1-glyoxylamide indolizines for treating cancer

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, or a substituted or unsubstituted aryl group selected from:

 provided that R 1 and R 2 are not both —H;

R 3 is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aryl group represented by Ring V:

 wherein Z is —O—, —S—, —NR—, or —CH═CH— and R is —H or C1-C4 alkyl;

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 3 is a substituted or unsubstituted alkyl or aryl group; R 1 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 Rings D, E, M, and N are independently unsubstituted or 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 , —NCONR 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 , —NH 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, benzyl group, substituted benzyl group, aryl group and 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.

4. The compound of claim 2 wherein Rings D, E, M, and N are independently unsubstituted or substituted with a group selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, —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 ,

—NN-(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—(C1C4 alkyl), C3-C7 cycloalkyl, phenyl, 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 .

5. The compound of claim 4 wherein R 2 is represented by a structural formula selected from:

and R 6 is —H or a substituted or unsubstituted alkyl group.

6. The compound of claim 4 wherein R 2 is represented by a structural formula selected from:

wherein:

R 10 is —H or an alkyl group.

7. The compound of claim 6 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.

8. The compound of claim 7 wherein:

Ring A is unsubstituted;

R 3 is a phenyl group that is unsubstituted or 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 ), —NR e COR f , —NHCONH 2 , —SO 2 ,and N(R e ) 2 ; and

each R e and R f are independently —H, an alkyl group or a substituted alkyl group.

9. The compound of claim 8 wherein R 3 is a phenyl ring that is unsubstituted or substituted with one or more substituents selected from —Cl, —F, —R e , —OR e , —CN, —NH 2 , —CONH 2 and —NHCOR f .

10. The compound of claim 9 wherein R 3 is a phenyl ring that is unsubstituted or substituted with one or more substituents selected from —CH 3 , —CH 2 CH 3 , —OCH 3 , —CN, —F and —Cl.

11. The compound of claim 10 wherein R 3 is a phenyl ring that is unsubstituted or monosubstituted wit —CH 2 CH 3 , —OCH 3 , —CN, —F or —Cl 3 and wherein the phenyl ring substituent is at the para position.

12. The compound of claim 3 wherein R 2 is represented by the following structural formula:

13. The compound of claim 1 wherein the compound is represented by the following structural formula:

wherein:

Rings A and V are independently substituted or unsubstituted;

X is —CH 2 —, —CH(CH 3 )—, —O—, —NH— or —NCH 3 —, and

R 10 is —H, an unsubstituted aliphatic group or a substituted aliphatic group.

14. The compound of claim 13 wherein Ring A is unsubstituted or substituted with —F, —Cl, —Br, —C1-C4 alkyl, C1-C4 alkoxy, —C1-C4 haloalkyl, C1-C4 haloalkoxy, —NH 2 or —CN; Ring V is substituted with one or more groups selected from —CH 3 , —CH 2 CH 3 , —F, —Cl, —CN, and —OCH 3 ; and R 10 is —H, methyl or ethyl.

15. The compound of claim 14 wherein Ring A is unsubstituted, Ring V is substituted with one or more groups R 11 ; and each R 11 is independently —CH 3 , —CH 2 CH 3 , —OCH 3 , —F, —Cl or —CN.

16. A compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein Rings A and U are independently substituted or unsubstituted and R 10 is —H, an unsttbstitured aliphatic group or a substituted aliphatic group.

17. The compound of claim 16 wherein Ring A is unsubstituted or substituted with —F, —Cl, —Br, —C1-C4 alkyl, C1-C4 alkoxy, —C1-C4 haloalkyl, C1-C4 haloalkoxy, —NH 2 or —CN; Ring U is substituted with one or more groups selected from —CH 3 , —CH 2 CH 3 , —F, —Cl, —CN, and —OCH 3 ; and R 10 is —H, methyl or ethyl.

18. The compound of claim 17 wherein Ring U is monosubstituted with —CH 3 , —CH 2 CH 3 , —F, —Cl, —CN or —OCH 3 ; and the Ring U substituent is in the para position.

19. A compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein R 11 is —CH 3 , —CH 2 C 3 , —OCH 3 , —F, —Cl or —CN.

20. 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, or an unsubstituted aryl group or a substituted aryl group selected from:

 provided that R 1 and R 2 are not both —H;

R 3 is a substituted or unsubstituted aliphatic group or a substituted or unsubstituted aryl group represented by Ring V:

 wherein Z is —O—, —S—, —NR—, or —CH═CH— and R is —H or C1-C4 alkyl;

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.

21. The method of claim 20 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 4R 5 )—, —N(R 4 )— or —O—.

22. The method of claim 21 wherein Rings D, E, M, and N are independently unsubstituted or 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 )—NH 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, benzyl group, substituted benzyl group, aryl group and 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.

23. The method of claim 21 wherein Rings D, E, M, and N are independently unsubstituted or substituted with group selected form C1-C4 alkyl, C1-C4 hydroxyalkyl, —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, —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 .

24. The method of claim 23 wherein R 2 is represented by a structural formula selected from:

and R 6 is —H or a substituted or unsubstituted alkyl group.

25. The method of claim 24 wherein R 2 is represented by a structural formula selected from:

wherein:

R 10 is —H or an alkyl group.

26. The method of claim 25 wherein Ring A is optionally substituted with one or more groups selected front —F, —Cl, —Br, —C1-C4 alkyl, C1-C4 alkoxy, —C1-C4 haloalkyl, C1-C4 haloalkoxy, —NH 2 and —CN.

27. The method of claim 26 wherein Ring A is unsubstituted; R 3 is a phenyl 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 , and —SO 2 N(R e ) 2 ; and each R e and R f are independently —H, an alkyl group or a substituted alkyl group.

28. The method of claim 27 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 .

29. The method of claim 29 wherein R 3 is a phenyl ring substituted wit one or more substituents selected from —CH 3 , —CH 2 CH 3 , —OCH 3 , —CN, —F and —Cl.

30. The method of claim 28 wherein R 3 is a phenyl ring monosubstituted with —CH 3 , —CH 2 CH 3 , —OCH 3 , —CN, —F or —Cl; and wherein the phenyl ring substituent is at the para position.

31. The method of claim 20 wherein the compound is represented by the following structural formula:

wherein:

Rings A and V are independently substituted or unsubstituted;

X is —CH 2 —, —CH(CH 3 )—, —O—, —NH— or —NCH 3 —; and

R 10 is —H, an unsubstituted aliphatic group or a substituted aliphatic group.

32. The method of claim 31 wherein Ring A is unsubstituted or substituted with —F, —Cl, —Br, —C1-C4 alkyl, C1-C4 alkoxy, —C1-C4 haloalkyl, C1-C4 haloalkoxy, —NH 2 or —CN; Ring U is substituted with one or more groups selected from —CH 3 , —CH 2 CH 3 , —F, —Cl, —CN, and —OCH 3 ; and R 10 is —H, methyl or ethyl.

33. The method of claim 32 wherein Ring A is unsubstituted, Ring V is substituted with one or more groups R 11 and each R 11 is independently —CH 3 , —CH 2 CH 3 , —OCH 3 , —F, —Cl or —CN.

34. The method of claim 21 wherein R 2 is represented by the following structural formula:

35. A method of treating a subject with cancer comprising administering to the subject a compound represented by the following structural formula:

or a pharmaceutically acceptable salts thereof, wherein Rings A and U are independently substituted or unsubstituted and R 10 is —H, an unsubstituted aliphatic group or a substituted aliphatic group.

36. The method of claim 35 wherein Ring A is unsubstituted or substituted wit one or more substituents selected from —F, —Cl, —Br, —C1-C4 alkyl, C1-C4 alkoxy, —C1-C4 haloalkyl, C1-C4 haloalkoxy, —NH 2 and —CN; Ring U is substituted with one or more groups selected from —CH 3 , —CH 2 CH 3 , —F, —Cl, and —OCH 3 ; and R 10 is —H, methyl or ethyl.

37. The method of claim 36 wherein Ring U is monosubstituted with —CH 3 , —CH 2 CH 3 , —F, —Cl, —CN, or —OCH 3 ; and the Ring U substituent is at the para position.

38. A method of treating a subject with cancer comprising administering to the subject a compound represented by the following structural formula:

or a pharmaceutically acceptable salt thereof, wherein R 11 is —CH 3 , —CH 2 CH 3 , —OCH 3 , —F, —Cl or —CN.

39. A compound represented by one of the following structural formulas, or a pharmaceutically acceptable salt thereof:

40. A method of treating a subject with cancer, comprising administering to the subject an effective amount of the compound of claim 39 .

41. A compound represented by the following structural formula, or a pharmaceutically acceptable salt thereof:

42. A method of treating a subject with cancer, comprising administering to the subject an effective amount of the compound of claim 41 .