Quinazolinones as inhibitors of human phosphatidylinositol 3-kinase delta

Abstract

Compounds that inhibit PI3Kδ activity, including compounds that selectively inhibit PI3Kδ activity, are disclosed. Methods of inhibiting phosphatidylinositol 3-kinase delta isoform (PI3Kδ) activity, and methods of treating diseases, such as disorders of immunity and inflammation in which PI3Kδ plays a role in leukocyte function, using the compounds also are disclosed.

1 - 26 . (canceled) 
     
     
         27 : A compound having the structure: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is hydrogen, fluoro, chloro, methyl, or 
       
       
         
           
           
               
               
           
         
         R 2  is hydrogen, methyl, chloro, or fluoro; 
         R 3  is hydrogen, methyl, chloro, or fluoro; 
         R 4  is hydrogen, fluoro, chloro, OH, OCH 3 , OCH 2 C≡CH, O(CH 2 )N(CH 3 ) 2 , C(═O)CH 3 , C≡CH, CN, C(═O)NH 2 , OCH 2 C(═O)NH 2 , O(CH 2 ) 2 OCH 3 ; O(CH 2 ) 2 N(CH 3 ) 2 , 
       
       
         
           
           
               
               
           
         
         R 5  is methyl, ethyl, propyl, phenyl, CH 2 OH, CH 2 OCH 2 C 6 H 5 , CH 2 CF 3 , CH 2 OC(CH 3 ) 3 , CH 2 C≡CH, (CH 2 ) 3 N(C 2 H 5 ) 2 , (CH 2 ) 3 NH 2 , (CH 2 ) 4 NH 2 , (CH 2 ) 3 NHC(═O)OCH 2 C 6 H 5 , or (CH 2 ) 4 NHC(═O)OCH 2 C 6 H 5 ; and 
         R 8  is methyl, trifluoromethyl, chloro, or fluoro. 
       
     
     
         28 : The compound of  claim 27 , wherein
 R 1  is hydrogen or fluoro;   R 2  is hydrogen or fluoro;   R 3  is hydrogen,   R 4  is hydrogen or fluoro;   R 5  is methyl or ethyl; and   R 8  is chloro or fluoro.   
     
     
         29 : The compound of  claim 28 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         30 : The compound of  claim 29 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         31 : The compound of  claim 28 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         32 : The compound of  claim 31 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         33 : A compound having the structure of formula (12) 
       
         
           
           
               
               
           
         
       
     
     
         34 : A compound having the structure of formula (173)