Administration of hypoxia activated prodrugs in combination with Chk1 inhibitors for treating cancer

1. A method of treating cancer, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a hypoxia activated prodrug in combination with a therapeutically effective amount of a Chk1 inhibitor, wherein said patient is identified as having a p53-deficient cancer prior to administration of the hypoxia activated prodrug and the Chk1 inhibitor.

2. The method of claim 1 , wherein the hypoxia activated prodrug is a compound of Formula I:

wherein

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

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-arylsulfonyloxyalkyl, and 2-heteroalkylsulfonyloxyalkyl;

R 1 has the formula L-Z 3 ;

L is C(Z 1 ) 2 ;

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 S , S, or O;

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

and 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.

3. The method of claim 2 , wherein said compound of Formula I is TH-302.

4. The method of claim 2 , wherein said Chk1 inhibitor is selected from the group consisting of AZD7762, LY2603618, PF-00477736, and SCH 900776.

5. A pharmaceutical formulation comprising a compound of Formula I:

wherein

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

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-arylsulfonyloxyalkyl, and 2-heteroalkylsulfonyloxyalkyl;

R 1 has the formula L-Z 3 ;

L is C(Z 1 ) 2 ;

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 S , S, or O;

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

and 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;

a Chk1 inhibitor, and at least a pharmaceutically acceptable excipient.

6. The pharmaceutical formulation of claim 5 , wherein said compound of Formula I is TH-302.

7. The pharmaceutical formulation of claim 6 wherein said Chk1 inhibitor is selected from the group consisting of AZD7762, LY2603618, PF-00477736, and SCH 900776.

8. A method of increasing antitumor effect of a compound of Formula I:

wherein

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

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-arylsulfonyloxyalkyl, and 2-heteroalkylsulfonyloxyalkyl;

R 1 has the formula L-Z 3 ;

L is C(Z 1 ) 2 ;

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 S , S, or O;

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

and 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 on a P53 deficient tumor cell, comprising coadministering to the tumor cell a Chk1 inhibitor.

9. The method of claim 8 , wherein the Chk1 inhibitor is AZD7762, PF00477736, or LY603618.

10. The method of claim 8 , wherein the compound of Formula I is TH-302.

11. The method of claim 3 , wherein said Chk1 inhibitor is selected from the group consisting of AZD7762, LY2603618, PF-00477736, and SCH 900776.

12. The method of claim 9 , wherein the compound of Formula I is TH-302.

13. A method of treating cancer, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a hypoxia activated prodrug in combination with a therapeutically effective amount of a Chk1 inhibitor, wherein said cancer is selected from bladder cancer, colon cancer, head and neck cancer, lung cancer, and ovarian cancer.