Small-molecule Hsp90 inhibitors

1. 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.

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

3. The compound 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 compound of claim 3 , wherein X 1 includes a cyclic portion.

5. The compound of claim 4 , wherein the cyclic portion includes at least one nitrogen.

6. The compound of claim 3 , wherein the linker is S.

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

8. The compound of claim 7 , wherein the cyclic portion includes at least one nitrogen.

9. The compound of claim 1 , wherein X 1 contains at least one nitrogen heteroatom.

10. The compound of claim 1 , wherein X 1 contains at least one oxygen heteroatom.

11. The compound of claim 1 , wherein X 1 includes a cyclic portion.

12. The compound of claim 11 , wherein the cyclic portion includes at least one heteroatom.

13. The compound of claim 11 , wherein the cyclic portion is a 6-membered ring.

14. The compound of claim 11 , wherein the cyclic portion is a 3-membered ring.

15. The compound of claim 1 , wherein the linker is CH 2 .

16. The compound of claim 15 , wherein X 2 is NH 2 , alkylamino or dialkylamino.

17. The compound of claim 16 , 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.

18. The compound of claim 17 , wherein X 1 includes a cyclic portion.

19. The compound of claim 18 , wherein the cyclic portion includes at least one nitrogen.

20. The compound of claim 1 , wherein the linker is S.

21. The compound of claim 20 , wherein X 1 includes a cyclic portion.

22. The compound of claim 21 , wherein the cyclic portion include at least one nitrogen.

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

24. The compound 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.

25. The compound of claim 1 , wherein X 1 is selected from the following:

26. A compound of the formula:

wherein:

X 6 is NH 2 ;

X 3 is hydrogen or halogen;

X 1 is hydrogen or a C1 to C10 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.

27. The compound of claim 26 , wherein X 2 is NH 2 , alkylamino or dialkylamino.

28. The compound of claim 26 , wherein X 1 includes a cyclic portion which optionally includes at least one heteroatom.

29. The compound of claim 26 , wherein the linker is CH 2 .

30. The compound of claim 29 , wherein X 1 includes a cyclic portion which optionally includes at least one nitrogen.

31. The compound of claim 26 , wherein the linker is S.

32. The compound of claim 31 , wherein X 1 includes a cyclic portion which optionally includes at least one nitrogen.

33. The compound of claim 30 , wherein the cyclic portion is a 6-membered ring or a 3-membered ring.

34. The compound of claim 32 , wherein the cyclic portion is a 6-membered ring or a 3-membered ring.

35. The compound of claim 1 , wherein X 2 is halogen.

36. The compound of claim 35 , 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.

37. The compound of claim 36 , wherein the linker is S.

38. The compound of claim 37 , wherein X 1 includes a cyclic portion.

39. The compound of claim 38 , wherein the cyclic portion includes at least one nitrogen.

40. The compound of claim 38 , wherein the cyclic portion is a 6-membered ring or 3-membered ring.

41. The compound of claim 36 , wherein the linker is CH 2 .

42. The compound of claim 41 , wherein X 1 includes a cyclic portion.

43. The compound of claim 42 , wherein the cyclic portion includes at least one nitrogen.

44. The compound of claim 42 , wherein the cyclic portion is a 6-membered ring or 3-membered ring.

45. The compound of claim 35 , wherein X 1 is selected from the following: