Inhibiting (alpha-v)(beta-6) integrin

Abstract

Disclosed are small molecule inhibitors of αvβ6 integrin, and methods of using them to treat a number of diseases and conditions.

1 - 30 . (canceled) 
     
     
         31 . A compound of formula (I):
   A-B—C  (I)
   wherein:
 A is 
   
       
         
           
           
               
               
           
         
          wherein each R 1  is independently H, alkyl, halide, alkoxy, CF 3 , OH, alkylene-OH, NO 2 , —N(H)R a , or NH 2 ; wherein R a  in A is H, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl, or —(C 1 -C 6 )alkylene-O—C(O)O(C 1 -C 6 )alkyl;
 B is alkylene, -alkylene-O—, or -alkylene-O-alkylene-; 
 C is 
 
       
       
         
           
           
               
               
           
         
          wherein each R 3  is independently selected from H, halide, CF 3 , C(H)F 2 , C(F)H 2 , alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; and n with respect to R 3  is 0, 1, 2, 3, or 4;
 R a  in C is H, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl, or —(C 1 -C 6 )alkylene-O—C(O)O(C 1 -C 6 )alkyl; 
 R 2  is 
 
       
       
         
           
           
               
               
           
         
          and n in R 2  is 0, 1, 2, 3, or 4;
 R 4  is independently selected from alkyl, —C(F 2 )CH 3 , cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, —O-alkylene-cycloalkyl, —O-cycloalkyl, —O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; 
 each R 5  is independently selected from H, halide, CF 3 , C(H)F 2 , C(F)H 2 , alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; 
 the absolute configuration at any stereocenter is R, S, or a mixture thereof; 
 or a pharmaceutically acceptable salt thereof; 
 provided that the compound is not selected from the group consisting of: 
 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 31 , wherein each R 1  is independently H, alkyl, halide, alkoxy, CF 3 , OH, alkylene-OH, —N(H)R a , or NH 2 ; and R a  in C is H, (C 1 -C 6 )alkyl, or —(C 1 -C 6 )alkylene-O(C 1 -C 6 )alkyl; and R a  in A is (C 1 -C 6 )alkyl, or —(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl. 
     
     
         33 . The compound of  claim 32 , wherein each R 3  is independently selected from H, halide, CF 3 , C(H)F 2 , C(F)H 2 , alkyl, cycloalkyl, -alkylene-alkoxy, hydroxyl, and alkoxy; and n with respect to R 3  is 0 or 1. 
     
     
         34 . The compound of  claim 33 , wherein each R 5  is independently selected from H, halide, CF 3 , C(H)F 2 , C(F)H 2 , alkyl, cycloalkyl, -alkylene-alkoxy, hydroxyl, and alkoxy. 
     
     
         35 . The compound of  claim 34 , wherein R 4  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         36 . The compound of  claim 31 , wherein:
 a. each R 1  is independently H, alkyl, halide, or alkoxy;   b. each R 3  is independently selected from the group consisting of: halide, alkyl, and alkoxy; and n with respect to R 3  is 0 or 1; and   c. each R 5  is independently selected from H, halide, CF 3 , C(H)F 2 , C(F)H 2 , alkyl, cycloalkyl, -alkylene-alkoxy, hydroxyl, and alkoxy.   
     
     
         37 . The compound of  claim 36 , wherein R 4  is independently selected from cycloalkyl, and heterocycloalkyl; and R a  in C is H. 
     
     
         38 . The compound of  claim 37 , wherein B is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         q is 0, 1, 2, or 3; and p is 0, 1, or 2. 
       
     
     
         39 . The compound of  claim 38 , wherein
 a. each R 3  is independently selected from H, and F; and   b. each R a  is H.   
     
     
         40 . The compound of  claim 36 , wherein R 4  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         41 . The compound of  claim 31 , wherein:
 a. all instances of R 1  are H;   b. B is alkylene-O—;   c. each R 3  is independently selected from H, halide, alkyl and alkoxy; and n with respect to R 3  is 0 or 1;   d. R 4  is selected from cycloalkyl and heterocycloalkyl;   e. each R 5  is independently selected from H, halide, CF 3 , C(H)F 2 , C(F)H 2 , alkyl, cycloalkyl, -alkylene-alkoxy, hydroxyl, and alkoxy;   f. R a  in C is H; and
 the absolute configuration at any stereocenter is R, S, or a mixture thereof; 
 or a pharmaceutically acceptable salt thereof. 
   
     
     
         42 . The compound of  claim 41 , wherein R 3  is independently selected from H and F. 
     
     
         43 . The compound of  claim 41 , wherein B is 
       
         
           
           
               
               
           
         
       
       and q is 0, 1, 2, or 3. 
     
     
         44 . The compound of  claim 43 , wherein:
 a. q is 0, 1, or 2;   b. R 3  is H or F; and   c. each R 5  is independently selected from H, F, CF 3 , C(H)F 2 , C(F)H 2 , methyl, cyclopropyl, methylene-cyclopropyl, hydroxyl, and methoxy.   
     
     
         45 . A pharmaceutical composition formulated for oral delivery of an αvβ6 integrin inhibitor, the composition comprising the αvβ6 integrin inhibitor compound of  claim 31  as an active compound and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the αvβ6 integrin inhibitor compound. 
     
     
         46 . A compound of formula (I):
   A-B—C  (I)
   wherein:
 A is 
   
       
         
           
           
               
               
           
         
          wherein each R 1  is independently H, alkyl, halide, alkoxy, CF 3 , OH, alkylene-OH, NO 2 , —N(H)R a , or NH 2 ; wherein R a  in A is H, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl, or —(C 1 -C 6 )alkylene-O—C(O)O(C 1 -C 6 )alkyl;
 B is alkylene, -alkylene-O—, or -alkylene-O-alkylene-; 
 C is 
 
       
       
         
           
           
               
               
           
         
          wherein each R 3  is independently selected from H, halide, CF 3 , C(H)F 2 , C(F)H 2 , alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; and n with respect to R 3  is 0, 1, 2, 3, or 4;
 R a  in C is H, (C 1 -C 6 )alkyl, —(C 1 -C 6 )alkylene-O—(C 1 -C 6 )alkyl, or —(C 1 -C 6 )alkylene-O—C(O)O(C 1 -C 6 )alkyl; 
 R 2  is 
 
       
       
         
           
           
               
               
           
         
          and m in R 2  is 0, 1, 2, 3, or 4;
 R 4  is independently selected from alkyl, —C(F 2 )CH 3 , cycloalkyl, heterocycloalkyl, -alkylene-cycloalkyl, —O-alkylene-cycloalkyl, —O-cycloalkyl, —O-alkyl, -alkylene-O-alkyl, -alkylene-O-cycloalkyl, and -alkylene-O-alkylene-cycloalkyl; 
 each R 5  is independently selected from H, halide, CF 3 , C(H)F 2 , C(F)H 2 , alkyl, cycloalkyl, -alkylene-alkoxy, aryl, hydroxyl, and alkoxy; and 
 the absolute configuration at any stereocenter is R, S, or a mixture thereof; 
 or a pharmaceutically acceptable salt thereof; 
 provided that the compound is not a compound of the formula: 
 
       
       
         
           
           
               
               
           
         
       
     
     
         47 . The compound of  claim 46 , wherein
 a. each R 1  is independently selected from the group consisting of: H, methyl, F, methoxy, CF 3 , OH, and alkylene-OH;   b. each R 3  in C is independently selected from H, halide, alkyl or alkoxy; and n with respect to R 3  is 0 or 1;   c. R a  in C is H; and   d. each R 5  is independently selected from the group consisting of H, halide, cyclopropyl, methylene-cyclopropyl, and methoxy.   
     
     
         48 . The compound of  claim 47 , wherein
 a. B is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         
           q is 0, 1, 2, or 3; and p is 0, 1, or 2; and 
         
         b. each R 1  is H. 
       
     
     
         49 . The compound of  claim 48 , wherein
 a. g is 0, 1, or 2; and p is 0 or 1;   b. n with respect to R 3  is 0;   C. R 4  is selected from the group consisting of: cycloalkyl and heterocycloalkyl; and   d. each R 5  is independently selected from the group consisting of H, F, cyclopropyl, methylene-cyclopropyl, and methoxy.   
     
     
         50 . A pharmaceutical composition formulated for oral delivery of an αvβ6 integrin inhibitor, the composition comprising the αvβ6 integrin inhibitor compound of  claim 46  as an active compound and a pharmaceutically acceptable carrier formulated for oral therapeutic administration of the αvβ6 integrin inhibitor compound.