1-glyoxylamide indolizines for treating cancer

Abstract

Disclosed is a compound represented by Structural Formula (I): Ring A is substituted or unsubstituted and optionally fused to an aryl group. Z 1 and Z 2 are independently ═O, ═S, ═N—OR 12 or ═NR 12 R 1 and R 2 are independently —H, an aliphatic group, a substituted aliphatic group, an unsubstituted non-aromatic heterocylic group, a substituted non-aromatic heterocylic group, an aryl group or a substituted aryl group, provided that R 1 and R 2 are not both —H. Alternatively, —NR 1 R 2 , taken together, is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group or a substituted or unsubstituted nitrogen-containing heteroaryl group. R 3 is a substituted or unsubstituted aryl group or a substituted or unsubstituted aliphatic group. X is a covalent bond, —C(R 4 R 5 )—, —N(R 4 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—, —C(═O)—N(R 4 )—, or —N(R 4 )—C(═O)—. R 4 and R 5 are independently —H or a substituted or unsubstituted aliphatic group. R 12 is —H or a substituted or unsubstituted alkyl group.

What is claimed is:  
     
         1 . 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, ═S, ═N—OR 12  or ═NR 12 ;  
 R 1  and R 2  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, provided that R 1  and R 2  are not both —H; or —NR 1 R 2 , taken together, is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group or a substituted or unsubstituted nitrogen-containing heteroaryl group;  
 R 3  is a substituted or unsubstituted aryl group or a substituted or unsubstituted aliphatic group;  
 X is a covalent bond, —C(R 4 R 5 )—, —N(R 4 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—, —C(═O)—N(R 4 )—, or —N(R 4 )—C(═O)—;  
 R 4  and R 5  are independently —H or a substituted or unsubstituted aliphatic group; and  
 R 12  is —H or a substituted or unsubstituted alkyl group.  
 
     
     
         2 . The compound of  claim 1  wherein: Ring A is substituted or unsubstituted; Z 1  and Z 2  are both ═O; R 1  is —H; R 2  is a substituted or unsubstituted alkyl or aryl group; R 3  is a substituted or unsubstituted aryl group; and X is —C(R 4 R 5 )—, —N(R 4 )— or —O—.  
     
     
         3 . The compound of  claim 2  wherein R 2  is represented by a structural formula selected from:  
       
         
           
           
               
               
           
         
         wherein Rings D-T are substituted or unsubstituted.  
       
     
     
         4 . The compound of  claim 3  wherein zero, one or more ring carbons atoms of Rings D-T are substituted 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)—(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 b , taken together, can also form a substituted or unsubstituted non-aromatic heterocyclic group.  
     
     
         5 . The compound of  claim 3  wherein zero one or more ring carbon atoms of Rings D-T are independently substituted with a group selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, N-morpholino, pyrimidyl, C1-C4 alkyl substituted pyrimidyl, —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 ,  
       
         
           
           
               
               
           
         
       
       —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)—N—(C1-C4 alkyl), C3-C7 cycloalkyl, phenyl, —C(O)—N-morpholino, —S—(C1-C4 alkyl), —CN, furyl, —S(O) 2 —(C1-C4 alkyl), —S(O) 2 —NH 2 , —S(O) 2 —NH(C1-C4 alkyl) and —S(O) 2 —N(C1-C4 alkyl) 2 .  
     
     
         6 . The compound of  claim 5  wherein R 2  is represented by a structural formula selected from:  
       
         
           
           
               
               
           
         
       
       and R 6  is —H or a substituted or unsubstituted alkyl group.  
     
     
         7 . The compound of  claim 5  wherein R 2  is represented by a structural formula selected from:  
       
         
           
           
               
               
           
         
         wherein:  
         X 3  is —CH— or —N—;  
         R 7  and R 8  are independently —H or an alkyl group or —NR 7 R 8 , taken together, is a nitrogen-containing non-aromatic heterocyclic group;  
         R 9  is an alkyl group; and  
         R 10  is —H or an alkyl group.  
       
     
     
         8 . The compound of  claim 7  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, —NH 2  and —CN.  
     
     
         9 . The compound of  claim 8  wherein Ring A is unsubstituted; R 3  is a phenyl group or pyridyl group substituted with zero, one or more substituents selected from —Br, —Cl, —F, —R e , —OR e , —CN, —COOR e , —N(R e ) 2 , —CON(R e ) 2 , —NR e COR f , —NHCONH 2  and —SO 2 N(R e ) 2 ; R 7  and R 8  are both —H and R 9  is methyl; and each R e  and R f  are independently —H, an alkyl group or a substituted alkyl group.  
     
     
         10 . The compound of  claim 9  wherein R 3  is a phenyl ring substituted with zero one or more substituents selected from —Cl, —F, —R e , —OR e , —CN, —NH 2 , —CONH 2  and —NHCOR f .  
     
     
         11 . The compound of  claim 10  wherein R 3  is a phenyl ring substituted with zero one or more substituents selected from —CH 3 , —CH 2 CH 3 , —OCH 3 , —CN, —F and —Cl.  
     
     
         12 . The compound of  claim 11  wherein R 3  is a phenyl ring that is unsubstituted or monosubstituted with —CH 2 CH 3 , —OCH 3 , —CN, —F or —Cl and wherein the phenyl ring substituent is at the para position.  
     
     
         13 . The compound of  claim 4  wherein R 2  is represented by the following structural formula:  
       
         
           
           
               
               
           
         
       
     
     
         14 . A method of treating a subject with cancer comprising administering to the subject an effective amount of a compound represented by the following structural formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salts thereof, wherein: 
 Ring A is substituted or unsubstituted and is optionally fused to an aryl group;  
 Z 1  and Z 2  are independently ═O, ═S, ═N—OR 12  or ═NR 12 .  
 R 1  and R 2  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, provided that R 1  and R 2  are not both —H; or —NR 1 R 2 , taken together, is a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclic group or a substituted or unsubstituted nitrogen-containing heteroaryl group;  
 R 3  is a substituted or unsubstituted aryl group or a substituted or unsubstituted aliphatic group;  
 X is a covalent bond, —C(R 4 R 5 )—, —N(R 4 )—, —O—, —S—, —S(O)—, —S(O) 2 —, —C(═O)—, —C(═O)—N(R 4 )—, or —N(R 4 )—C(═O)—;  
 R 4  and R 5  are independently —H or a substituted or unsubstituted aliphatic group; and  
 R 12  is —H or a substituted or unsubstituted alkyl group.  
 
     
     
         15 . The method of  claim 14  wherein: Ring A substituted or unsubstituted, Z 1  and Z 2  are both ═O; R 1  is —H; R 2  is a substituted or unsubstituted alkyl or aryl group; R 3  is a substituted or unsubstituted aryl group; and X is —C(R 4 R 5 )—, —N(R 4 )— or —O—;  
     
     
         16 . The method of  claim 15  wherein R 2  is represented by a structural formula selected from:  
       
         
           
           
               
               
           
         
         wherein Rings D-T are substituted or unsubstituted.  
       
     
     
         17 . The method of  claim 16  wherein zero, one or more ring carbons atoms of Rings D-T 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 b , taken together, can also form a substituted or unsubstituted non-aromatic heterocyclic group.  
     
     
         18 . The method of  claim 16  wherein zero one or more ring carbon atoms of Rings D-T are independently substituted with a group selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, N-morpholino, pyrimidyl, C1-C4 alkyl substituted 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 —NH(C1-C4 alkyl), —C(O)O—CH 2 CH 2 —N(C1-C4 alkyl) 2 ,  
       
         
           
           
               
               
           
         
       
       —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 —(C1-C4 alkyl), —S(O) 2 —NH 2 , —S(O) 2 —NH(C1-C4 alkyl) and —S(O) 2 —N(C1-C4 alkyl) 2 .  
     
     
         19 . The method of  claim 18  wherein R 2  is represented by a structural formula selected from:  
       
         
           
           
               
               
           
         
       
       and R 6  is —H or a substituted or unsubstituted alkyl group  
     
     
         20 . The method of  claim 19  wherein R 2  is represented by a structural formula selected from:  
       
         
           
           
               
               
           
         
         wherein:  
         X 3  is —CH— or —N—;  
         R 7  and R 8  are independently —H or an alkyl group or —NR 7 R 8 , taken together, is a nitrogen-containing non-aromatic heterocyclic group;  
         R 9  is an alkyl group; and  
         R 10  is —H or an alkyl group.  
       
     
     
         21 . The method of  claim 20  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, —NH 2  and —CN.  
     
     
         22 . The method of  claim 21  wherein Ring A is unsubstituted; R 3  is a phenyl group or pyridyl group substituted with one or more substituents selected from —Br, —Cl, —F, —R e , —OR e , —CN, —COOR e , —N(R e ) 2 , —CON(R e ) 2 , —NR e COR f , —NHCONH 2  or —SO 2 N(R e ) 2 ; R 7  and R 8  are both —H and R 9  is methyl; and each R e  and R f  are independently —H, an alkyl group or a substituted alkyl group.  
     
     
         23 . The method of  claim 22  wherein R 3  is a phenyl ring substituted with one or more substituents selected from —Cl, —F, —R e , —OR e , —CN, —NH 2 , —CONH 2  and —NHCOR f .  
     
     
         24 . The method of  claim 23  wherein R 3  is a phenyl ring substituted with one or more substituents selected from —CH 3 , —CH 2 CH 3 , —OCH 3 , —CN, —F and —Cl.  
     
     
         25 . The method of  claim 23  wherein R 3  is a phenyl ring monosubstituted with —CH 3 , —CH 2 CH 3 , —OCH 3 , —CN, —F and —Cl and wherein the phenyl ring substituent is at the para position.  
     
     
         26 . The method of  claim 16  wherein R 2  is represented by the following structural formula: