Novel pyridopyrimidine derivatives and use thereof

Abstract

The invention provides novel substituted pyridopyrimidines represented by Formula I or a pharmaceutically acceptable salt, solvate, polymorph, ester, tautomer or prodrug thereof, and a composition comprising these compounds. The compounds provided can be used as inhibitors of the phosphoinositide 3′ OH kinase family (PI3K) for the treatment of inflammatory diseases, cancer, cardiovascular diseases, allergy, asthma and autoimmune disorders.

1 .- 3 . (canceled) 
     
     
         4 . A method for inhibiting PI3K enzyme, the method comprising contacting PI3K enzyme with an effective amount of a compound of formula I, 
       
         
           
           
               
               
           
         
         Wherein X is C or O or N or S; 
         Y is CH or N; 
         R 1  is selected from the group consisting of: acyl, amino, substituted amino, C1-C6alkyl, substituted C1-C6alkyl, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted C3-C7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, nitro; 
         R 2  is selected from the group consisting of: hydrogen, halogen, acyl, amino, substituted amino, C1-C6alkyl, substituted C1-C6alkyl, C3-C7cycloalkyl, substituted C3-7 Ccycloalkyl, C3-7Cheterocycloalkyl, substituted C3-C7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, nitro, alkoxy, C3-C7cycloalkyloxy, substituted C3-C7cycloalkyloxy, C3-C7heterocycloalkyloxy, substituted C3-7Cheterocycloalkyloxy, acyloxy, aryloxy; 
         R 3 =NR 4′ SO 2 R 4 , SO 2 NR 4′ R 4 , NR 4′ COR 4 , CONR 4′ R 4 , NR 4′ CONHR 4 ; 
         R 4  is selected from the group consisting of: alkyl, substituted alkyl, amino, halo, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; 
         R 4′  is H or C1-C6 alkyl; 
         R 5  is selected from the group consisting of: hydrogen, halogen, C1-C6alkyl; 
         R 6  is selected from the group consisting of: hydrogen, halogen, acyl, alkoxy, amino, substituted amino, arylamino, C1-C6alkyl, substituted C1-C6 alkyl, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
         n is 0 or 1; m is 0 or 1; 
         or a pharmaceutically acceptable salt, ester, or tautomer thereof. 
       
     
     
         5 . A method for the treatment or prophylaxis of a PI3K mediated disorder or disease, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I, 
       
         
           
           
               
               
           
         
         Wherein X is C or O or N or S; 
         Y is CH or N; 
         R 1  is selected from the group consisting of: acyl, amino, substituted amino, C1-C6alkyl, substituted C1-C6alkyl, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted C3-C7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, nitro; 
         R 2  is selected from the group consisting of: hydrogen, halogen, acyl, amino, substituted amino, C1-C6alkyl, substituted C1-C6alkyl, C3-C7cycloalkyl, substituted C3-7 Ccycloalkyl, C3-7Cheterocycloalkyl, substituted C3-C7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, nitro, alkoxy, C3-C7cycloalkyloxy, substituted C3-C7cycloalkyloxy, C3-C7heterocycloalkyloxy, substituted C3-7Cheterocycloalkyloxy, acyloxy, aryloxy; 
         R 3 =NR 4′ SO 2 R 4 , SO 2 NR 4′ R 4 , NR 4′ COR 4 , CONR 4′ R 4 , NR 4′ CONHR 4 ; 
         R 4  is selected from the group consisting of: alkyl, substituted alkyl, amino, halo, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; 
         R 4′  is H or C1-C6 alkyl; 
         R 5  is selected from the group consisting of: hydrogen, halogen, C1-C6alkyl; 
         R 6  is selected from the group consisting of: hydrogen, halogen, acyl, alkoxy, amino, substituted amino, arylamino, C1-C6alkyl, substituted C1-C6 alkyl, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
         n is 0 or 1; m is 0 or 1; or a pharmaceutically acceptable salt, ester, or tautomer. 
       
     
     
         6 . A method for the treatment or prophylaxis of proliferative disorders, the method comprising administering to a patient in need thereof an effective amount of a compound of formula I, 
       
         
           
           
               
               
           
         
         Wherein X is C or O or N or S; 
         Y is CH or N; 
         R 1  is selected from the group consisting of: acyl, amino, substituted amino, C1-C6alkyl, substituted C1-C6alkyl, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted C3-C7 heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, nitro; 
         R 2  is selected from the group consisting of: hydrogen, halogen, acyl, amino, substituted amino, C1-C6alkyl, substituted C1-C6alkyl, C3-C7cycloalkyl, substituted C3-7 Ccycloalkyl, C3-7Cheterocycloalkyl, substituted C3-C7heterocycloalkyl, alkylcarboxy, arylamino, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl, substituted arylalkyl, arylcycloalkyl, substituted arylcycloalkyl, heteroarylalkyl, substituted heteroarylalkyl, cyano, nitro, alkoxy, C3-C7cycloalkyloxy, substituted C3-C7cycloalkyloxy, C3-C7heterocycloalkyloxy, substituted C3-7Cheterocycloalkyloxy, acyloxy, aryloxy; 
         R 3 =NR 4′ SO 2 R 4 , SO 2 NR 4′ R 4 , NR 4′ COR 4 , CONR 4′ R 4 , NR 4′ CONHR 4 ; 
         R 4  is selected from the group consisting of: alkyl, substituted alkyl, amino, halo, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; 
         R 4′  is H or C1-C6 alkyl; 
         R 5  is selected from the group consisting of: hydrogen, halogen, C1-C6alkyl; 
         R 6  is selected from the group consisting of: hydrogen, halogen, acyl, alkoxy, amino, substituted amino, arylamino, C1-C6alkyl, substituted C1-C6 alkyl, C3-C7cycloalkyl, substituted C3-C7cycloalkyl, C3-C7heterocycloalkyl, substituted C3-C7heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
         n is 0 or 1; m is 0 or 1; 
         or a pharmaceutically acceptable salt, ester, or tautomer thereof. 
       
     
     
         7 . The method of  claim 6 , wherein the proliferative disorders are selected from the group consisting of inflammatory diseases, cancer, cardiovascular diseases, allergy, asthma and autoimmune disorders.