3-glyoxylamideindoles for treating cancer

Abstract

Disclosed is an anti-cancer compound represented by Structural Formula (I): The variables in Structural Formula (I) are described hereinbelow. Also disclosed is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound represented by Structural Formula (I) (preferably an effective amount). Also disclosed is a method of treating a subject with cancer by administering to the subject an effective amount of a compound represented by Structural Formula (I).

1 - 20 . (canceled)  
   
   
       21 . A method of treating a subject with cancer, said method comprising administering to the subject an effective amount of a compound represented by the following structural formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
 Ring A is substituted or unsubstituted and is optionally fused to an aryl group;  
 Z 1  and Z 2  are independently ═O or ═S;  
 R 1  is —H, an aliphatic group, a substituted aliphatic group, an unsubstituted aryl group or a substituted aryl group;  
 R 2  is an aryl group substituted with —C(O)—NR 5 R 6 , —S(O) 2 R 5 R 6  or —S(O) 2 R 5 R 6  or is represented by a structural formula selected from:  
                     
 R 3  is a substituted or unsubstituted aryl group or a substituted or unsubstituted aliphatic group;  
 R 4  is —H, a substituted alkyl group or an unsubstituted alkyl group;  
 R 5  and R 6  are independently —H, an aliphatic group, a substituted aliphatic group, an unsubstituted non-aromatic heterocylic group, a substituted non-aromatic heterocylic group, an unsubstituted aryl group or a substituted aryl group; or —NR 5 R 6 , taken together, is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group or a substituted or unsubstituted nitrogen-containing heteroaryl group;  
 X is a covalent bond, —C(R 7 R 8 )—, —N(R 7 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—,  − C(═O)—N(R 4 )—, or —N(R 7 )—C(═O)—;  
 R 7  and R 9  are independently —H or a substituted or unsubstituted aliphatic group, wherein the cancer is selected from the group consisting of uterine cancer, leukemia and breast cancer.  
 
   
   
       22 . The method of  claim 21  wherein R 2  is an aryl group substituted with —C(O)—NR 5 R 6  or is represented by a structural formula selected from:  
     
       
         
         
             
             
         
       
     
   
   
       23 . The method of  claim 22  wherein: 
 Ring A is substituted or unsubstituted;    Z 1  and Z 2  are both ═O;    R 1  and R 4  are both —H;    R 3  is a substituted or unsubstituted aryl group; and    X is a —C(R 7 R 8 )—, —N(R 7 )— and —O—.    
   
   
       24 . The method of  claim 23  wherein X is —C(R 7 R 8 )—.  
   
   
       25 . The method of  claim 24  wherein R 3  is a substituted or unsubstituted phenyl or pyridyl group and R 7  and R 8  are both —H.  
   
   
       26 . The method of  claim 25  wherein zero, one or more ring carbons atoms of Rings B-P are substituted with a group independently selected from —OH, —Br, —Cl, —I, —F, —OR a , —O—COR a , —COR a , —CN, —NO 2 , —COOH, —SO 3 H, —NH 2 , —NHR a , —N(R a R b ), —COOR a , —CHO, —CONH 2 , —CONHR a , —CON(R a R b ), —NHCOR a , —NRCOR a , —NHCONH 2 , —NHCONR a H, —NHCON(R a R b ), —NR c CONH 2 , —NR c CONR a H, —NR c CON(R a R b ), —C(═NH)—NH 2 , —C(═NH)—NHR a , —C(═NH)—N(R a R b ), —C(═NR c )—NH 2 , —C(═NR c )—NHR a , —C(═NR c )—N(R a R b ), —NH—C(═NH)—NH 2 , —NH—C(═NH)—NHR a , —NH—C(═NH)—N(R a R b ), —NH—C(═NR c )—NH 2 , —NH—C(═NR c )—NHR a , —NH—C(═NR c )—N(R a R b ), —NR d H—C(═NH)—NH 2 , —NR d —C(═NH)—NHR a , —NR d —C(═NH)—N(R a R b ), —NR d —C(═NR c )—NH 2 , NR d —C(═NR c )—NHR a , NR d —C(═NR c )—N(R a R b ), —NHNH 2 , —NHNHR a , NHR a R b , —SO 2 NH 2 , —SO 2 NHR a , —SO 2 NR a R b , —CH═CHR a , —CH═CR a R b , —CR c ═CR a R b , —CR c ═CHR a , —CR c ═CR a R b , —CCR a , —SH, —SR a , —S(O)R a , —S(O) 2 R a , alkyl groups, substituted alkyl group, non-aromatic heterocyclic group, substituted non-aromatic heterocyclic group, benzyl group, substituted benzyl group, aryl group or substituted aryl group wherein R a -R d  are each independently an alkyl group, substituted alkyl group, benzyl, substituted benzyl, aryl or substituted aryl group, or, —NR a R d , taken together, can also form a substituted or unsubstituted non-aromatic heterocyclic group.  
   
   
       27 . The method of  claim 26  wherein zero one or more ring carbon atoms of Rings B-P are independently substituted with a group selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, N-morpholino, pyrimidyl, C1-C4 alkyl substituted with pyrimidyl, —NH(C1-C4 alkyl), —N(C1-C4 alkyl) 2 , —C(O)NH 2 , —C(O)NH(C1-C4 alkyl), C(O)N(C1-C4 alkyl) 2 , —NHC(O)(C1-C4 alkyl), —NO 2 , C1-C4 alkoxy, —C(O)O—CH 2 CH 2 —N(C1-C4 alkyl) 2 , —C(O)O—CH 2 CH 2 —NH(C1-C4 alkyl),  
     
       
         
         
             
             
         
       
     
     —NH-(phenyl), —NH 2 , —CH 2 NH—C(O)—O—(C1-C4 alkyl), —CH 2 NH 2 , —Cl, —F, —C(O)—O—(C1-C4 alkyl), —C(O)—NH—(C1-C4 alkyl), C3-C7 cycloalkyl, phenyl, —C(O)—N-morpholino, —S—(C1-C4 alkyl), —CN, furyl, —S(O) 2 —(C 1 -C 4  alkyl), —S(O) 2 —NH 2 , —S(O) 2 —NH(C1-C4 alkyl), —S(O) 2 —N(C1-C4 alkyl) 2 .  
   
   
       28 . The method of  claim 26  wherein R 2  is represented by a structural formula selected from:  
     
       
         
         
             
             
         
       
     
     wherein X 2  is —N— or —CH— and R 12  and R 13  are independently a C1-C4 alkyl group.  
   
   
       29 . The method of  claim 28  wherein R 5  and R 6  are independently —H or a C1-C4 alkyl group.  
   
   
       30 . The method of  claim 29  wherein Ring A is optionally substituted with one or more groups selected from —F, —Cl, —Br, —C1-C4 alkyl, C1-C4 alkoxy, —C1-C4 haloalkyl, C 1 -C 4  haloalkoxy, —CN or —NH 2 .  
   
   
       31 . The method of  claim 30  wherein: 
 R 3  is a phenyl or pyridyl group substituted with zero, one or more groups selected from —Br, —Cl, —F, —R e , —OR e , —CH 3 , —CF 3 , —CN, —COOR e , —N(R e ) 2 , —CON(R e ) 2 , —NR e COR f , —NHCONH 2 , —SO 2  R e and —SO 2  N(R e ) 2 ; and    each R e  and R f  are independently selected from —H, alkyl or substituted alkyl.    
   
   
       32 . The method of  claim 31  wherein R 3  is a phenyl group substituted with zero, one or more groups selected from —Cl, —F, —R e , —OR e , —CN, —NH 2 , —CONH 2  or —NHCOR f .  
   
   
       33 . The method of  claim 32  wherein R 3  is a phenyl group substituted with zero, one or more groups selected from —CH 3 , —CH 2 CH 3 , —F, —Cl, —CN or —OCH 3  and R 5  and R 6  are both —H.  
   
   
       34 . The method of  claim 33  wherein R 3  is represented by the following structural formula:  
     
       
         
         
             
             
         
       
       R 14  is —CH 3 , —CH 2 CH 3 , —OCH 3 , —CN, —F or —Cl.  
     
   
   
       35 . The method of  claim 34  wherein Ring A is unsubstituted.  
   
   
       36 - 42 . (canceled)  
   
   
       43 . A method of treating a subject with cancer, said method comprising administering to the subject an effective amount of a compound represented by the following structural formula:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein: 
 Ring A is substituted or unsubstituted and is optionally fused to an aryl group;  
 Z 1  and Z 2  are independently ═O or ═S;  
 R 1  is —H, an aliphatic group, a substituted aliphatic group, an unsubstituted aryl group or a substituted aryl group;  
 R 3  is a substituted or unsubstituted aryl group or a substituted or unsubstituted aliphatic group;  
 R 4  is —H, a substituted alkyl group or an unsubstituted alkyl group;  
 X is a covalent bond, —C(R 7 R 8 )—, —N(R 7 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—, —C(═O)—N(R 4 )—, or —N(R 7 )—C(═O)—;  
 R 7  and R 8  are independently —H or a substituted or unsubstituted aliphatic group; and  
 Ring B is substituted or unsubstituted,  
 wherein the cancer is selected from the group consisting of uterine cancer, leukemia and breast cancer.  
 
   
   
       44 . The method of  claim 43  wherein: 
 Ring A is substituted or unsubstituted;    Z 1  and Z 2  are both ═O;    R 1  and R 4  are both —H;    R 3  is a substituted or unsubstituted aryl group; and    X is a —C(R 7 R 8 )—, —N(R 7 )— and —O—.    
   
   
       45 . The method of  claim 44  wherein X is —C(R 7 R 8 )—.  
   
   
       46 . The method of  claim 45  wherein R 3  is a substituted or unsubstituted phenyl or pyridyl group and R 7  and R 8  are both —H.  
   
   
       47 . The method of  claim 46  wherein zero, one or more ring carbons atoms of Ring B is substituted with a group independently selected from —OH, —Br, —Cl, —I, —F, —OR a , —O—COR a , —COR a , —CN, —NO 2 , —COOH, —SO 3 H, —NH 2 , —NHR a , —N(R a R b ), —COOR a , —CHO, —CONH 2 , —CONHR a , —CON(R a R b ), —NHCOR a , —NRCOR a , —NHCONH 2 , —NHCONR a H, —NHCON(R a R b ), —NR c CONH 2 , —NR c CONR a H, —NR c CON(R a R b ), —C(═NH)—NH 2 , —C(═NH)—NHR a , —C(═NH)—N(R a R b ), —C(═NR c )—NH 2 , C(═NR c )—NHR a , —C(═NR c )—N(R a R b ), —NH—C(═NH)—NH 2 , —NH—C(═NH)—NHR a , —NH—C(═NH)—N(R a R b ), —NH—C(═NR c )—NH 2 , —NH—C(═NR c )—NHR a , —NH—C(═NR c )—N(R a R b ), —NR d H—C(═NH)—NH 2 , —NR d —C(═NH)—NHR a , —NR d —C(═NH)—N(R a R b ), —NR d —C(═NR c )—NH 2 , —NR d —C(═NR c )—NHR a , —NR d —C(═NR c )—N(R a R b ), —NHNH 2 , —NHNHR a , —NHR a R b , —SO 2 NH 2 , —SO 2 NHR a , —SO 2 NR a R b , —CH═CHR a , —CH═CR a R b , —CR c ═CR a R b , —CR c ═CHR a , —CR c ═CR a R b , —CCR a , —SH, —SR a , —S(O)R a , —S(O) 2 R a , alkyl groups, substituted alkyl group, non-aromatic heterocyclic group, substituted non-aromatic heterocyclic group, benzyl group, substituted benzyl group, aryl group or substituted aryl group wherein R a -R d  are each independently an alkyl group, substituted alkyl group, benzyl, substituted benzyl, aryl or substituted aryl group, or, —NR a R d , taken together, can also form a substituted or unsubstituted non-aromatic heterocyclic group.  
   
   
       48 . The method of  claim 47  wherein R 2  is represented by the following structural formula:  
     
       
         
         
             
             
         
       
     
     wherein X 2  is —N— or —CH— and R 13  are independently a C1-C4 alkyl group.  
   
   
       49 . The method of  claim 48  wherein R 5  and & are independently —H or a C1-C4 alkyl group.  
   
   
       50 . The method of  claim 49  wherein Ring A is optionally substituted with one or more groups selected from —F, —Cl, —Br, —C1-C4 alkyl, C1-C4 alkoxy, —C1-C4 haloalkyl, C1-C4 haloalkoxy, —CN or —NH 2 .  
   
   
       51 . The method of  claim 50  wherein: 
 R 3  is a phenyl or pyridyl group substituted with zero, one or more groups selected from —Br, —Cl, —F, —R e , —OR e , —CH 3 , —CF 3 , —CN, —COOR e , —N(R e ) 2 , —CON(R e ) 2 , —NR e COR f , —NHCONH 2 , —SO 2  R e  and —SO 2  N(R e ) 2 ; and    each R e  and R f  are independently selected from —H, alkyl or substituted alkyl.