Phosphoramidate alkylator prodrugs

1. A compound of formula (I):

wherein

Y 1 is O, S, NR 6 or NSO 2 R 6

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

R 1 is a Trigger, T, having the formula L-Z 3 ;

L is selected from the group consisting of:

—[C(Z 1 ) 2 —Y 3 ] v —[C(═O)—O)] q —[C(Z 1 ) 2 —Z 2 —Y 4 ] u —[C(Z 1 ) 2 ] Z —[C(Z 1 )═C(Z 1 )] g ;

—[C(Z 1 ) 2 —Y 3 ] v —(S(═O) 2 ) q —[C(Z 1 ) 2 —Z 2 —Y 4 ] u —[C(Z 1 ) 2 ] Z —[C(Z 1 )═C(Z 1 )] g ;

—[C(Z 1 ) 2 —Y 3 ]—[C(Z 1 ) 2 —Z 2 —Y 4 ]—[C(Z 1 ) 2 ] Z —[C(Z 1 )═C(Z 1 )]—;

—[C(Z 1 ) 2 —Y 3 ]—[C(Z 1 ) 2 ] z —[C(Z 1 )═C(Z 1 )]—;

—[C(Z 1 ) 2 —Y 3 ]—[C(Z 1 ) 2 ] Z —;

—[C(Z 1 ) 2 —Y 3 ]—(C(═O)—O)—[C(Z 1 ) 2 ] Z —[C(Z 1 )═C(Z 1 )]—;

—[C(Z 1 ) 2 —Y 3 ]—(C(═O)—O)—[C(Z 1 ) 2 ] Z —;

—[C(Z 1 ) 2 —Y 3 ]—(C(═O)—O)—[C(Z 1 ) 2] Z —[C(Z 1 )═C(Z 1 )]—;

—[C(Z 1 ) 2 —Z 2 —Y 4 ]—[C(Z 1 ) 2 ] Z —[C(Z 1 )═C(Z 1 )]—;

—[C(Z 1 ) 2 ] Z —[C(Z 1 )═C(Z 1 )]—; and

—[C(Z 1 ) 2 ] Z :

wherein each z, v, q, u, and g independently is 0 or 1;

Y 3 is S, O, or NR 7 wherein each R 7 is independently hydrogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 heteroalkyl, C 3 -C 8 cycloalkyl, heterocyclyl, C 1 -C 6 alkoxy, C 1 -C 6 alkylamino, C 1 -C 6 dialkylamino, aryl, heteroaryl, C 1 -C 6 acyl, C 1 -C 6 heteroacyl, aroyl, or heteroaroyl;

Y 4 is O, S, or —NR 7 —C(═O)—O—;

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;

Z 2 is C 1 -C 6 alkylene, C 1 -C 6 heteroalkylene,

wherein each X 1 is independently N or CR 8 wherein R 8 is independently hydrogen, OH, OP(═O)(OH) 2 , halogen, nitro, cyano, CHF 2 , CF 3 , CH 2 CF 3 , CO 2 H, amino, C 1 -C 6 alkyl, C 1 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -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;

X 2 is NR 7 , S, or O; and

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

with the proviso that in formula (I):

(a) NR 2 R 3 is NHR 3 ; NR 4 R 5 is NHR 5 and R 3 and R 5 independently are selected from the group consisting of 2-haloalkyl, 2- C 1 -C 6 alkylsulfonyloxyalkyl, heteroalkylsulfonyloxyalkyl, 2-arylsulfonyloxyalkyl, and 2-heteroarylsulfonyloxyalkyl;

(b) NR 2 R 3 is NHR 3 ; and R 3 independently is selected from the group consisting of 2-haloalkyl, 2-C 1 -C 6 alkylsulfonyloxyalkyl, 2-heteroalkylsulfonyloxyalkyl 2-arylsulfonyloxyalkyl, and 2 -heteroarylsulfonyloxyalkyl; and NR 4 R 5 is

 or

(c) NR 2 R 3 and NR 4 R 5 are

an individual stereoisomer or a racemic or non-racemic mixture of stereoisomers, or a pharmaceutically acceptable salt, solvate, or hydrate, thereof.

2. The compound of claim 1 wherein Y 1 and Y 2 are O.

3. The compound of claim 1 of formula (II) or (III):

4. The compound of claim 3 wherein L is selected from the group consisting of:

[C(Z 1 ) 2 —Y 3 ]—(C(═O)—O)—[C(Z 1 ) 2 —Z 2 —Y 4 ]—[C(Z 1 ) 2 ] Z —[C(Z 1 )═C(Z 1 )]—;

[C(Z 1 ) 2 —Y 3 ]—[C(Z 1 ) 2 —Z 2 —Y 4 ]—[C(Z 1 ) 2 ] Z —[C(Z 1 )═C(Z 1 )]—;

[C(Z 1 ) 2 —Y 3 ]—[C(Z 1 ) 2 ] Z —[C(Z 1 )═C(Z 1 )]—;

[C(Z 1 ) 2 —Y 3 ]—[C(Z 1 ) 2 ] Z —;

[C(Z 1 ) 2 —Y 3 ]—(C(═O)—O)—[C(Z 1 ) 2 ] Z —[C(Z 1 )═C(Z 1 )]—;

[C(Z 1 ) 2 —Y 3 ]—(C(═O)—O)—[C(Z 1 ) 2 ] Z —;

[C(Z 1 ) 2 —Y 3 ]—(C(═O)—O)—[C(Z 1 ) 2 ] Z —[C(Z 1 )═C(Z 1 )]—;

[C(Z 1 ) 2 —Z 2 —Y 4 ]—[C(Z 1 ) 2 ] Z —[C(Z 1 )═C(Z 1 )]—;

—[C(Z 1 ) 2 ] Z —[C(Z 1 )═C(Z 1 )]—;

and —[C(Z 1 ) 2 ] Z —.

5. The compound of claim 3 having the formula (VI) or (VII):

wherein each R 9 independently is hydrogen or C 1 -C 4 alkyl;

each R 11 is hydrogen, and X 4 is halo, C 1 -C 6 alkylsulfonyloxy, heteroalkylsulfonyloxy, arylsulfonyloxy, or heteroarylsulfonyloxyalkyl.

6. The compound of claim 5 of formula (VI) wherein each R 9 independently is hydrogen, methyl, ethyl, propyl, or isopropyl, and R 11 is hydrogen.

7. The compound of claim 1 wherein T has the formula:

8. The compound of claim 1 wherein T has the formula:

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

9. The compound of claim 5 of formula (XII), or (XIV):

wherein;

each R 11 is hydrogen.

10. The compound of claim 3 of formula (II) wherein T is —CH 2 —Z 3 or —CH(Z 1 )—Z 3 wherein Z 1 is C 1-6 alkyl and Z 3 is:

11. The compound of claim 5 wherein T is selected from the group consisting of:

12. The compound of claim 11 wherein Z 1 is hydrogen, methyl, or ethyl; R 7 is methyl, trifluoroethyl, ethyl, propyl, or cyclohexyl; R 8 is OH or OP(═O)(OH) 2 ; R 9 is hydrogen or C 1 -C 6 alkyl and each X 4 is halo, C 1 -C 6 alkylsulfonyloxy, heteroalkylsulfonyloxy, arylsulfonyloxy or heteroarylsulfonyloxy.

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

14. The compound of claim 13 of formula:

wherein T is L-Z 3 ;

L is CH 2 , CHMe, CMe 2 ,

and Z 3 is selected from the group consisting of:

15. A pharmaceutical formulation comprising the compound of claim 1 and a pharmaceutically acceptable excipient, carrier, or diluent.

16. A method of treating a cancer selected from the group consisting of pancreatic cancer, lung cancer and colorectal cancer, comprising administering to a patient in need of therapy thereof, the pharmaceutical formulation of claim 15 .

17. A method of making a compound of claim 1 comprising reacting a compound having the formula:

with a compound having the formula R 1 —Y 2 —H.

18. The compound of claim 14 having the formula:

19. The compound of claim 1 having the formula:

20. The method of claim 16 , wherein the cancer is pancreatic cancer.