Pyrimidine compounds and uses thereof

Abstract

This invention features pyrimidine compounds of formula (I): R t is aryl, or heteroaryl; each of R 2 and R 4 , independently, is halogen, nitro, cyano, isothionitro, SR c , or OR c ; or R 2 and R 4 , taken together, is carbonyl; R 3 is R c , alkenyl, alkynyl, OR c , OC(O)R c , SO 2 R c , S(O)R c , S(O 2 )NR c R d , NR c R d , NR c COR d , NR c C(O)OR d , NR c C(O)NR c R d , NR c SO 2 R d , COR c , C(O)OR c , or C(O)NR c R d ; R 5 is H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; X is O, S, S(O), S(O 2 ), or NR c ; Y is a covalent bond, CH 2 , C(O), C═N—R c , C═N—OR c , C═N—SR c , O, S, S(O), S(O 2 ), or NR c ; Z is N or CH; one of U and V is N, and the other is CR c ; and W is O, S, S(O), S(O 2 ), NR c , or NC(O)R c ; in which each of R a and R b , independently, is H, alkyl, aryl, heteroaryl; and each of R c and R d , independently, is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl. The featured compounds inhibit the production of IL-12, IL-23 and IL-27 and are useful for treating disorders associated with IL-12, IL-23 and IL-27 overproduction or misregulation, such as inflammatory and immune disorders,

1 - 44 . (canceled) 
     
     
         45 . A method of treating a subject with an IL-10, and/or IL-12 related disorder selected from the group consisting of adjuvant arthritis, inflammatory bowel disease, and Crohn's disease, said method comprising administering to the subject an effective amount of a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 R 1  is 
 
       
       
         
           
           
               
               
           
         
       
       aryl, or heteroaryl;
   each of R 2  and R 4 , independently, is R c , halogen, nitro, cyano, isothionitro, SR c , or OR c ; or R 2  and R 4 , taken together, is carbonyl.   R 3  is R c , alkenyl, alkynyl, OR c , OC(O)R c , SO 2 R c , S(O)R c , S(O 2 )NR c R d , SR c , NR c R d , NR c COR d , NR c C(O)OR d , NR c C(O)NR c R d , NR c SO 2 R d , COR c , C(O)OR c , or C(O)NR c R d ;   R 5  is H or alkyl;   n is 0, 1, 2, 3, 4, 5, or 6;   X is O, S, S(O), S(O 2 ), or NR c ;   Y is a covalent bond, CH 2 , C(O), C═N—R c , C═N—OR c , C═N—SR c , O, S, S(O), S(O 2 ), or NR c ;   Z is N or CH;   one of U and V is N, and the other is CR c ; and   W is O, S, S(O), S(O 2 ), NR c , or NC(O)R c ;   
 in which each of R a  and R b , independently, is H, alkyl, aryl, heteroaryl; and each of R c  and R d , independently, is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl. 
 
     
     
         46 . The method of  claim 45 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         47 . The method of  claim 46 , wherein U is N and V is CH. 
     
     
         48 . The method of  claim 46 , wherein Z is N and W is O. 
     
     
         49 . The method of  claim 46 , wherein X is NR c . 
     
     
         50 . The method of  claim 49 , wherein R c  is H, methyl, ethyl, or acetyl. 
     
     
         51 . The method of  claim 46 , wherein Y is O or CH 2 , and n is 0, 1, 2, 3, or 4. 
     
     
         52 . The method of  claim 46 , wherein one of R a  and R b  is 
       
         
           
           
               
               
           
         
         wherein:
 B is NR i , O, or S; 
 B′ is N or CR i ; 
 R g  is H, alkyl, or alkoxyl; 
 R h  is halogen, NO 2 , CN, alkyl, aryl, heteroaryl, OR c , OC(O)R c , SO 2 R c , S(O)R B , S(O 2 )NR c R d , SR c , NR c R d , NR c COR d , NR c C(O)OR d , NR c O(O)NR c R d , NR c SO 2 R d , COR c , C(O)OR c , or C(O)NR c R d ; 
 R i  is H, alkyl, or alkylcarbonyl; 
 p is 0, 1, or 2; and 
 q is 0, 1, 2, 3, or 4. 
 
       
     
     
         53 . The method of  claim 52 , wherein one of R a  and R b  is 
       
         
           
           
               
               
           
         
       
       and
   the other of R a  and R b  is H or alkyl.   
 
     
     
         54 . The method of  claim 53 , wherein R g  is H, methyl, ethyl, propyl, cyclopropyl, methoxy, or ethoxy; R h  is F, Cl, CN, methyl, methoxy, ethoxy, OC(O)CH 3 , OC(O)C 2 H 5 , C(O)OH, C(O)OC 2 H 5 , C(O)NH 2 , NHC(O)CH 3 , or S(O 2 )NH 2 ; R i  is H, methyl, ethyl, or acetyl, and q is 0, 1, or 2. 
     
     
         55 . The method of  claim 54 , wherein R g  is methyl or methoxy; R i  is H; and q is 0. 
     
     
         56 . The method of  claim 54 , wherein U is N and V is CH. 
     
     
         57 . The method of  claim 56 , wherein Z is N and W is O. 
     
     
         58 . The method of  claim 57 , wherein X is NR c ; and R c  is H, methyl, ethyl, or acetyl. 
     
     
         59 . The method of  claim 58 , wherein Y is O or CH 2 ; and n is 0, 1, 2, 3, or 4. 
     
     
         60 . The method of  claim 54 , wherein Y is O or CH 2 , and n is 0, 1, 2, 3, or 4. 
     
     
         61 . The method of  claim 60 , wherein R 3  is aryl or heteroaryl. 
     
     
         62 . The method of  claim 60 , wherein R 3  is pyridinyl. 
     
     
         63 . The method of  claim 45 , wherein R 1  is aryl or heteroaryl. 
     
     
         64 . The method of  claim 45 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.