Small-molecule Hsp90 inhibitors

1. A method of treating cancer in an individual, comprising administering to the individual a compound of the formula:

wherein:

X 6 is NH 2 ;

X 3 is hydrogen or halogen;

X 1 is a C 1 to C 10 alkyl, alkenyl, or alkynyl group, wherein the alkyl, alkenyl, or alkynyl group includes a heteroatom;

the linker is selected from the group consisting of CH 2 , O, NH and S;

Y is independently CH or N;

X 2 is halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, COO-alkyl, NH 2 , OH, CN, SO 2 X 7 , NO 2 , NO, C═SR 2 , NHSO 2 X 7 , C═OR 2 where X 7 is F, NH 2 , alkyl or H, and R 2 is alkyl, NH 2 , NH-alkyl or O-alkyl; and

n is 1 or 2,

or a pharmaceutically acceptable salt thereof,

wherein the cancer is breast cancer, prostate cancer, colon cancer, myelocytic leukemia, small cell lung cancer, non-small cell lung cancer, neuroblastoma, or vulvar cancer.

2. The method of claim 1 , wherein X 2 is NH 2 , alkylamino or dialkylamino.

3. The method of claim 1 , wherein X 1 is an amino alkyl moiety, optionally substituted on the amino nitrogen with one or two carbon-containing substituents selected independently from the group consisting of alkyl, alkenyl and alkynyl substituents, wherein the total number of carbons in the amino alkyl moiety is from 1 to 10.

4. The method of claim 1 , wherein X 1 contains at least one nitrogen heteroatom.

5. The method of claim 1 , wherein X 1 contains at least one oxygen heteroatom.

6. The method of claim 1 , wherein X 1 includes a cyclic portion.

7. The method of claim 1 , wherein the linker is CH 2 or S.

8. The method of claim 1 , wherein X 1 comprises a secondary or tertiary amine forming a 6-membered ring with the nitrogen.

9. The method of claim 1 , wherein X 1 is —(CH 2 ) n —N—R 10 R 11 , wherein n is 2 or 3 and R 10 and R 11 are independently selected from hydrogen, methyl, ethyl, ethene, ethyne, propyl, isopropyl, isobutyl, ethoxy, cyclopentyl, an alkyl group forming a 3 or 6-membered ring including the N, or a secondary or tertiary amine forming a 6-membered ring with the nitrogen.

10. The method of claim 1 , wherein X 2 is halogen.

11. The method of claim 10 , wherein X 1 is —(CH 2 ) n —N—R 10 R 11 , wherein n is 2 or 3 and R 10 and R 11 are independently selected from hydrogen, methyl, ethyl, ethene, ethyne, propyl, isopropyl, isobutyl, ethoxy, cyclopentyl, an alkyl group forming a 3 or 6-membered ring including the N, or a secondary or tertiary amine forming a 6-membered ring with the nitrogen.

12. The method of claim 10 , wherein the linker is CH 2 or S.

13. The method of claim 10 , wherein X 1 is selected from the following:

14. The method of claim 1 , wherein the compound is administered in combination with radiation and/or chemotherapy.

15. The method of claim 1 , wherein the cancer is breast cancer, prostate cancer, neuroblastoma, myelocytic leukemia, colon cancer, or non-small cell lung cancer.

16. A method of treating cancer in an individual, comprising administering to the individual a compound of the formula:

wherein:

X 6 is NH 2 ;

X 3 is hydrogen or halogen;

X 1 is hydrogen or a C 1 to C 10 alkyl, alkenyl, or alkynyl group, optionally including a heteroatom;

the linker is selected from the group consisting of CH 2 , O, NH and S;

Y is independently CH or N;

X 2 is alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, COO-alkyl, NH 2 , OH, CN, SO 2 X 7 , NO 2 , NO, C═SR 2 , NHSO 2 X 7 , C═OR 2 where X 7 is F, NH 2 , alkyl or H, and R 2 is alkyl, NH 2 , NH-alkyl or O-alkyl; and

n is 1 or 2,

or a pharmaceutically acceptable salt thereof,

wherein the cancer is breast cancer, prostate cancer, colon cancer, myelocytic leukemia, small cell lung cancer, non-small cell lung cancer, neuroblastoma, or vulvar cancer.

17. The method of claim 16 , wherein X 2 is NH 2 , alkylamino or dialkylamino.

18. The method of claim 16 , wherein X 1 includes a cyclic portion which optionally includes at least one heteroatom.

19. The method of claim 16 , wherein the linker is CH 2 or S.

20. The method of claim 16 , wherein the compound is administered in combination with radiation and/or chemotherapy.

21. The method of claim 16 , wherein the cancer is breast cancer, prostate cancer, neuroblastoma, myelocytic leukemia, colon cancer, or non-small cell lung cancer.