Compounds for inflammation and immune-related uses

Abstract

The invention relates to certain compounds, 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 a linker having 1-6 atoms; 
 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 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, (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 1 -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 0-5; and 
 p is 0-2; 
 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, 
 provided that when Z is a bond, Y 2  is CH, X 1  and X 2  are both C, and R 2  is methyl, then R1 is other than furan-2-yl, 1,3-oxazol-2-yl, furan-3-yl, 1,3-oxazol-5-yl, pyridine-3-yl, 1,3-thiazol-2-yl, 1-methyl-1H-imidazol-5-yl, 1H-imidazol-5-yl, 3-chloro-pyridin-4-yl, 3-methyl-pyridin-4-yl, 3-methoxy-pyridin-4-yl, 2-methoxy-5-chloro-pyridin-3-yl, 1,3,4-oxadiazol-2-yl, and 1-ethyl-1H-imidazol-5-yl; 
 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; 
 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-oxazol-5-yl, isoxazol-5-yl, 1,3-thiazol-2-yl and 1H-imidazol-5-yl; and 
 when Z is a bond, Y 2  is CH, X 1  and X 2  are both N and R 2  is methyl, then R 1  is other than 1,3-oxazol 5 yl, 1-methyl-1H-imidazol-5-yl, 1H-imidazol-5-yl, 1,3-thiazol-2-yl. 
 
       
     
     
         2 . The compound of  claim 1 , wherein Z is (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 may be N-substituted with (C 1 -C 6 )alkyl, which may in turn be 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 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 . 
     
     
         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 S, 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 l. 
     
     
         21 - 29 . (canceled)