PI-3 kinase inhibitor prodrugs

1. A compound of the formula:

wherein,

Ring A is benzo;

Z 1 and Z 2 are O;

R 1 and R 2 independently are 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 are H, optionally substituted aliphatic, optionally substituted aryl, heterocycle, aryloxy, carboxy, or, are taken together to form an optionally substituted heterocycle or optionally substituted heteroaryl;

R 6 represents H, optionally substituted aliphatic, optionally substituted aryl, alkoxy, carboxy, amino, heterocycle, aryloxy, and optionally substituted therewith a targeting agent;

L represents a linker group; and

the bond between N + and L is hydrolyzable.

2. The compound of claim 1 , wherein R 4 and R 5 independently are optionally substituted aliphatic, optionally substituted aryl, heterocycle, aryloxy, carboxy, or, are taken together to form an optionally substituted heterocycle or optionally substituted heteroaryl.

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

4. The compound of claim 2 , wherein R 4 —N—R 5 is selected from the group consisting of:

5. The compound of claim 2 , wherein R 6 is selected from the group consisting of:

6. The compound of claim 2 , wherein N + -L-R 6 is of the formula:

wherein,

Z 3 and Z 4 independently are S or O; and

R 7 represents —CH 2 —, —CH(CH 3 )—, —CH(Ph)-, —C(CH3)(COOH)— or CH(CH(CH3)2)—.

7. The compound of claim 6 , wherein the bond between R 7 and the quaternary amine is hydrolyzable.

8. The compound of claim 6 , wherein R 6 is substituted with a targeting agent and is of the formula:

wherein, T is a targeting agent.

9. The compound of claim 8 , wherein the targeting agent is selected from the group consisting of vitamins, peptides, proteins, liposomes, bone-seeking agents, and cartilage-seeking agents.

10. The compound of claim 9 , wherein the vitamin is folate or vitamin C.

11. The compound of claim 9 , wherein the peptide is an RGD-containing peptide selected from the group consisting of RGDs, c(RGDfK), vitronectin, fibronectin, somatostatin-receptor agonists and somatostatin-receptor antagonists.

12. The compound of claim 9 , wherein the protein is a tumor-specific monoclonal antibody or fragment thereof.

13. The compound of claim 9 , wherein the bone-seeking agent is selected from the group consisting of a phosphonate, phosphonic acid, aminomethylphosphonic acid, phosphate, polyphosphate, and hydroxyapatite-binding polypeptides.

14. The compound of claim 13 , wherein the bone-seeking agent is EDTMP, DOTMP, ABDTMP, BAD, MTX-BP, CF—BP, (Asp) 6 , (Glu) 6 , alendronate, pamidronate, 4-aminobutylphosphonic acid, 1-hydroxyethane-1,1-diphosphonic acid, aminomethylenebisphosphonic acid, phytic acid, and N,N-bis(methylphosphono)-4-amino-benzoic acid.

15. A compound of the formula:

wherein,

X represents a halo group;

Y represents —CH 2 —, —CH(CH 3 )—, —CH(Ph)-, —C(CH3)(COOH)— or CH(CH(CH3) 2 )—;

Z 1 and Z 2 independently are S or O; and

n=0 to 1.

16. The compound of claim 15 ,

wherein,

X represents Cl or I;

Y represents —CH 2 —, —CH(CH 3 )—, —CH(Ph)-, —C(CH3)(COOH)— or CH(CH(CH3) 2 )-

Z 1 and Z 2 are each 0; and

n=0.

17. The compound of claim 15 ,

wherein,

X represents Cl or I;

Z 1 and Z 2 are each 0; and

n=1.

18. A method of purifying a compound according to claim 2 , comprising:

(a) adding a composition comprising said compound to a solution, wherein said solution comprises at least 0.1% by (v/v) of an acid;

(b) adding the solution of (a) comprising said compound to a chromatography system; and

(c) isolating said compound.

19. The method of claim 18 wherein said chromatography system is HPLC.

20. The compound of claim 2 , wherein the compound is of the formula:

and pharmaceutically acceptable salts thereof.