Substituted biaryl 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 A, Y, L, R 1 , W 1 and W 2 are defined herein. These compounds are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

1 . A compound represented by formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         A is —O—, —S—, —NR′ 11 —, —CR a ═CR b —, —N═CR a —, —CR a ═N—, or —N═N—; 
         W 1  and W 2  are each, independently, CR a  or N; 
         Y 1  is an optionally substituted alkyl, an optionally substituted alkenyl, or —C(O)OR′ 5 ; 
         L is a linker; 
         R″ 1  is an optionally substituted aryl or an optionally substituted heteroaryl; provided that R″ 1  is not an optionally substituted triazolyl, pyrazolyl, indolizinyl, benzamidazolyl, imidazo[4,5-c]pyrid-1-yl, or imidazo[4,5-b]pyrid-3-yl)-phenyl; 
         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′ 5 , —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; and 
         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′ 9  and R′ 10  are each, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, or an optionally substituted alkynyl; or R′ 9  and R′ 10 , together with the carbon atoms to which they are attached, form an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl; 
         R′ 11  is 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, —OR′ 5 , —SR′ 5 , —NR′ 6 R′ 7 , —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 , or —C(NR′ 8 )SR′ 5 ; and 
         provided that Ring A is not a thiophene, a thiazole, a thiadiazole, a pyrazine or a pyridazine. 
       
     
     
         2 . The compound of  claim 1 , wherein L is —NRCH 2 —, —CH 2 NR—, —NRC(O)—, —C(O)NR—, —C(O)—, C(S)—, —NRC(S)—, —C(S)NR—, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)NR—, —NRC(S)NR—, NRS(O) 2 NR—, NR—CH 2 —NR—, —N═CR—, —CR═N—, —NR—NR—C(O)—, —CH═CH—, —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; and 
 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. 
 
     
     
         3 . The compound of  claim 2 , wherein L is —NHCH 2 — or —NRC(O)—. 
     
     
         4 - 71 . (canceled) 
     
     
         72 . A compound represented by formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         X 3  and X 4  are each, independently, CH, CZ 1 , or N, provided that X 3  and X 4  are not both N; 
         L″ 1  is —NRCH 2 —, —CH 2 NR—, —NRC(O)—, —C(O)NR—, —C(O)—, C(S)—, —NRC(S)—, —C(S)NR—, —NRS(O) 2 —, —S(O) 2 NR—, —NRC(O)CH 2 —, —NRC(O)NR—, —NRC(S)NR—, NRS(O) 2 NR—, NR—CH 2 —NR—, —CH═CH—, —NRN═CR 6 —, —C(NR)—, or —CR 6 ═NNR—; 
         Z 1  and Z 2  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 ; 
         Z 4  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 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 , 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, for each occurrence, is independently —H, alkyl, —C(O)R 7 , or —C(O)OR 7 ; 
         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 , R 5 , R 7 , and R 8 , 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; 
         R 6 , for each occurrence, is —H or alkyl; and 
         p is 0, 1, or 2. 
       
     
     
         73 . The compound of  claim 72 , wherein L″ 1  is —NHS(O) 2 —, —S(O) 2 NH—, —NHS(O) 2 NH—, —NHC(O)NH—, —NHC(NH)NH—, —NHC(S)NH—, —NHCH 2 NH—, —NHN═CR 6 —, —C(NH)—, —CR 6 ═NNH—; —CH═CH— or —C≡C—. 
     
     
         74 . The compound of  claim 72 , wherein L″ 1  is —NHCH 2 —, —CH 2 NH—, —NHC(O)—, —C(O)NH—, —C(O)—, —C(S)—, —NHC(S)—, or —C(S)—NH—. 
     
     
         75 . The compound of  claim 74 , wherein L″ 1  is —NHCH 2 — or —NH—C(O)—. 
     
     
         76 . The compound of  claim 72 , wherein Z 4  is an optionally substituted phenyl, —C(O)OR 4 , an optionally substituted oxazolyl, an optionally substituted thiazolyl, an optionally substituted imidazolyl, an optionally substituted pyridinyl, an optionally substituted pyrazolyl, an optionally substituted pyrrolyl, an optionally substituted thienyl, an optionally substituted furanyl, an optionally substituted thiadiazolyl, an optionally substituted oxadiazolyl, or an optionally substituted tetrazolyl. 
     
     
         77 . The compound of  claim 76 , wherein Z 4  is oxazol-2-yl or —C(O)OCH 3 . 
     
     
         78 . The compound of  claim 76 , wherein Z 4  is substituted with one substituent selected from the group consisting of lower alkyl, lower halo alkyl, lower alkyl sulfanyl, halo or amino. 
     
     
         79 . The compound of  claim 72 , wherein Z 2  is halo, a lower alkyl, or a lower alkoxy. 
     
     
         80 - 85 . (canceled) 
     
     
         86 . The compound of  claim 72 , wherein one of R 8  is —H and the other is an optionally substituted phenyl. 
     
     
         87 . The compound of  claim 86 , wherein the phenyl is substituted with 1, 2, or 3 substituents selected from the group consisting of 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 . 
     
     
         88 . The compound of  claim 87 , wherein the phenyl is substituted with amino, lower dialkyl amino, lower alkyl amino, lower alkyl, halo, haloalkyl, nitro, lower alkoxy, or lower alkyl sulfanyl. 
     
     
         89 . The compound of  claim 88 , wherein the phenyl is substituted with amino, dimethylamino, methyl, trifluoromethyl, chloro, bromo, fluoro, nitro, methoxy, or methyl sufanyl. 
     
     
         90 . The compound of  claim 72 , wherein:
 L″ 1  is —NHC(O)—;   X 3  and X 4  are each CH;   Z 2  is halo, a lower alkyl, or a lower alkoxy;   Z 4  is a substituted phenyl, an optionally substituted oxazolyl, an optionally substituted thiazolyl, an optionally substituted imidazolyl, an optionally substituted pyridinyl, an optionally substituted pyrazolyl, an optionally substituted pyrrolyl, an optionally substituted thienyl, an optionally substituted furanyl, an optionally substituted thiadiazolyl, an optionally substituted oxadiazolyl, or an optionally substituted tetrazolyl;   one of R 8  is —H and the other is an optionally substituted phenyl; and   n is 0.   
     
     
         91 . The compound of  claim 90 , wherein Z 4  is oxazol-2-yl or —C(O)OCH 3 . 
     
     
         92 . The compound of  claim 91 , wherein one of R 8  is —H and the other is a phenyl substituted with 1, 2, or 3 substituents selected from the group consisting of amino, lower dialkyl amino, lower alkyl amino, lower alkyl, halo, haloalkyl, nitro, lower alkoxy, or lower alkyl sulfanyl. 
     
     
         93 - 117 . (canceled) 
     
     
         118 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of  claim 1 . 
     
     
         119 - 147 . (canceled)