Phosphoramidate alkylator prodrugs

1. A compound of formula (I):

wherein

Y 2 is O, S, NR 6 , NCOR 6 , or NSO 2 R 6 wherein R 6 is (C 1 -C 6 ) alkyl, C 1 -C 6 heteroalkyl, aryl, or heteroaryl;

R 3 and R 4 are independently selected from the group consisting of 2-haloalkyl, 2-alkylsulfonyloxyalkyl, 2-heteroalkylsulfonyloxyalkyl, 2-arylsulfonyloxyalkyl, and 2-heteroalkylsulfonyloxyalkyl;

R 1 has the formula L-Z 3 ;

L is C(Z 1 ) 2 ; and

each Z 1 independently is hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, aryl, heteroaryl, C 3 -C 8 cycloalkyl, heterocyclyl, C 1 -C 6 acyl, C 1 -C 6 heteroacyl, aroyl, or heteroaroyl; or L is:

Z 3 is a bioreductive group having a formula selected from the group consisting of:

each X 1 is independently N or CR 8 ;

X 2 is NR 7 , S, or O;

R 7 is independently selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl and heteroaryl;

R 8 is independently hydrogen, halogen, cyano, CHF 2 , CF 3 , CO 2 H, amino, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 1 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, aryl, CON(R 7 ) 2 , C 1 -C 6 acyl, C 1 -C 6 heteroacyl, aroyl or heteroaroyl; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 2 is O.

3. The compound of claim 1 selected from one of the following formulae:

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the Z 3 is selected from the group consisting of:

5. The compound of claim 3 selected from one of the following formulae:

wherein each R 9 independently is hydrogen, C 1 -C 4 alkyl or C 3 -C 8 cycloalkyl;

X 4 is halo, alkylsulfonyloxy, heteroalkylsulfonyloxy, arylsulfonyloxy, or heteroalkylsulfonyloxy,

or a pharmaceutically acceptable salt thereof.

6. The compound of claim 5 of the formula:

wherein each R 9 is independently hydrogen, methyl, ethyl, propyl, isopropyl, or cyclopropyl; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 5 of the formula:

wherein each R 9 independently is hydrogen, methyl, ethyl, propyl, isopropyl, or cyclopropyl;

or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein L-Z 3 has the formula:

wherein each Z 1 independently is H or C 1 -C 6 alkyl.

9. The compound of claim 5 of formula:

wherein each X 4 is selected from the group consisting of Cl, Br, alkylsulfonyloxy, heteroalkylsulfonyloxy, arylsulfonyloxy, and heteroarylsulfonyloxy; or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 of the formula:

wherein L is —CH 2 or CH(Z 1 ) wherein Z 1 is C 1 -C 6 alkyl;

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein L-Z 3 is selected from the group consisting of:

and R 7 is independently C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, or heteroaryl.

12. The compound of claim 11 , or a pharmaceutically acceptable salt thereof, wherein Z 1 is hydrogen, methyl, or ethyl; R 7 is selected from the group consisting of methyl, trifluoroethyl, ethyl, propyl, and cyclohexyl; R 9 independently is hydrogen or C 1 -C 6 alkyl and each X 4 is halo, alkylsulfonyloxy, heteroalkylsulfonyloxy, arylsulfonyloxy, or heteroarylsulfonyloxy.

13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein R 9 is hydrogen, methyl, ethyl, isopropyl, or isobutyl; and X 4 is chloro, bromo, or methanesulfonyloxy.

14. The compound of claim 1 of formula:

wherein;

L is CH 2 , CHMe, CMe 2 ,

and Z 3 is selected from the group consisting of:

each R 9 is independently selected from the group consisting of hydrogen, methyl, ethyl, propyl, isobutyl, isopropyl and cyclopropyl; and

each X 4 is independently selected from the group consisting of Cl, Br, alkylsulfonyloxy, heteroalkylsulfonyloxy, arylsulfonyloxy and heteroarylsulfonyloxy;

or a pharmaceutically acceptable salt thereof.

15. A compound having the formula:

wherein both X 4 are Cl or both X 4 are Br.

16. The compound of claim 15 having the formula:

17. A compound having the formula:

18. A pharmaceutical formulation comprising the compound of claim 15 and a pharmaceutically acceptable excipient, carrier, or diluent.

19. A pharmaceutical formulation comprising the compound of claim 16 and a pharmaceutically acceptable excipient, carrier, or diluent.

20. A pharmaceutical formulation comprising the compound of claim 17 and a pharmaceutically acceptable excipient, carrier, or diluent.