Methods and compositions for use in treating cancer

1. A pharmaceutical composition comprising a therapeutically effective amount of a compound having the formula:

wherein A is a C 1-6 saturated or C 2-6 unsaturated hydrocarbon skeleton, said skeleton being unsubstituted or having between 1 and 10 substituents, inclusive, independently selected from cyano, halo, azido, oxo, and Q 1 ;

each Q 1 is independently selected from OR 1 , SR 1 , SO 2 R 1 , OSO 2 R 1 , NR 2 R 1 , NR 2 (CO)R 1 , NR 2 (CO)(CO)R 1 , NR 4 (CO)NR 2 R 1 , NR 2 (CO)OR 1 , (CO)OR 1 , O(CO)R 1 , (CO)NR 2 R 1 , and O(CO)NR 2 R 1 ;

each of R 1 , R 2 , R 4 , R 5 , and R 6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 6-10 aryl, C 6-10 haloaryl, C 6-10 hydroxyaryl, C 1-3 alkoxy-C 6 aryl, C 6-10 aryl-C 1-6 alkyl, C 1-6 alkyl-C 6-10 aryl, C 6-10 haloaryl-C 1-6 alkyl, C 1-6 alkyl-C 6-10 haloaryl, (C 1-3 alkoxy-C 6 aryl)-C 1-3 alkyl, C 2-9 heterocyclic radical, C 2-9 heterocyclic radical-C 1-6 alkyl, C 2-9 heteroaryl, and C 2-9 heteroaryl-C 1-6 alkyl;

each of D and D′ is independently selected from R 3 and OR 3 , wherein R 3 is H, C 1-3 alkyl, or C 1-3 haloalkyl;

n is 0 or 1;

E is R 5 or OR 5 ;

G is O, S, CH 2 , or NR 6 ;

each of J and J′ is independently H, C 1-6 alkoxy, or C 1-6 alkyl; or J and J′ taken together are ═CH 2 or —O-(straight or branched C 1-5 alkylene)-O—;

Q is C 1-3 alkyl;

T is ethylene or ethenylene, optionally substituted with (CO)OR 7 , where R 7 is H or C 1-6 alkyl;

each of U and U′ is independently H, C 1-6 alkoxy, or C 1-6 alkyl; or U and U′ taken together are ═CH 2 or —O-(straight or branched C 1-5 alkylene)-O—;

X is H or C 1-6 alkoxy;

each of Y and Y′ is independently H or C 1-6 alkoxy; or Y and Y′ taken together are ═O, ═CH 2 , or —O-(straight or branched C 1-5 alkylene)-O—; and

each of Z and Z′ is independently H or C 1-6 alkoxy; or Z and Z′ taken together are ═O, ═CH 2 or —O-(straight or branched C 1-5 alkylene)-O—;

or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition of claim 1 , wherein n is 0.

3. The pharmaceutical composition of claim 1 , wherein each of D and D′ is independently selected from R 3 , C 1-3 alkoxy, and C 1-3 haloalkyloxy.

4. The pharmaceutical composition of claim 1 , wherein R 5 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, C 1-6 aminoalkyl, C 6-10 aryl, C 6-10 haloaryl, C 6-10 hydroxyaryl, C 1-3 alkoxy-C 6 aryl, C 6-10 aryl-C 1-6 alkyl, C 1-6 alkyl-C 6-10 is aryl, C 6-10 haloaryl-C 1-6 alkyl, C 1-6 , alkyl-C 6-10 haloaryl, (C 1-3 alkoxy-C 6 alkyl)-C 1-3 alkyl, C 2-9 heterocyclic radical, C 2-9 heterocyclic radical-C 1-6 alkyl, C 2-9 heteroaryl, and C 2-9 heteroaryl-C 1-6 alkyl.

5. The pharmaceutical composition of claim 1 , wherein A comprises a C 1-6 saturated or C 2-6 unsaturated hydrocarbon skeleton, said skeleton having at least one substituent selected from cyano, halo, azido, oxo, and Q 1 ;

each Q 1 is independently selected from OR 1 , SR 1 , S 0 2 R 1 , OSO 2 R 1 , NR 2 R 1 , NR 2 (CO)R 1 , and O(CO)NR 2 R 1 ;

n is 0;

G is O;

J and J′ taken together are ═CH 2 ;

Q is methyl;

T is ethylene;

U and U′ taken together are ═CH 2 ;

X is H;

each of Y and Y′ is H; and

Z and Z′ taken together are ═O or ═CH 2 .

6. The pharmaceutical composition of claim 1 , wherein each Q 1 is independently selected from OR 1 , SR 1 , SO 2 R 1 , OSO 2 R 1 , NH(CO)R 1 ,NH(CO)(CO)R 1 , and O(CO)NHR 1 ;

each R 1 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 6 aryl, C 6 haloaryl, C 1-3 alkoxy-C 6 aryl, C 6 aryl-C 1-3 alkyl, C 1-3 alkyl-C 6 aryl, C 6 haloaryl-C 1-3 alkyl, C 1-3 alkyl-C 6 haloaryl, (C 1-3 alkoxy-C 6 aryl)-C 1-3 alkyl, C 29 heterocyclic radical, C 2-9 heteroaryl, and C 2-9 heteroaryl-C 1-6 alkyl;

one of D and D′ is methyl or methoxy, and the other is H;

n is 0;

G is O;

J and J′ taken together are ═CH 2 ;

Q is methyl;

T is ethylene;

U and U′ taken together are ═CH 2 ;

X is H;

each of Y andY′ is H; and

Z and Z′ taken together are ═O.

7. The pharmaceutical composition of claim 5 , wherein A has at least one substituent selected from hydroxyl, amino, azido, halo, and oxo.

8. The pharmaceutical composition of claim 7 , wherein A comprises a saturated hydrocarbon skeleton having at least one substituent selected from hydroxyl, amino and azido.

9. The pharmaceutical composition of claim 8 , wherein A has at least two substituents independently selected from hydroxyl, amino, and azido.

10. The pharmaceutical composition of claim 8 , wherein A has at least two substituents independently selected from hydroxyl and amino.

11. The pharmaceutical composition of claim 8 , wherein A has at least one hydroxyl substituent and at least one amino substituent.

12. The pharmaceutical composition of claim 8 , wherein A has at least two hydroxyl substituents.

13. The pharmaceutical composition of claim 8 , wherein A comprises a C 2-4 hydrocarbon skeleton.

14. The pharmaceutical composition of claim 8 , wherein A comprises a C 3 hydrocarbon skeleton.

15. The pharnmceutical composition of claim 13 , wherein A has an (S)-hydroxyl on the carbon atom alpha to the carbon atom linking A to the ring containing G.

16. The pharmaceutical composition of claim 5 , wherein A comprises a C 1-6 saturated hydrocarbon skeleton having at least one substituent selected from hydroxyl and cyano.

17. The pharmaceutical composition of claim 6 , wherein Q 1 is independently selected from OR 1 , SR 1 , SO 2 R 1 , and OSO 2 R 1 where each R 1 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 6 aryl, C 6 haloaryl, C 1-3 alkoxy-C 6 aryl, C 6 aryl-C 1-3 alkyl, C 1-3 alkyl-C 6 aryl, C 6 haloaryl-C 1-3 alkyl, C 1-3 alkyl-C 6 haloaryl, and (C 1-3 alkoxy-C 6 aryl)-C 1-3 alkyl.

18. The pharmaceutical composition of claim 1 , comprising a compound of the following structure

or a pharmaceutically acceptable salt thereof.

19. The pharmaceutical composition of claim 1 , comprising a compound of the following structure

or a pharmaceutically acceptable salt thereof.

20. The pharmaceutical composition of claim 1 , further comprising a pharmaceutically-acceptable carrier.

21. The pharmaceutical composition of claim 1 , further comprising one or more other pharmaceutically-active agents.

22. The pharmaceutical composition of claim 21 , wherein the one or more other pharmaceutically-active agents is selected from the group consisting of anti-tumor agents, immune-stimulating agents, interferons, cytokines, anti-MDR agents, and anti-angiogenesis agents.

23. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is formulated for administration by oral, topical, parenteral, intramuscular, or intravenous routes, or administration by injection or inhalation.

24. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition is a controlled-release formulation.