Novel Anti-Cancer Agents

Abstract

The present invention provides a compound of Formula (I), or a pharmaceutical acceptable derivative, salt or prodrug thereof. Further provided is a method of treatment of cancer in a subject comprising administering to said subject an effective amount of a compound of Formula (I), or a pharmaceutical acceptable derivative, salt or prodrug thereof. Further provided is the use of a compound of Formula (I), or a pharmaceutical acceptable derivative, salt or prodrug thereof in the preparation of a medicament for the treatment of cancer. In addition, the present invention also provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutical acceptable derivative, salt or prodrug thereof.

1 . A compound of Formula I, or a pharmaceutical acceptable derivative, salt or prodrug thereof, wherein: 
       
         
           
           
               
               
           
         
         E and G are each independently selected from the group consisting of C 1-4 alkyl, —NH—, —N(C 1-4 alkyl)-, —O— and, in either orientation, —NH—C 1-4 alkyl-, —N(C 1-4 alkyl)-C 1-4 alkyl-, and —O—C 1-4 alkyl-; and 
            is a single or double bond;
 when   is a single bond, K is independently selected from CH and N, and J is independently selected from NH and CH 2 ; or 
 when   is a double bond, K is C, and J is independently selected from N and CH; 
 
         R 1  is 0-2 substituents wherein each substituent is independently selected from the group consisting of —C 1-4 alkyl, —C 3-6 cycloalkyl, —OH, —O—C 1-4 alkyl, N(R 4 ) 2 , —C 1-4 alkylN(R 4 ) 2 , —O—C 1-4 alkyl-N(R 4 ) 2 , —C 3-6 cycloalkyl-N(R 4 ) 2 , —O-phenyl, —O-benzyl, —NO 2 , halogen, and CF 3 ;
 each R 4  is independently selected from the group consisting of H, OH, —C 1-4 alkyl, —C(O)OC 1-4 alkyl, —C 1-4 alkyl-OR 7 , and —C(O)R 5 , provided that if one R 4  is OH then the other R 4  cannot be OH; or 
 —N(R 4 ) 2  forms a pyrrolidinyl, piperidinyl, piperazinyl, or morpholino group optionally substituted with C 1-4 alkyl; 
 
         R 2  is 0-2 substituents wherein each substituent is independently selected from the group consisting of —C 1-4 alkyl, —C 3-6 cycloalkyl, —OH, —O—C 1-4 alkyl, —N(R 6 ) 2 , —C 1-4 alkylN(R 6 ) 2 , —O—C 1-4 alkyl-N(R 6 ) 2 , —C 3-6 cycloalkyl-N(R 6 ) 2 , —O-phenyl, —O-benzyl, —NO 2 , halogen, and CF 3 ;
 each R 6  is independently selected from the group consisting of —H, —OH, —C 1-4 alkyl, —C(O)OC 1-4 alkyl, —C 1-4 alkyl-OR 7 , and —C(O)R 8 , provided that if one R 6  is OH then the other R 6  cannot be OH; or 
 —N(R 6 ) 2  forms a pyrrolidinyl, piperidinyl, piperazinyl, or morpholino group optionally substituted with C 1-4 alkyl; 
 wherein each of R 5  and R 8  are independently selected from the group consisting of —C 1-4 alkyl and phenyl; 
 
         R 3  is selected from the group consisting of H, —C 1-4 alkyl, aryl, and alkylaryl; and
 wherein R 7  is selected from the group consisting of —H and —C 1-4 alkyl. 
 
       
     
     
         2 . A compound according to  claim 1  of Formula II or a pharmaceutical derivative, salt or prodrug thereof, wherein: 
       
         
           
           
               
               
           
         
         E and G are each independently selected from the group consisting of C 1-4 alkyl, —NH—, —O— and, in either orientation —NH—C 1-4 alkyl-, and —O—C 1-4 alkyl-; and 
         R 1  is 0-2 substituents wherein each substituent is independently selected from the group consisting of —C 1-4 alkyl, —C 3-6 cycloalkyl, —OH, —O—C 1-4 alkyl, N(R 4 ) 2 , —C 1-4 alkylN(R 4 ) 2 , —O—C 1-4 alkyl-N(R 4 ) 2 , —C 3-6 cycloalkyl-N(R 4 ) 2 , —O-phenyl, —O-benzyl, —NO 2 , halogen, and CF 3 ;
 each R 4  is independently selected from the group consisting of H, OH, —C 1-4 alkyl, —C(O)OC 1-4 alkyl, —C 1-4 alkyl-OR 7 , and —C(O)R 5 , provided that if one R 4  is OH then the other R 4  cannot be OH; or 
 N(R 4 ) 2  forms a pyrrolidinyl, piperidinyl, piperazinyl, or morpholino group optionally substituted with C 1-4 alkyl; 
 
         R 2  is 0-2 substituents wherein each substituent is independently selected from the group consisting of —C 1-4 alkyl, —C 3-6 cycloalkyl, —OH, —O—C 1-4 alkyl, —N(R 6 ) 2 , —C 1-4 alkylN(R 6 ) 2 , —O—C 1-4 alkyl-N(R 6 ) 2 , —C 3-6 cycloalkyl-N(R 6 ) 2 , —O-phenyl, —O-benzyl, —NO 2 , halogen, and CF 3 ;
 each R 6  is independently selected from the group consisting of —H, —OH, —C 1-4 alkyl, —C(O)OC 1-4 alkyl, —C 1-4 alkyl-OR 7 , and —C(O)R 8 , provided that if one R 6  is OH then the other R 6  cannot be OH; or 
 —N(R 6 ) 2  forms a pyrrolidinyl, piperidinyl, piperazinyl, or morpholino group optionally substituted with C 1-4 alkyl; 
 wherein each of R 5  and R 8  are independently selected from the group consisting of —C 1-4 alkyl and phenyl; 
 
         R 3  is selected from the group consisting of H, C 1-4 alkyl, and aryl;
 wherein R 7  is selected from the group consisting of —H and —C 1-4 alkyl. 
 
       
     
     
         3 . A compound according to  claim 1  of Formula III or a pharmaceutical derivative, salt or prodrug thereof, wherein: 
       
         
           
           
               
               
           
         
         E and G are each independently selected from the group consisting of C 1-4 alkyl, —NH—, —O— and, in either orientation, —NH—C 1-4 alkyl-, and —O—C 1-4 alkyl-; 
         R 1  is 0-2 substituents wherein each substituent is independently selected from the group consisting of —C 1-4 alkyl, —C 3-6 cycloalkyl, —OH, —O—C 1-4 alkyl, —N(R 4 ) 2 , —C 1-4 alkylNHR 4 , —O—C 1-4 alkyl-N(R 4 ) 2 , —C 3-6 cycloalkyl-N(R 4 ) 2 , —O-phenyl, —O-benzyl, —NO 2 , halogen, and CF 3 ;
 wherein each R 4  is independently selected from the group consisting of —H, —OH, C 1-4 alkyl, —C(O)OC 1-4 alkyl, —C 1-4 alkyl-OR 7 , and —C(O)R 5 , provided that if one R 4  is OH then the other R 4  cannot be OH; or 
 —N(R 4 ) 2  forms a pyrrolidinyl, piperidinyl, piperazinyl, or morpholino group optionally substituted with C 1-4 alkyl; 
 
         R 2  is 0-2 substituents wherein each substituent is independently selected from the group consisting of —C 1-4 alkyl, —C 3-6 cycloalkyl, —OH, —O—C 1-4 alkyl, —N(R 6 ) 2 , —C 1-4 alkylN(R 6 ) 2 , —O—C 1-4 alkyl-N(R 6 ) 2 , —C 3-6 cycloalkyl-N(R 6 ) 2 , —O-phenyl, —O-benzyl, —NO 2 , halogen, and CF 3 ;
 each R 6  is independently selected from the group consisting of —H, —OH, —C 1-4 alkyl, —C(O)OC 1-4 alkyl, —C 1-4 alkyl-OR 7 , and —C(O)R 8 , provided that if one R 6  is OH then the other R 6  cannot be OH; or 
 —N(R 6 ) 2  forms a pyrrolidinyl, piperidinyl, piperazinyl, or morpholino group optionally substituted with C 1-4 alkyl; 
 wherein each of R 5  and R 8  are independently selected from the group consisting of —C 1-4 alkyl and phenyl; 
 
         R 3  is selected from the group consisting of H, C 1-4 alkyl, and aryl; and
 wherein R 7  is selected from the group consisting of —H and —C 1-4 alkyl. 
 
       
     
     
         4 . A compound according to  claim 1  wherein each of E and G are both independently selected from —NHC 1-4 alkyl. 
     
     
         5 . A compound according to  claim 4  wherein the heteroatoms of E and G are both bonded to the triazine ring. 
     
     
         6 . A compound according to  claim 1  wherein R 1  and R 2  are each independently 1-2 substituents. 
     
     
         7 . A compound according to  claim 1 , wherein each of R 1  and R 2  is at least one para substituent. 
     
     
         8 . A compound according to  claim 1 , wherein each R 1  substituent is independently selected from the group consisting of —OH, —O—C 1-4 alkyl, and —C 1-4 alkyl 
     
     
         9 . A compound according to  claim 1 , wherein each R 2  substituent is independently selected from the group consisting of —OH, O—C 1-4 alkyl, and —C 1-4 alkylN(R 6 ) 2    
     
     
         10 . A compound according to  claim 1 , wherein R 3  is selected from the group consisting of H, methyl, propyl, butyl and phenyl. 
     
     
         11 . A compound according to  claim 1 , wherein R 3  is hydrogen. 
     
     
         12 . A compound according to  claim 1  selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         13 . A compound according to  claim 12  selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
     
     
         14 . A method of treatment of cancer in a subject comprising administering to said subject an effective amount of a compound according to  claim 1  or a pharmaceutically acceptable derivative, salt or prodrug thereof. 
     
     
         15 . A method according to  claim 14  wherein the cancer is colon cancer, non-small lung cancer, brain cancer or breast cancer 
     
     
         16 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable carrier, diluent or excipient.