Methionine aminopeptidase-2 inhibitors and methods of use thereof

1. A method of treating a subject having a lymphoid malignancy, comprising administering to the subject a therapeutically effective amount of a compound comprising the structure of Formula I,

wherein

A is a Met-AP2 inhibitory core;

W is O or NR 2 ;

R 1 and R 2 are each, independently, hydrogen or alkyl;

X is alkylene or substituted alkylene;

n is 0 or 1;

R 3 and R 4 are each, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 3 and R 4 , together with the carbon atom to which they are attached, form a carbocyclic or heterocyclic group; or R 3 and R 4 together form an alkylene group;

Z is —C(O)— or alkylene-C(O)—; and

P is a peptide comprising from 1 to about 100 amino acid residues attached at its amino terminus to Z or a group OR 5 or N(R 6 )R 7 , wherein

R 5 , R 6 and R 7 are each, independently, hydrogen, alkyl, substituted alkyl, azacycloalkyl or substituted azacycloalkyl; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic ring structure; or

Z is —O—, —NR 8 —, alkylene-O— or alkylene-NR 8 —, where R 8 is hydrogen or alkyl; and

P is hydrogen, alkyl or a peptide consisting of from 1 to about 100 amino acid residues attached at its carboxy terminus to Z.

2. The compound of claim 1 , wherein at least one of R 1 , R 3 and R 4 is a substituted or unsubstituted alkyl group.

3. The compound of claim 2 , wherein at least one of R 1 , R 3 and R 4 is a substituted or unsubstituted normal, branched or cyclic C 1 –C 6 alkyl group.

4. The compound of claim 3 , wherein at least one of R 1 , R 3 and R 4 is a normal or branched C 1 –C 4 alkyl group.

5. The compound of claim 1 , wherein one of R 3 and R 4 is a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted heteroarylalkyl group, or a substituted or unsubstituted aryl alkyl group.

6. The compound of claim 5 , wherein one of R 3 and R 4 is selected from the group consisting of phenyl, naphthyl, indolyl, imidazolyl, pyridyl, benzyl, naphthylmethyl, indolylmethyl, imidazolylmethyl and pyridylmethyl.

7. The compound of claim 1 , wherein n is 1 and X is C 1 –C 6 -alkylene.

8. The compound of claim 7 , wherein X is methylene or ethylene.

9. The compound of claim 1 , wherein Z is C 1 –C 6 -alkylene-C(O)—.

10. The compound of claim 9 , wherein Z is methylene-C(O)— or ethylene-C(O)—.

11. The compound of claim 1 , wherein at least one of R 6 and R 7 is alkyl, substituted alkyl, substituted or unsubstituted azacycloalkyl or substituted or unsubstituted azacycloalkylalkyl.

12. The compound of claim 11 , wherein at least one of R 6 and R 7 is an azacycloalkyl group having an N-alkyl substituent.

13. The compound of claim 12 , wherein the N-alkyl substituent is a C 1 –C 4 -alkyl group.

14. The compound of claim 13 , wherein the N-alkyl substituent is a methyl group.

15. The compound of claim 1 , wherein R 6 and R 7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted five or six-membered aza- or diazacycloalkyl group.

16. The compound of claim 15 , wherein R 6 and R 7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted five or six-membered diazacycloalkyl group which includes an N-alkyl substituent.

17. The compound of claim 16 , wherein the N-alkyl substituent is a C 1 –C 4 -alkyl group.

18. The compound of claim 17 , wherein the N-alkyl substituent is a methyl group.

19. The compound of claim 1 , wherein P is NH2 or one of the groups shown below:

20. A method of treating a subject having a parasitic infection, comprising administering to the subject a therapeutically effective amount of a compound comprising the structure of Formula I,

wherein

A is a Met-AP2 inhibitory core;

W is O or NR 2 ;

R 1 and R 2 are each, independently, hydrogen or alkyl;

X is alkylene or substituted alkylene;

n is 0 or 1;

R 3 and R 4 are each, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 3 and R 4 , together with the carbon atom to which they are attached, form a carbocyclic or heterocyclic group; or R 3 and R 4 together form an alkylene group;

Z is —C(O)— or alkylene-C(O)—; and

P is a peptide comprising from 1 to about 100 amino acid residues attached at its amino terminus to Z or a group OR 5 or N(R 6 )R 7 , wherein

R 5 , R 6 and R 7 are each, independently, hydrogen, alkyl, substituted alkyl, azacycloalkyl or substituted azacycloalkyl; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic ring structure; or

Z is —O—, —NR 8 —, alkylene-O— or alkylene-NR 8 —, where R 8 is hydrogen or alkyl; and

P is hydrogen, alkyl or a peptide consisting of from 1 to about 100 amino acid residues attached at its carboxy terminus to Z.

21. The method of claim 20 , wherein said parasitic infection is malaria.

22. The method of claim 20 , wherein said parasitic infection is Leishmaniasis.

23. A method of treating a thymoma in a subject, comprising administering to the subject a therapeutically effective amount of an angiogenesis inhibitor compound comprising the structure

wherein

A is a MetAP-2 inhibitory core;

W is O or NR;

each R is, independently, hydrogen or alkyl;

Z is —C(O)— or -alkylene-C(O)—;

P is NHR, OR or a peptide consisting of one to about one hundred amino acid residues connected at the N-terminus to Z;

Q is hydrogen, linear, branched or cyclic alkyl or aryl, provided that when P is —OR, Q is not hydrogen; or

Z is -alkylene-O— or -alkylene-N(R)—;

P is hydrogen or a peptide consisting of from one to about one hundred amino acid residues connected to Z at the carboxyl terminus;

Q is hydrogen, linear, branched or cyclic alkyl or aryl, provided that when P is hydrogen, Q is not hydrogen; and a pharmaceutically acceptable salt thereof,

thereby treating the thymoma in the subject.

24. A method of treating a thymoma in a subject, comprising administering to the subject a therapeutically effective amount of a compound comprising the structure

wherein

A is a Met-AP2 inhibitory core;

W is O or NR 2 ;

R 1 and R2 are each, independently, hydrogen or alkyl;

X is alkylene or substituted alkylene;

n is 0 or 1;

R 3 and R4 are each, independently, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; or R 3 and R 4 , together with the carbon atom to which they are attached, form a carbocyclic or heterocyclic group; or R 3 and R 4 together form an alkylene group;

Z is —C(O)— or alkylene-C(O)—; and

P is a peptide comprising from 1 to about 100 amino acid residues attached at its amino terminus to Z or a group OR 5 or N(R 6 )R 7 , wherein

R 5 , R 6 and R 7 are each, independently, hydrogen, alkyl, substituted alkyl, azacycloalkyl or substituted azacycloalkyl; or R 6 and R 7 , together with the nitrogen atom to which they are attached, form a substituted or unsubstituted heterocyclic ring structure; or

Z is —O—, —NR 8 —, alkylene-O— or alkylene-NR 8 —, where R 8 is hydrogen or alkyl; and

P is hydrogen, alkyl or a peptide consisting of from 1 to about 100 amino acid residues attached at its carboxy terminus to Z.

25. A method of treating a thymoma in a subject, comprising administering to the subject a therapeutically effective amount of a compound comprising a structure selected from the group consisting of

{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-3-methyl-butyric acid methyl ester;

2-{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3 -methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-3-methyl-butyric acid methyl ester;

2-{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3 -methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-4-methyl-pentanoic acid methyl ester;

{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R )-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-phenyl-acetic acid methyl ester;

(1-Carbamoyl-2-methyl-propyl)-carbamic acid-(3R, 4S, 5S, 6R )-5-methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5 ]oct-6-yl ester;

(1-Carbamoyl-2-methyl-propyl)-carbamic acid-(3R, 4S, 5S, 6R )-5-methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-butyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

(1-Hydroxymethyl-2-methyl-propyl)-carbamic acid-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

2-{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-3,3-dimethyl-butyric acid methyl ester;

Cyclohexyl-2-{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-acetic acid methyl ester;

2-{(3R, 4S, 5S, 6R )-5-Methoxy-4-[(2R, 3R)-2-methyl-3-3 -methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-3-methyl-pentanoic acid methyl ester;

[1-(1-Carbamoyl-2-hydroxy-ethylcarbamoyl)-2-methyl-propyl]-carbamic acid-(3R, 4S, 5S, 6R )-5-methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl]-oxiranyl-1-oxa-spiro[2.5]oct-6-yl ester;

2-(3-{(3R, 4S, 5S, 6R )-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]1-oxa-spiro[2.5]oct-6-yl}-ureido)-3-methyl-butyramide;

2-{(3R, 4S, 5S, 6R)-5-Methoxy-4-[(2R, 3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonylamino}-3-methyl-butyric acid;

N-Carbamoyl-Gly-Arg-Gly-Asp-Ser-Pro-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-butyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:31);

N-Carbamoyl-Gly-Arg-Gly-Asp-Tyr-(OMe)-Arg-Glu-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-butyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:30);

N-Carbamoyl-Gly-Arg-Gly-Asp-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-butyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:32);

N-Carbamoyl-Gly-Arg-Gly-3-amino-3-pyridyl-propionic acid-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:40);

N-Carbamoyl-Gly-Pro-Leu-Gly-Met-Trp-Ala-Gly-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:39);

N-Carbamoyl-Gly-Pro-Leu-(Me)Gly-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:26);

N-Carbamoyl-Gly-Pro-Leu-Gly-(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester (SEQ ID NO:27);

Ac-Pro-Leu-Gly-Met-Trp-Ala-(2R-{(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonyl}-amino-3-methyl-butanol) ester (SEQ ID NO:24);

Ac-Pro-Leu-Gly-Met-GIy-(2R-{(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonyl}-amino-3-methyl-butanol) ester (SEQ ID NO:3 6);

Met-Trp-Ala-(2R-{(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonyl}-amino-3-methyl-butanol) ester (SEQ ID NO:37);

Met-Gly-(2R-{(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonyl}-amino-3-methyl-butanol) ester (SEQ ID NO :38);

Ac-Pro-Leu-Gly-Met-Ala-(2R-{(3R, 4S, 5S, 6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yloxycarbonyl}-amino-3-methyl-butanol) ester (SEQ ID NO:34);

{2-Methyl-1-[methyl-(1-methyl-piperidin-4-yl)-carbamoyl]-propyl}-carbamic acid-5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

[1-(2-Dimethylamino-ethylcarbamoyl)-2-methyl-propyl]-carbamic acid-5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

{1-[(2-Dimethylamino-ethyl)-methyl-carbamoyl]-2-methyl-propyl}-carbamic acid-5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

[1-(3-Dimethylamino-propylcarbamoyl)-2-methyl-propyl]-carbamic acid-5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

[1-(3-Dimethylamino-2,2-dimethyl-propylcarbamoyl)-2-methyl-propyl]-carbamic acid-5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

[2-Methyl-1-(4-methyl-piperazine-1-carbonyl)-propyl]-carbamic acid-5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

{2-Methyl-1-[2-(1-methyl-pyrrolidin-2-yl)-ethylcarbamoyl]-propyl}-carbamic acid-5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester;

[2-Methyl-1-(4-pyrrolidin-1-yl-piperidine-1-carbonyl)-propyl]-carbamic acid-5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester; and

[1-(4-Benzyl-piperazine-1-carbonyl)-2-methyl-propyl]-carbamic acid-5-methoxy-4-[2-methyl-3-(3-methyl-but-2-enyl)-oxiranyl]-1-oxa-spiro[2.5]oct-6-yl ester.

26. The method of claim 1 , wherein said lymphoid malignancy is a lymphoma.

27. The method of claim 26 , wherein said lymphoma is a B cell lymphoma.

28. The method of claim 1 , wherein said lymphoid malignancy is leukemia.

29. The method of claim 1 , wherein said subject is human.

30. The method of claim 20 , wherein said subject is human.

31. The method of claim 23 , wherein said subject is human.

32. The method of claim 24 , wherein said subject is human.

33. The method of claim 25 , wherein said subject is human.

34. The method of claim 1 , wherein said compound is administered to the subject using a pharmaceutically acceptable formulation.

35. The method of claim 20 , wherein said compound is administered to the subject using a pharmaceutically acceptable formulation.

36. The method of claim 23 , wherein said compound is administered to the subject using a pharmaceutically acceptable formulation.

37. The method of claim 24 , wherein said compound is administered to the subject using a pharmaceutically acceptable formulation.

38. The method of claim 25 , wherein said compound is administered to the subject using a pharmaceutically acceptable formulation.

39. The method of claim 1 , wherein said compound is administered to the subject intravenously, intramuscularly or orally.

40. The method of claim 20 , wherein said compound is administered to the subject intravenously, intramuscularly or orally.

41. The method of claim 23 , wherein said compound is administered to the subject intravenously, intramuscularly or orally.

42. The method of claim 24 , wherein said compound is administered to the subject intravenously, intramuscularly or orally.

43. The method of claim 25 , wherein said compound is administered to the subject intravenously, intramuscularly or orally.