Antagonists of human integrin (alpha4)(beta7)

Abstract

Disclosed are small molecule antagonists of α4β7 integrin, and methods of using them to treat a number of specific diseases or conditions.

1 . A method of treating inflammatory bowel disease or gastroenteritis, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is H, alkyl, alkylene-cycloalkyl, heterocyclyl, alkylene-O-alkyl, aryl, heteroaryl, or alkylene-CF 3 ; 
 R 2  is heterocyclyl; 
 R 3  is 
 
       
       
         
           
           
               
               
           
         
         
           R 4  is H, or (C 1 -C 6 )-alkyl; 
           R c  is H, alkyl, cycloalkyl, heterocyclyl, or alkylene-CF 3 ; 
           R d  is aryl, heteroaryl, heterocyclyl, —O-cycloalkyl, —O-aryl, or —O-heterocyclyl; and 
           R e  is aryl, heteroaryl, or heterocyclyl; 
           or a pharmaceutically acceptable salt thereof. 
         
       
     
     
         2 . The compound of  claim 1 , wherein R 1  is alkyl. 
     
     
         3 .- 17 . (canceled) 
     
     
         18 . The compound of  claim 1 , wherein R 2  is heterocyclyl. 
     
     
         19 .- 21 . (canceled) 
     
     
         22 . The compound of  claim 1 , wherein R 2  is a 6- to 12-membered heterocyclyl optionally substituted with one or more substituents selected from amino, alkyl and alkoxy, wherein alkyl or alkoxy is optionally substituted with morpholino, a cyclic amino, or an acyclic amino, and wherein said alkyl, alkoxy, morpholino, cyclic amino, or acyclic amino moiety is optionally substituted with one or more alkoxyls or fluorines. 
     
     
         23 .- 25 . (canceled) 
     
     
         26 . The compound of  claim 1 , wherein R 2  is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 1 , wherein R 2  is selected from 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         28 .- 47 . (canceled) 
     
     
         48 . The compound of  claim 1 , wherein R 3  is 
       
         
           
           
               
               
           
         
       
     
     
         49 . The compound of  claim 48 , wherein R c  is H, alkyl, or CF 3 . 
     
     
         50 .- 51 . (canceled) 
     
     
         52 . The compound of  claim 1 , wherein R 3  is 
       
         
           
           
               
               
           
         
       
     
     
         53 . The compound of  claim 52 , wherein R d  is aryl, heteroaryl, or heterocyclyl. 
     
     
         54 .- 56 . (canceled) 
     
     
         57 . The compound of  claim 53 , wherein R d  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         58 .- 61 . (canceled) 
     
     
         62 . The compound of  claim 53 , wherein R d  is 
       
         
           
           
               
               
           
         
       
     
     
         63 . (canceled) 
     
     
         64 . The compound of  claim 53 , wherein R d  is selected from 
       
         
           
           
               
               
           
         
       
     
     
         65 . The compound of  claim 1 , wherein R 3  is 
       
         
           
           
               
               
           
         
       
     
     
         66 .- 69 . (canceled) 
     
     
         70 . The compound of  claim 65 , wherein R e  is or 
       
         
           
           
               
               
           
         
       
     
     
         71 .- 73 . (canceled) 
     
     
         74 . The compound of  claim 65 , wherein R e  is 
       
         
           
           
               
               
           
         
       
     
     
         75 . The compound of  claim 1 , wherein R 4  is H. 
     
     
         76 . The compound of  claim 1 , wherein R 4  is (C 1 -C 6 )-alkyl. 
     
     
         77 .- 92 . (canceled) 
     
     
         93 . The method  claim 1 , wherein the disease or condition is inflammatory bowel disease. 
     
     
         94 . The method of  claim 93 , wherein the inflammatory bowel disease is colitis, Crohn's disease, ileitis, Celiac disease, nontropical Sprue, enteropathy associated with seronegative arthropathies, gastroenteritis, or pouchitis. 
     
     
         95 . The method of  claim 94 , wherein the disease or condition is colitis; and the colitis is ulcerative colitis, microscopic colitis, or collagenous colitis. 
     
     
         96 . (canceled) 
     
     
         97 . The method of  claim 1 , wherein the disease or condition is gastroenteritis. 
     
     
         98 .- 104 . (canceled) 
     
     
         105 . The method of  claim 94 , wherein the inflammatory bowel disease is Crohn's disease. 
     
     
         106 . The method of  claim 95 , wherein the colitis is ulcerative colitis.