Heat shock protein 90 inhibitors

Patent metadata

Field	Value
Publication number	US-11479528-B2
Application number	US-201816496355-A
Country	US
Kind code	B2
Filing date	Mar 20, 2018
Priority date	Mar 20, 2017
Publication date	Oct 25, 2022
Grant date	Oct 25, 2022

Abstract

This disclosure is related to aromatic compounds of formula (I), and methods of their use in treating medical conditions associated with Heat Shock Protein-90 (HSP90), e.g., cancer. Compounds of formula (I) have the following structure:Also disclosed are pharmaceutical compositions comprising compounds of formula (I).

First claim

What is claimed is:

1. A compound of formula (I):

wherein
X is CO;
Y is N;
Z is phenyl, and R 5 is CF 3 , CN, NO 2 , NR 6 R 7 , —NHCO(CH 2 ) n CONHOH, —CONH(CH 2 ) n CONHOH, CONHOH, CO 2 NH 2 , C 1-6 alkoxyl, C 3-10 cycloalkyl, aryl, or heteroaryl; or
Z is selected from

and R 5 is H, halogen, CF 3 , CN, NO 2 , NR 6 R 7 , —NHCO(CH 2 ) n CONHOH, —CONH(CH 2 ) n CONHOH, CONHOH, CO 2 NH 2 , CH 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, aryl, or heteroaryl;
each of R 1 and R 2 , independently, is OH or NH 2 ;
R 3 is C 1-6 alkyl or halogen; and
R 4 is C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkylamine, or C 1-6 alkyl alcohol;
in which each of R 6 and R 7 , independently, is H, C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, aryl, or heteroaryl; or R 6 , together with R 7 and the nitrogen atom bonded to R 6 and R 7 , is C 3-10 heterocycloalkyl; or R 6 , together with Z and the nitrogen atom bonded to R 6 and R 7 , forms a fused bicycle; and
n is 5 to 7.

2. The compound of claim 1 , wherein each of R 1 and R 2 is OH and R 3 is isopropyl.

3. The compound of claim 1 , wherein Z is phenyl and R 5 is —NHCO(CH 2 ) n CONHOH or —CONH(CH 2 ) n CONHOH, or Z is

4. The compound of claim 1 , wherein Z is selected from

5. The compound of claim 3 , wherein Z is phenyl and R 5 is —NHCO(CH 2 ) n CONHOH or —CONH(CH 2 ) n CONHOH.

6. The compound of claim 3 , wherein Z is

and R 7 is C 1-6 alkyl.

7. The compound of claim 4 , wherein Z is

8. The compound of claim 7 , wherein Z is

and R 4 is C 1-6 alkyl.

9. The compound of claim 8 , wherein the compound is one of the following compounds:

10. The compound of claim 1 , wherein Z is selected from

11. The compound of claim 10 , wherein Z is

12. The compound of claim 11 , wherein Z is

and R 4 is C 1-6 alkyl.

13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

14. A method of treating breast cancer, non-small cell lung cancer, gastric cancer, lymphoma, or multiple myeloma, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (I):

wherein
X is CO;
Y is N;
Z is phenyl, and R 5 is CF 3 , CN, NO 2 , NR 6 R 7 , —NHCO(CH 2 ) n CONHOH, —CONH(CH 2 ) n CONHOH, CONHOH, CO 2 NH 2 , C 1-6 alkoxyl, C 3-10 cycloalkyl, aryl, or heteroaryl; or
Z is selected from

and R 5 is H, halogen, CF 3 , CN, NO 2 , NR 6 R 7 , —NHCO(CH 2 ) n CONHOH, —CONH(CH 2 ) n CONHOH, CONHOH, CO 2 NH 2 , CH 2 NR 6 R 7 , C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, aryl, or heteroaryl;
each of R 1 and R 2 , independently, is OH or NH 2 ;
R 3 is C 1-6 alkyl or halogen; and
R 4 is C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkylamine, or C 1-6 alkylalcohol;
in which each of R 6 and R 7 , independently, is H, C 1-6 alkyl, C 1-6 alkoxyl, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, aryl, or heteroaryl; or R 6 , together with R 7 and the nitrogen atom bonded to R 6 and R 7 , is C 3-10 heterocycloalkyl; or R 6 , together with Z and the nitrogen atom bonded to R 6 and R 7 , forms a fused bicycle; and n is 5 to 7.

15. The method of claim 14 , wherein each of R 1 and R 2 is OH, and R 3 is isopropyl.

16. The method of claim 15 , wherein Z is heteroaryl selected from the group consisting of

17. The method of claim 16 , wherein the compound is one of the following compounds:

18. The method of claim 17 , wherein the compound is

19. The method of claim 14 , wherein the compound is administered orally.

Assignees

• Univ Taipei Medical

Inventors

• Liou Jing-Ping
• Teng Che-Ming
• Pan Shiow-Lin

Classifications

• C07D215/38

  Nitrogen atoms (nitro radicals C07D215/18) · CPC title

• C07D231/40

  Acylated on said nitrogen atom · CPC title

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07D213/75 Primary

  Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates · CPC title

• C07C49/835

  having unsaturation outside an aromatic ring · CPC title