Small-molecule HSP90 inhibitors

Patent metadata

Field	Value
Publication number	US-9701678-B2
Application number	US-201414256510-A
Country	US
Kind code	B2
Filing date	Apr 18, 2014
Priority date	Feb 1, 2005
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

Abstract

Hsp90 inhibitors having are provided having the formula: (I) with a 2′,4′,5′-substitution pattern on the right-side aryl moiety. X1 represents two substituents, which may be the same or different, disposed in the 4′ and 5′ positions on the aryl group, wherein X1 is selected from halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, amido, alkylamido dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO 2 -alkyl, COO-alkyl, KH 2 , OH, CN, SO 2 X 5 , NO 2 , NO, C═SR 2 NSO 2 X 5 , C═OR 2 , where X 5 is F, NH2, alkyl or H, and R 2 is alkyl, NH 2 , NH-alkyl or O-alkyl, C 1 to C 6 alkyl or alkoxy; or wherein X 1 has the formula —O—(CH 2 ) n —O—, wherein n is an integer from 0 to 2, preferably 1 or 2, and one of the oxygens is bonded at the 5′-position and the other at the 4′-position of the aryl ring. The compounds are useful in cancer therapy and as radioimaging ligands.

First claim

The invention claimed is:

1. A compound of the formula:

or a salt thereof,
wherein the right side aryl ring optionally comprises one or more heteroatoms which are N or O,
R is

X 4 is hydrogen or halogen, wherein the halogen is F or Cl, or Br;
X 3 is CH 2 , CF 2 , S, SO, SO 2 , O, NH, or NR 2 , wherein R 2 is alkyl; and
X 2 is halogen, alkyl, alkoxy, halogenated alkoxy, hydroxyalkyl, pyrollyl, optionally substituted aryloxy, alkylamino, dialkylamino, carbamyl, alkylamido, dialkylamido, acylamino, alkylsulfonylamido, trihalomethoxy, trihalocarbon, thioalkyl, SO 2 -alkyl, COO-alkyl, NH 2 , OH, or CN;
X 1 has the formula —O—(CH 2 ) n —O—, wherein n is 1 or 2, and one of the oxygens is bonded at the 5′-position of the aryl ring and the other at the 4′-position of the aryl ring; and
the compound comprises a radiolabeled atom.

2. The compound of claim 1 , wherein the radiolabeled atom is radiolabeled iodine as X 2 .

3. The compound of claim 2 , wherein the radiolabeled iodine is 124 I.

4. The compound of claim 2 , wherein the radiolabeled iodine is 131 I or 123 I.

5. The compound of claim 1 , wherein the radiolabeled atom is 18 F present at position X 4 or at position X 2 as a fluorine substituent or a part of a fluorinated substituent.

6. The compound of claim 1 , wherein the n of the formula —O—(CH 2 ) n —O— is 1.

7. The compound of claim 1 , wherein the n of the formula —O—(CH 2 ) n —O is 2.

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

9. The compound of claim 1 , wherein X 3 is S.

10. The compound of claim 1 , wherein X 3 is CH 2 .

11. The compound of claim 1 , wherein R is

12. The compound of claim 1 , wherein R is

13. The compound of claim 2 , wherein R is

14. The compound of claim 2 , wherein R is

15. The compound of claim 5 , wherein R is

16. The compound of claim 5 , wherein R is

17. The compound of claim 6 , wherein R is

18. The compound of claim 6 , wherein R is

19. The compound of claim 7 , wherein R is

20. The compound of claim 7 , wherein R is

21. The compound of claim 8 , wherein R is

22. The compound of claim 8 , wherein R is

23. The compound of claim 9 , wherein R is

24. The compound of claim 9 , wherein R is

25. The compound of claim 10 , wherein R is

26. The compound of claim 10 , wherein R is

27. The compound of claim 1 , wherein X 4 is halogen.

28. The compound of claim 27 , wherein R is

29. The compound of claim 27 , wherein R is

Assignees

• Memorial Sloan Kettering Cancer Center

Inventors

• Chiosis Gabriela
• He Huazhong
• Llauger-Bufi Laura
• Kim Joungnam
• Larson Steve M
• Smith-Jones Peter

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• C07D473/34 Primary

  attached in position 6, e.g. adenine · CPC title

• C07D491/056

  with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring · CPC title

• G01N33/60

  involving radioactive labelled substances · CPC title