[1,3]DIAZINO[5,4-d]PYRIMIDINES AS HER2 INHIBITORS

Abstract

The present invention relates to new [1,3]diazino[5,4-d]pyrimidines and derivatives of Formula (I) wherein the groups R 1 , R 2 , R 3 and R 4 have the meanings given in the claims and specification, their use as inhibitors of HER2 and its mutants, pharmaceutical compositions which contain such compounds and their use as medicaments, especially as agents for treatment and/or prevention of oncological diseases.

1 - 14 . (canceled) 
     
     
         15 . A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a compound according to Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof, 
         wherein: 
         R 1  is halogen, CH 3 , C≡CH, or OCH 3 ; 
         R 2  is H or halogen; 
         R 3  is formula (i.1), formula (i.2), formula (i.3), or formula (i.4): 
       
       
         
           
           
               
               
           
         
         R 4  is R 4.a  or R 4.b : 
       
       
         
           
           
               
               
           
         
         Q is a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl contains one nitrogen heteroatom, and further wherein one carbon atom of the 4- to 6-membered heterocyclyl is optionally substituted with CH 3 ; 
         Z is a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl contains one nitrogen heteroatom, and further wherein one carbon atom of the 4- to 6-membered heterocyclyl is optionally substituted with CH 3 ; and 
         R 5  is H or CH 3 ; 
         with the proviso that at least one of R 1  and R 2  is not H. 
       
     
     
         16 . The pharmaceutically acceptable composition according to claim  1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1  is F. 
     
     
         17 . The pharmaceutically acceptable composition according to claim  1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1  is Cl. 
     
     
         18 . The pharmaceutically acceptable composition according to claim  1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1  is CH 3 . 
     
     
         19 . The compound according to claim  1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1  is C═CH. 
     
     
         20 . The compound according to claim  1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1  is OCH 3 . 
     
     
         21 . The compound according to claim  1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2  is H. 
     
     
         22 . The compound according to claim  1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 2  is Cl. 
     
     
         23 . The pharmaceutical composition according to claim  1 , or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 4  is R 4.a  or R 4.b ; 
       
         
           
           
               
               
           
         
         wherein: 
         R 4.a  is R 4.a.1   
       
       
         
           
           
               
               
           
         
         wherein: 
         R 6  is H or CH 3 ; 
         m is 1 or 2; and 
         n is 1 or 2; 
         and 
         R 4.b  is R 4.b.1 : 
       
       
         
           
           
               
               
           
         
         wherein: 
         p is 1 or 2; and 
         q is 1 or 2. 
       
     
     
         24 . The pharmaceutical composition according to claim  1 , or a stereoisomer thereof, wherein the compound, or stereoisomer thereof, is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         25 . A pharmaceutical composition comprising one or more pharmaceutically acceptable excipients and a therapeutically effective amount of a compound according to Formula (I) 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or stereoisomer thereof, and 
         wherein: 
         R 1  is halogen, CH 3 , C≡CH, or OCH 3 ; 
         R 2  is H or halogen; 
         R 3  is formula (i.1), formula (i.2), formula (i.3), or formula (i.4): 
       
       
         
           
           
               
               
           
         
         R 4  is R 4.a  or R 4.b : 
       
       
         
           
           
               
               
           
         
         
           Q is a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl contains one nitrogen heteroatom, and further wherein one carbon atom of the 4- to 6-membered heterocyclyl is optionally substituted with CH 3 ; 
           Z is a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl contains one nitrogen heteroatom, and further wherein one carbon atom of the 4- to 6-membered heterocyclyl is optionally substituted with CH 3 ; and 
         
         R 5  is H or CH 3 ; 
         with the proviso that at least one of R 1  and R 2  is not H; and 
         a pharmaceutically active substance selected from the group consisting of a cytostatic active substance and a cytotoxic active substance.