Diazinopyrimidines

Abstract

Compounds of formula I are p38 inhibitors: or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen or alkyl; R 2 is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl, or —Y 1 —C(O)—Y 2 —R 11 (where Y 1 and Y 2 are independently either absent or an alkylene group and R 11 is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino); R 3 is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterosubstituted cycloalkyl, heterocyclyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, -alkylene-C(═O)—R 4 (where R 4 is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), or acyl; Ar 1 is aryl; X 1 is O, NR 5 or S, where R 5 is hydrogen or alkyl; and X 2 is a bond, O, NR 6 , S or CH 2 , where R 6 is hydrogen or alkyl.

1 - 21 . (canceled)  
   
   
       22 . A method for treating a p38 MAP kinase mediated disorder comprising administering to a patient in need of such treatment, an effective amount of a compound of of formula I:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof,  
     wherein 
 R 1  is hydrogen or alkyl;  
 R 2  is alkyl, haloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, cycloalkylalkyl, heteroalkylsubstituted cycloalkyl, heterosubstituted cycloalkyl, heteroalkyl, cyanoalkyl, heterocyclyl, heterocyclylalkyl, or —Y 1 —C(O)—Y 2 —R 11  (where Y 1  and Y 2  are independently either absent or an alkylene group and R 11  is hydrogen, alkyl, haloalkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino);  
 R 3  is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterosubstituted cycloalkyl, heterocyclyl, aryl, aralkyl, haloalkyl, heteroalkyl, cyanoalkyl, -alkylene-C(═O)—R 4  (where R 4  is hydrogen, alkyl, hydroxy, alkoxy, amino, monoalkylamino or dialkylamino), or acyl;  
 Ar 1  is aryl;  
 X 1  is O, NR 5  or S, where R 5  is hydrogen or alkyl; and  
 X 2  is a bond, O, NR 6,  S or CH 2 , where R 6  is hydrogen or alkyl.  
 
   
   
       23 . The method of  claim 22 , wherein the p38 mediated disorder is arthritis, Crohn's disease, inflammatory bowel disease, adult respiratory distress syndrome, or chronic obstructive pulmonary disease.  
   
   
       24 . The method of  claim 22 , wherein the p38 mediated disorder is Alzheimer's disease.  
   
   
       25 - 35 . (canceled)  
   
   
       36 . The method of  claim 22 , wherein said compound is of the formula:  
     
       
         
         
             
             
         
       
     
   
   
       37 . The method of  claim 36 , wherein X 1  is O.  
   
   
       38 . The method of  claim 37 , wherein R 1  is hydrogen.  
   
   
       39 . The method of  claim 38 , wherein R 3  is hydrogen, alkyl, aryl, cycloalkyl, heterocyclyl, heterosubstituted cycloalkyl or heteroalkyl.  
   
   
       40 . The method of  claim 39 , wherein R 3  is alkyl, heterocyclyl, heterosubstituted cycloalkyl or heteroalkyl.  
   
   
       41 . The method of  claim 39 , wherein R 2  is heteroalkyl, cycloalkyl, heterocyclyl, heterosubstituted cycloalkyl, heteroaryl or aryl.  
   
   
       42 . The method of  claim 41 , wherein R 2  is optionally substituted phenyl.  
   
   
       43 . The method of  claim 41 , wherein R 2  is heterocyclylphenyl, alkylthiophenyl, alkylsulfinylphenyl, alkylsulfonylphenyl, phenyl, halophenyl, hydroxyphenyl, acylphenyl, cyanophenyl, alkoxycarbonylphenyl, carboxamidophenyl, N-alkylcarboxamidophenyl, N,N-dialkylcarboxamidophenyl, alkylsulfonyloxyphenyl, carbamoylphenyl, N-alkylcarbamoylphenyl or N,N-dialkylcarbamoylphenyl  
   
   
       44 . The method of  claim 36 , wherein R 3  is alkyl, heterocyclyl, heterosubstituted cycloalkyl or heteroalkyl.  
   
   
       45 . The method of  claim 36 , wherein Ar 1  is 2-halophenyl, 4-halophenyl, 2,4-dihalophenyl, 2,6-dihalophenyl, 2-alkylphenyl, 1-alkoxyphenyl, 2-alkoxyphenyl, 4-alkoxphenyl, 3,5-dialkoxy-phenyl, 2-halo-5-alkoxyphenyl or 2-dialkylamino-6-fluorophenyl.  
   
   
       46 . The method of  claim 22 , wherein R 1  is hydrogen.  
   
   
       47 . The method of  claim 46 , wherein R 2  is heteroalkyl, cycloalkyl, heterocyclyl, heterosubstituted cycloalkyl, heteroaryl or aryl.  
   
   
       48 . The method of  claim 47 , wherein R 3  is hydrogen, alkyl, aryl, cycloalkyl, heterocyclyl, heterosubstituted cycloalkyl or heteroalkyl.  
   
   
       49 . The method of  claim 48 , wherein Ar 1  is 2-halophenyl, 4-halophenyl, 2,4-dihalophenyl, 2,6-dihalophenyl, 2-alkylphenyl, 1-alkoxyphenyl, 2-alkoxyphenyl, 4-alkoxphenyl, 3,5-dialkoxy-phenyl, 2-halo-5-alkoxyphenyl or 2-dialkylamino-6-fluorophenyl.  
   
   
       50 . The method of  claim 22 , wherein X 2  is a bond or CH 2 .  
   
   
       51 . The method of  claim 50 , wherein R 3  is hydrogen, alkyl, aryl, cycloalkyl, heterocyclyl, heterosubstituted cycloalkyl or heteroalkyl.  
   
   
       52 . The method of  claim 51 , wherein R 1  is hydrogen.  
   
   
       53 . The method of  claim 52 , wherein R 2  is heteroalkyl, heterocyclyl, or heterosubstituted cycloalkyl.  
   
   
       54 . The method of  claim 53 , wherein X 1  O.