Hypoxia activated drugs of nitrogen mustard alkylators

1. A compound having a structure of formula:

or a pharmaceutically acceptable salt thereof,

wherein each of X 1 and X 2 is independently selected from the group consisting of chloro, bromo, iodo, and sulfonate;

Y is selected from the group consisting of O and NR 6 ;

each of R 1 and R 2 is independently selected from the group consisting of hydrogen, halogen, and optionally substituted C 1-6 alkyl;

each of R 3 and R 4 is independently selected from the group consisting of hydrogen and optionally substituted C 1-6 alkyl;

R 5 is a bioreductive group selected from the group consisting of:

R 6 is selected from the group consisting of hydrogen and optionally substituted C 1-6 alkyl;

R 7 is selected from the group consisting of hydrogen and optionally substituted C 1-6 alkyl;

R 37 is hydrogen, or together with R 7 and the carbon atoms to which they are bonded, form an optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl moiety;

R 8 is optionally substituted C 1-6 alkyl; and

q is 0, 1, or 2.

2. The compound of claim 1 having the structure of formula:

wherein each X 1 and X 2 independently is selected from the group consisting of chloro, bromo, and sulfonate;

R 1 is selected from the group consisting of hydrogen and fluoro;

R 3 is selected from the group consisting of hydrogen and an optionally substituted alkyl moiety having a structure of formula -L-P 1 —R 20 ;

L is optionally substituted C 1-4 alkylene;

P 1 is selected from the group consisting of a bond, —S(═O) 2 —, and —NR 21 (S═O) 2 —;

R 20 is selected from the group consisting of an optionally substituted C 1-4 alkyl; optionally substituted C 2-4 alkynyl; an aryl substituted with a substituent selected from the group consisting of amino, substituted amino, and acylamino; aryloxy; cycloalkyloxy; an optionally substituted heteroaryl moiety containing a basic nitrogen atom that is either part of the heteroaryl ring or is a heteroaryl ring substituent; and an optionally substituted heterocycle containing up to 2 nitrogen atoms; and

R 21 is selected from the group consisting of hydrogen and optionally substituted C 1-4 alkyl.

3. The compound of claim 1 having the structure of formula:

wherein each of R 31 and R 32 is independently selected from the group consisting of hydrogen, optionally substituted alkyl, and —C(═O)—CR 33 (R 34 )(R 35 ); R 33 is amino; R 34 is selected from the group consisting of hydrogen and optionally substituted C 1-4 alkyl; and R 35 is C 1-6 alkyl optionally substituted with a substituent selected from the group consisting of optionally substituted amino and optionally substituted guanidino.

4. The compound of claim 1 having the structure of formula:

wherein R 39 is hydrogen or optionally substituted C 1-4 alkyl.

5. The compound of claim 1 having the structure of formula:

wherein R 20 is selected from the group consisting of C 1-4 alkyl optionally substituted with up to 2 hydroxy groups, an optionally substituted aryloxy, optionally substituted heteroaryloxy, and a nitrogen containing heterocycle wherein the point of attachment of said heterocycle to the SO 2 moiety is through a nitrogen atom.

6. The compound of claim 2 , wherein R 1 is hydrogen and L is selected from the group consisting of —CH 2 — and —CH 2 —CH 2 —.

7. The compound of claim 2 , wherein R 1 is fluoro.

8. The compound of claim 7 , wherein R 3 is hydrogen.

9. The compound of claim 6 , wherein P 1 is a bond, L is —CH 2 —, and R 20 is an optionally substituted heteroaryl moiety containing a basic nitrogen atom selected from the group consisting of benzotriazolyl, imidazopyridyl, imidazolyl, and pyridyl.

10. The compound of claim 9 having the structure of formula:

wherein R 20 is substituted pyridyl having the structure of formula:

R 23 is selected from the group consisting of hydrogen, C 1-4 alkyl optionally substituted with up to 2 hydroxy groups, and —(C═O)CR 27 (R 28 )(R 29 );

R 24 is selected from the group consisting of hydrogen and optionally substituted C 1-4 alkyl;

R 25 is selected from the group consisting of hydrogen and halogen;

X is selected from the group consisting of NR 26 , O, and a bond;

each of R 26 , R 27 , and R 28 independently is selected from the group consisting of hydrogen and optionally substituted C 1-4 alkyl; and

R 29 is selected from the group consisting of hydroxyl, optionally substituted alkoxy, and optionally substituted C 1-4 alkyl

with the proviso that when X is a bond, R 23 is hydrogen and

with the proviso that when X is O, R 23 excludes —(C═O)CR 27 (R 28 )(R 29 ).

11. The compound of claim 9 having the structure of formula:

wherein R 20 is selected from the group consisting of:

wherein R 30 is optionally substituted C 1-4 alkyl and R 36 is C 1-4 alkyl optionally substituted with up to 2 hydroxy groups.

12. The compound of claim 5 , wherein R 20 is a piperazinyl moiety having the structure of formula:

wherein R 22 is C 1-4 alkyl.

13. The compound of claim 10 , wherein R 27 and R 28 is methyl and R 29 is hydroxy.

14. The compound of claim 10 , wherein X is O.

15. The compound of claim 1 selected from the group consisting of:

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(2-methylsulfonyl)ethyl)methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(2-(2-hydroxyethoxy)pyridin-5-yl-methyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(benzotriazol-1-yl-methyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(4-aminophenylmethyl))methyl-2-nitrothiophene (trifluoroacetate salt);

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(1-(2-hydroxyethyl)benzotriazol-6-yl-methyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(2-phenoxysulfonylethyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-((2-methylamino)pyridin-5-yl)methyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(1-(2-hydroxyethyl)benzotriazol-5-yl-methyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(phenylsulfonylaminomethyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(imidazopyridin-2-yl-methyl))methyl-2 -nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(pyridin-3-yl-methyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(2-hydroxypyridin-5-yl-methyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(2-(hydroxyacetylamino)pyridin-5-yl-methyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(2-(lactic acylamino)pyridine-5-yl-methyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(2-((N-methylpiperazin-4-yl)sulfonyl)ethyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(N-methylimidazol-2-yl-methyl))methyl-2-nitrothiophene;

3-((3-Fluoro-4-(N,N-bis-(2-chloroethyl)amino)phenoxy)sulfonyl)methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(2-(2-hydroxyethylsulfonyl)ethyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(N-methylimidazol-5-yl-methyl))-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(2-aminopyridin-5-yl-methyl))methyl-2-nitrothiophene trifluoroacetate;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(imidazopyidin-5-yl-methyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(2-(2-hydroxyethoxy)-4-chloro-6-methylpyridin-5-yl-methyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(2-(N-methoxyacetyl-N-methylamino)pyridin-5-yl-methyl))methyl-2-nitrothiophene;

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(2-(lysylamino)pyridine-5-yl-methyl))methyl-2-nitrothiophene (dihydrochloride salt); and

3-(4-(N,N-bis-(2-Chloroethyl)amino)phenoxysulfonyl-(2-chloro-4-aminophenylmethyl))methyl-2-nitrothiophene (trifluoroacetate salt).

16. A pharmaceutical formulation comprising the compound of any one of claims 1 and 15 and a pharmaceutically acceptable carrier, excipient, or diluent.

17. A method of treating cancer comprising administering a therapeutically effective amount of the compound of any one of claims 1 and 15 to a patient in need of such treatment, wherein the cancer is lung cancer, colon cancer, or fibrosarcoma.