Substituted pyridine compounds for inflammation and immune-related uses

Abstract

The invention relates to certain compounds of Formula (I): or pharmaceutically acceptable salts, solvates, clathrates, or prodrugs thereof, that are useful as immunosuppressive agents and for treating and preventing inflammatory conditions, allergic disorders, and immune disorders.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein:
 each of X 1  and X 2  is independently N, C or N + O − ; provided that one of X 1  or X 2  is C, and the other is N or N + O − ; 
 Y 1  is S or CH; 
 Y 2  is S, N, or CH; 
 Z is a bond or divalent radicals of alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, alkylaminoalkyl, cycloalkyl, heteroaryl, alkylcycloalkyl, or alkyl-substituted alkylcycloalkyl, wherein one or more carbon atoms is optionally replaced with O, S, or N; 
 Y 3  is CH 2  or C═O; 
 R 1  is heteroaryl, aryl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl, wherein each substituent represented by R 1  is independently and optionally substituted with one to three halo, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, COR E , COOR 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 CON(R 6 ) 2 , NR 6 CSN(R 6 ) 2 , OR 6 , S(O) p R 6 , S(O) p N(R 6 ) 2 , CN, NO 2 , or N 3 ; 
 R 2  is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, heteroaryl, heteroaryl(C 1 -C 2 )alkyl, heteroaryl(C 2 )alkenyl, heteroaryl(C 2 )alkynyl, aryl(C 1 -C 2 )alkyl, aryl(C 2 )alkenyl, aryl(C 2 )alkynyl, CN, COR 6 , COOR 6 , CON(R 6 ) 2 , CSR 6 , CSOR 6 , or CSN(R 6 ) 2 , wherein each substituent represented by R 2  is independently and optionally substituted with one to three halo, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, COR 6 , COOR 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 CON(R 6 ) 2 , NR 6 CSN(R 6 ) 2 , OR 6 , SR 6 , CN, NO 2 , or N 3 ; 
 R 3  is H, halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, aryl, heteroaryl, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, COR 6 , COOR 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 CON(R 6 ) 2 , NR 6 CSN(R 6 ) 2 , OR 6 , S(O) p R 6 , CN, NO 2 , S(O) p N(R 6 ) 2  or N 3 , wherein each substituent represented by R 3  having a hydrogen atom is optionally and independently substituted with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, —OH, —NH 2 , NH(C 1 -C 3 )alkyl, N((C 1 -C 3 )alkyl) 2 , or CN; 
 R 4  is H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, heteroaryl, heteroaryl(C 1 -C 2 )alkyl, heteroaryl(C 2 )alkenyl, heteroaryl(C 2 )alkynyl, aryl, aryl(C 1 -C 2 )alkyl, aryl(C 2 )alkenyl, aryl(C 2 )alkynyl, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, OR 6 , or CON(R 6 ) 2 ; 
 each R 5  is independently halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, heteroaryl, heteroaryl(C 1 -C 2 )alkyl, heteroaryl(C 2 )alkenyl, heteroaryl(C 2 )alkynyl, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, aryl, aryl(C 1 -C 2 )alkyl, aryl(C 2 )alkenyl, aryl(C 2 )alkynyl, (C 1 -C 6 )haloalkyl, COR 6 , COOR 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 CON(R 6 ) 2 , NR 6 CSN(R 6 ) 2 , OR 6 , S(O) p R 6 , CN, NO 2 , or N 3 , wherein each substituent represented by R 5  having a hydrogen atom is optionally an independently substituted with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, aryl, heteroaryl, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, —OH, —NH 2 , NH(C 1 -C 3 )alkyl, N((C 1 -C 3 )alkyl) 2 , or CN; 
 each R 6  is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 7 )cycloalkyl, heterocycloalkyl, heteroaryl, heteroaryl(C 1 -C 2 )alkyl, heteroaryl(C 2 )alkenyl, heteroaryl(C 2 )alkynyl, aryl, aryl(C 1 -C 2 )alkyl, aryl(C 2 )alkenyl, or aryl(C 2 )alkynyl or two R 6  substituents attached to the same or adjacent atoms are taken together to form a heterocycloalkyl or heteroaryl; 
 n is 0, 1, 2, 3, 4, or 5; and 
 p is 0, 1, or 2; 
 wherein one but not both of Y 1  and Y 2  is S; and one of the dashed bonds is a double bond, and one is a single bond; 
 when Z is a bond, Y 2  is CH, X 1  is N, X 2  is C, and R 2  is methyl, then R 1  is other than 1,3-oxazol-5-yl; and 
 when Z is a bond, Y 2  is CH, X 1  is C, X 2  is N and R 2  is methyl, then R 1  is other than 1-methyl-1H-imidazol-5-yl, 1,3-thiazol-2-yl and 1H-imidazol 5 yl. 
 
     
     
         2 . The compound of  claim 1 , wherein Z is divalent radicals of (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, heteroaryl, CO, COO, CON(R 6 ), CS, CSO, or CSN(R 6 ). 
     
     
         3 . (canceled) 
     
     
         4 . The compound of  claim 1 , wherein Z is a bond. 
     
     
         5 . The compound of  claim 1 , wherein R 1  is heteroaryl. 
     
     
         6 . The compound of  claim 5 , wherein R 1  is pyridinyl, pyrazolyl, oxazolyl, imidazolyl, or tetrazolyl, each of which is optionally N-substituted with (C 1 -C 6 )alkyl, which is optionally substituted with N(R 6 ) 2 . 
     
     
         7 . The compound of  claim 1 , wherein R 2  is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or heteroaryl, each of which is optionally substituted with one to three halo, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, COR E , COOR 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 CON(R 6 ) 2 , NR 6 CSN(R 6 ) 2 , OR 6 , SR 6 , CN, NO 2 , or N 3 . 
     
     
         8 . The compound of  claim 1 , wherein R 3  and R 4  are H. 
     
     
         9 . The compound of  claim 1 , wherein n is 2, and R 5  is halo. 
     
     
         10 - 11 . (canceled) 
     
     
         12 . The compound of  claim 1 , wherein X 1  is C, and X 2  is N. 
     
     
         13 . The compound of  claim 1 , wherein X 1  is N, and X 2  is C. 
     
     
         14 . The compound of  claim 1 , wherein Y 1  is S, and Y 2  is CH. 
     
     
         15 . The compound of  claim 1 , wherein Y 1  is S, and Y 2  is N. 
     
     
         16 . The compound of  claim 1 , wherein Y 2  is S. 
     
     
         17 . (canceled) 
     
     
         18 . A compound of formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein:
 one of X 1  and X 2  is N provided that the other is C; 
 Y 1  is N or CH; 
 Z is a bond; a —CH 2 — group; a C 2  alkylene, alkenylene, or alkynylene group; or a carbonyl group; 
 R 1  is heteroaryl, aryl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl, and is optionally substituted with one to three halo, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, COR 6 , COOR 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 CON(R 6 ) 2 , NR 6 CSN(R 6 ) 2 , OR 6 , S(O) p R 6 , S(O) p N(R 6 ) 2 , CN, NO 2 , or N 3 ; 
 R 2  is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl, and is optionally substituted with one to three halo, (C 1 -C 4 )alkyl, (C 2 -C 4 )alkenyl, (C 2 -C 4 )alkynyl, COR 6 , COOR 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 CON(R 6 ) 2 , NR 6 CSN(R 6 ) 2 , OR 6 , SR 6 , CN, NO 2 , or N 3 ; 
 R 3  is H, halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, COR 6 , COOR 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 CON(R 6 ) 2 , NR 6 CSN(R 6 ) 2 , OR 6 , S(O) p R 6 , CN, NO 2 , S(O) p N(R 6 ) 2  or N 3 , and is optionally and independently substituted with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, —OH, —NH 2 , NH(C 1 -C 3 )alkyl, N((C 1 -C 3 )alkyl) 2 , or CN; 
 R 4  is H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, OR 6 , or CON(R 6 ) 2 ; 
 each R 5  is independently halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, COR 6 , COOR 6 , CON(R 6 ) 2 , N(R 6 ) 2 , NR 6 CON(R 6 ) 2 , NR 6 CSN(R 6 ) 2 , OR 6 , S(O) p R 6 , CN, NO 2 , or N 3 , and is optionally substituted with halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, (C 1 -C 6 )haloalkoxy, (C 1 -C 6 )hydroxyalkyl, —OH, —NH 2 , NH(C 1 -C 3 )alkyl, N((C 1 -C 3 )alkyl) 2 , or CN; 
 each R 6  is independently H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl; 
 n is 0, 1, 2, 3, 4 or 5; and 
 p is 0, 1 or 2. 
 
     
     
         19 . (canceled) 
     
     
         20 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of  claim 1 . 
     
     
         21 - 29 . (canceled)