     
         15 . (canceled) 
     
     
         16 . The compound of  claim 1 , wherein
 Y is a difluorophenyl;   L is —NHC(O)—;   R 1  is selected from the group consisting of halo and an optionally substituted lower alkyl; and   m is 0.   
     
     
         17 . The compound of  claim 1 , wherein the compound is represented by one of the following structures: 
       
         
           
           
               
               
           
         
         wherein 
         R 31  is halo, 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 1, 2, 3, 4 or 5. 
       
     
     
         18 - 30 . (canceled) 
     
     
         31 . The compound of  claim 17 , wherein the compound is represented by one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         32 - 47 . (canceled) 
     
     
         48 . The compound of  claim 1 , wherein the compound is represented by one of the following structures: 
       
         
           
           
               
               
           
         
         wherein 
         each of X 7 , X 8 , X 9 , X 10 , and X 11  are independently CH, CR 2 , or N, provided that at least one of X 7 , X 8 , X 9 , X 10 , or X 11  is N; 
         R 31  is halo, 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 1, 2, 3, 4 or 5. 
       
     
     
         49 - 59 . (canceled) 
     
     
         60 . The compound of  claim 48 , wherein the compound is represented by one of the following structures: 
       
         
           
           
               
               
           
         
       
     
     
         61 - 76 . (canceled) 
     
     
         77 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of  claim 1 . 
     
     
         78 . The pharmaceutical composition of  claim 77 , further comprising one or more additional therapeutic agents. 
     
     
         79 - 106 . (canceled)