Compounds for inflammation and immune-related uses

Abstract

The invention relates to compounds of structural formulas (I), (VII) and (XI): or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein X 1 , X 2 , X 3 , Y, Z, L, R 1 , R 2 , R 3 , R 18 and n 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 (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         L is a linker selected from the group consisting of a covalent bond, —NRCH 2 —, —CH 2 NR—, —C(O)—, —NR—C(O)—, —C(O)—NR—, —OC(O)—, —C(O)O—, —C(S)—, —NR—C(S)—, and —C(S)—NR—; 
         X 1  and X 3  are each, independently, CH or N; 
         X 2  is CH, CR 10  or N; 
         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, and lower haloalkoxy; 
         R, for each occurrence is independently selected from —H, an alkyl, —C(O)R 5 , and —C(O)OR 5 ; 
         R 1  and R 2  are each, independently, a halo, a haloalkyl, a lower alkyl, a lower alkoxy, or a haloalkoxy; 
         R 3  is an alkyl, a haloalkyl, a halo, a haloalkoxy, —OR 5 , —SR 5 , or —NR 6 R 7 ; 
         R 18  is a halo, cyano, nitro, —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(O)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(S)NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —C(NR 8 )NR 6 R 7 , —S(O) p R 5 , —S(O) p NR 5 , —S(O) p OR 5 , —P(O)(OR 5 ) 2 , —OP(O)(OR 5 ) 2 , —P(O)(R 5 ) 2 , a five or six membered optionally substituted heterocycloalkyl, a five or six membered optionally substituted heterocyclyl, or a five or six membered optionally substituted heteroaryl; 
         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 10  is a lower alkyl, a lower alkoxy, a halo, a lower haloalkyl, a lower haloalkoxy, a cyano, nitro, —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(O)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(S)NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —C(NR 8 )NR 6 R 7 , —S(O) p R 5 , —P(O)(OR 5 ) 2 , —OP(O)(OR 5 ) 2 , or —P(O)(R 5 ) 2 ; 
         n is zero or an integer from 1 to 4; and 
         p, for each occurrence, is independently 1 or 2. 
       
     
     
         2 . The compound of  claim 1 , wherein L is —NR—C(O)—. 
     
     
         3 - 7 . (canceled) 
     
     
         8 . The compound of  claim 1 , wherein the compound is represented by formula (II): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         R 4  is a halo, cyano, nitro, —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(O)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(S)NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —C(NR 8 )NR 6 R 7 , —S(O) p R 5 , —S(O) p NR 5 , —S(O) p OR 5 , —P(O)(OR 5 ) 2 , —OP(O)(OR 5 ) 2 , —P(O)(R 5 ) 2 , or an ester, amide or carboxylic acid bioisostere. 
       
     
     
         9 - 10 . (canceled) 
     
     
         11 . The compound of  claim 8 , wherein L is —NHC(O)—. 
     
     
         12 - 19 . (canceled) 
     
     
         20 . The compound of  claim 11 , wherein the compound is represented by structural formula (IV): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. 
       
     
     
         21 - 27 . (canceled) 
     
     
         28 . The compound of  claim 11 , wherein the compound is represented by structural formula (V): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. 
       
     
     
         29 . The compound of  claim 28 , wherein R 1  and R 2  are each, independently, a halo. 
     
     
         30 . The compound of  claim 29 , wherein R 3  is a lower alkyl, a lower alkoxy, a lower alkyl sulfanyl, a lower alkylamino, a lower dialkylamino, or a halo. 
     
     
         31 . The compound of  claim 30 , R 4  is a bioisostere of an ester, amide, or carboxylic acid. 
     
     
         32 . The compound of  claim 31 , wherein R 4  is a 5-membered heteroaryl. 
     
     
         33 . The compound of  claim 32 , wherein R 4  is an optionally substituted oxazolyl, an optionally substituted thiazolyl, an optionally substituted 1H-tetrazolyl, an optionally substituted 1H-imidazolyl, an optionally substituted [1,2,4]oxadiazolyl, or an optionally substituted 4H-[1,2,4]-triazolyl. 
     
     
         34 . The compound of  claim 30 , wherein R 4  is a halo, —C(O)R 9 , —S(O) p R 11 , —S(O) p NR 5 , —S(O) p OR 5 , —P(O)(OR 12 ) 2 , or —P(O)(R 11 ) 2 , wherein:
 R 9  is a lower alkoxy, lower alkyl sulfanyl, or an alkoxyalkoxy; 
 R 11 , for each occurrence, is independently, a lower alkyl; and 
 R 12 , for each occurrence, is independently, H or a lower alkyl. 
 
     
     
         35 . The compound of  claim 30 , wherein R 1  and R 2  are each a fluoro group. 
     
     
         36 . The compound of  claim 11 , wherein the compound is represented by structural formula (VI): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. 
       
     
     
         37 - 44 . (canceled) 
     
     
         45 . A compound represented by formula (VII): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         L is a linker selected from the group consisting of a covalent bond, —NRCH 2 —, —CH 2 NR—, —C(O)—, —NR—C(O)—, —C(O)—NR—, —OC(O)—, —C(O)O—, —C(S)—, —NR—C(S)—, and —C(S)—NR—; 
         X 1  is CH or N; 
         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, for each occurrence is independently selected from —H, an alkyl, —C(O)R 5 , and —C(O)OR 5 ; 
         R 1  is a halo, a haloalkyl, a lower alkyl, a lower alkoxy, or a haloalkoxy; 
         R 3  is an alkyl, a haloalkyl, a halo, a haloalkoxy, —OR 5 , —SR 5 , or —NR 6 R 7 ; 
         R 18  is a halo, cyano, nitro, —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(O)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(S)NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —C(NR 8 )NR 6 R 7 , —S(O) p R 5 , —S(O) p NR 5 , —S(O) p OR 5 , —P(O)(OR 5 ) 2 , —OP(O)(OR 5 ) 2 , —P(O)(R 5 ) 2 , a five or six membered optionally substituted heterocycloalkyl, a five or six membered optionally substituted heterocyclyl, or a five or six membered optionally substituted heteroaryl; 
         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 ; 
         n is zero or an integer from 1 to 4; and 
         p, for each occurrence, is independently 1 or 2. 
       
     
     
         46 . The compound of  claim 45 , wherein L is —NR—C(O)—. 
     
     
         47 - 51 . (canceled) 
     
     
         52 . The compound of  claim 45 , wherein the compound is represented by formula (VI): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein: 
         R 4  is a halo, cyano, nitro, —C(O)R 5 , —C(O)OR 5 , —C(O)SR 5 , —C(O)NR 6 R 7 , —C(S)R 5 , —C(S)OR 5 , —C(S)SR 5 , —C(S)NR 6 R 7 , —C(NR 8 )R 5 , —C(NR 8 )OR 5 , —C(NR 8 )SR 5 , —C(NR 8 )NR 6 R 7 , —S(O) p R 5 , —S(O) p NR 5 , —S(O) p OR 5 , —P(O)(OR 5 ) 2 , —OP(O)(OR 5 ) 2 , —P(O)(R 5 ) 2 , or an ester, amide or carboxylic acid bioisostere. 
       
     
     
         53 - 54 . (canceled) 
     
     
         55 . The compound of  claim 52 , wherein L is —NHC(O)—. 
     
     
         56 . The compound of  claim 55 , wherein the compound is represented by formula (IX): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. 
       
     
     
         57 - 115 . (canceled) 
     
     
         116 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of  claim 1  and optionally further comprising one or more additional therapeutic agents. 
     
     
         117 - 119 . (canceled) 
     
     
         120 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of  claim 45  and optionally further comprising one or more additional therapeutic agents.