PI-3 kinase inhibitor prodrugs

1. A compound produced by a process comprising reacting Compound 2 of the formula:

with a halomethyl ester of the formula:

wherein,

hal is a halogen atom;

Z 1 and Z 2 represent O;

Z 3 and Z 4 represent O;

R 1 and R 2 independently represent H, optionally substituted aliphatic, optionally substituted aryl, hydroxyl, halogen, alkoxy, heterocycle, cyano, amino, or, are taken together to form an optionally substituted cycloaliphatic or optionally substituted aryl;

R 3 represents H, optionally substituted aliphatic, and optionally substituted aryl;

R 4 and R 5 independently represent H, optionally substituted aliphatic, optionally substituted aryl, heterocycle, aryloxy, alkoxy, carboxy, or, are taken together to form an optionally substituted heterocycle or optionally substituted heteroaryl;

R 6 independently represent H, optionally substituted aliphatic, optionally substituted aryl, heterocycle, aryloxy, alkoxy, amino, or carboxy, and any of which are optionally substituted with a targeting agent (T); and

R 7 represents —CH 2 —, —CH(CH 3 ), —CH(Ph), —C(CH 3 )(COOH) or CH(CH(CH 3 ) 2 .

2. The compound of claim 1 , wherein R 1 -Ring A-R 2 is selected from the group consisting of:

wherein R 4 —N—R 5 is selected from the group consisting of:

wherein R 6 is selected from the givup consisting of:

3. The compound of claim 1 , wherein R 6 is substituted with a targeting agent forming R 6 -T, which is selected from the group consisting of:

4. The compound of claim 1 , 2 , or 3 , wherein the targeting agent is selected from a carbohydrate, vitamin, peptide or peptidomimetic, protein, nucleoside, nucleotide, nucleic acid, liposome, lipid, bone-seeking agent, cartilage-seeking agent, diazepine, glucose, galactose, mannose or mannose-6-phosphate.

5. The compound of claim 4 , wherein the targeting agent is a peptide which is an RGD-moiety.

6. The compound of claim 5 , wherein the RGD-moiety is selected from the group consisting of RGDs, c(RGDfK), vitronectin, fibronectin, somatostatin-receptor agonists and somatostatin-receptor antagonists.

7. The compound of claim 1 , wherein Compound 2 is of the formula:

8. The compound of claim 7 , wherein R 6 is substituted with a targeting agent forming R 6 -T, which is selected from the group consisting of:

9. The compound of claim 8 , wherein the targeting agent is selected from a carbohydrate, vitamin, peptide or peptidomimetic, protein, nucleoside, nucleotide, nucleic acid, liposome, lipid, bone-seeking agent, cartilage-seeking agent, diazepine, glucose, galactose, mannose or mannose-6-phosphate.

10. The compound of claim 9 , wherein the targeting agent is a peptide which is an RGD-moiety.

11. The compound of claim 10 , wherein the RGD-moiety is selected from the group consisting of RGDs, c(RGDfK), vitronectin, fibronectin, somatostatin-receptor agonists and somatostatin-receptor antagonists.

12. The compound of claim 1 , wherein the halomethyl ester is halomethyl-t-butyl succinate.

13. The compound of claim 12 , wherein the process further comprises:

(a) removing the t-butyl group from the product produced by reacting Compound 2 with halomethyl-t-butyl succinate, thereby producing a free carboxylic acid group;

(b) converting the carboxylic acid group of the product of (a) to an acid chloride or an active ester; and

(c) contacting the product of (b) with a targeting agent (I) comprising a free amino group.

14. The compound of claim 13 , wherein the halomethyl-t-butyl succinate is chloromethyl-t-butyl succinate, and wherein Compound 2 is LY294002.

15. The compound of claim 13 , wherein the targeting agent (T) of step (c) is selected from a carbohydrate, vitamin, peptide or peptidomimetic, protein, nucleoside, nucleotide, nucleic acid, liposome, lipid, bone-seeking agent, cartilage-seeking agent, diazepine, glucose, galactose, mannose or mannose-6-phosphate.

16. The compound of claim 15 , wherein the targeting agent is a peptide which is an RGD-moiety.

17. The compound of claim 16 , wherein the RGD-moiety is selected from the group consisting of RGDs, c(RGDfK), vitronectin, fibronectin, somatostatin-receptor agonists and somatostatin-receptor antagonists.

18. The compound of claim 16 , wherein the protected RGDS-moiety has a free arginine alpha-amino group.

19. The compound of claim 18 , wherein the process further comprises a step (d) removing a protecting group from the RGDS-moiety.

20. The compound of claim 19 , wherein the process further comprises identifying and isolating the product of (d) using preparative reverse phase liquid chromatography mass spectrum (LCMS) wherein the isolated product has a mass of M+=853 in the positive mode of LCMS.

21. The compound of claim 19 , wherein the process further comprises exchanging any anion counterions with chloride counterions (salt).