Resorcinol derivative as HSP90 inhibitor

Patent metadata

Field	Value
Publication number	US-10035792-B2
Application number	US-201615545598-A
Country	US
Kind code	B2
Filing date	Jan 22, 2016
Priority date	Jan 22, 2015
Publication date	Jul 31, 2018
Grant date	Jul 31, 2018

Abstract

The present invention relates to a compound represented by formula (I) of a resorcinol derivative as an HSP90 inhibitor or pharmaceutically accepted salts thereof. The compound in the present invention has the activity of inhibiting heat shock protein HSP90. Therefore, the compound in the present invention is used to treat proliferative diseases such as cancer and neurodegenerative diseases. The present invention further provides the compounds and preparation methods for pharmaceutical compositions comprising the compounds, a method for treating diseases, and pharmaceutical compositions comprising the compounds.

First claim

What is claimed is:

1. A compound represented by formula (I), or a pharmaceutically acceptable salt thereof,

wherein:
X and Y are each independently selected from N, O or S;
X 1 , X 2 , Y 1 , Y 2 and the carbon atom linking X 1 and X 2 together form a 5- to 7-membered aromatic ring, aliphatic saturated ring or aliphatic unsaturated ring;
X 1 and X 2 are each independently selected from C, O, S, N, —C═C—, —C═N—;
C in X 1 or X 2 may be unsubstituted, or may be substituted with R 01 or R 02 ;
R 01 and R 02 are each independently selected from halogen, CN, OH, SH, NH 2 ,CHO, COOH, C 1-10 alkyl, N—C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkoxy, C 1-10 alkanoyl, C 1-10 alkoxycarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkyl, C 3-10 cycloalkylamino, C 3-10 cycloalkoxy, C 3-10 cycloalkyl acyl, C 3-10 cycloalkoxycarbonyl, C 3-10 cycloalkylsulfonyl, C 3-10 cycloalkylsulfinyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl;
Y 1 and Y 2 are each independently selected from C or N;
two substituents on Y 1 and Y 2 are linked together to form a five-, six- or seven-membered nitrogen-containing saturated ring or aromatic ring having substituents R 1 , R 2 and R 3 ;
R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-10 alkyl, hydroxyl C 1-10 alkyl, C 1-6 alkoxy-C 1-6 alkyl, halo C 1-10 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, C 1-6 alkylamido-C 1-6 alkyl, N,N-di(C 1-6 alkyl)aminoacyl-C 1-6 alkyl, N,N-di(C 1-6 alkyl)amino-C 1-6 alkanoyl, morpholinyl-C 1-6 alkanoyl, N-C 1-10 alkylamino, N,N-di(C 1-10 alkyl)amino, C 1-10 alkoxy, C 1-10 alkanoyl, C 1-10 alkoxycarbonyl, C 1-10 alkylsulfonyl, C 1-10 alkylsulfinyl, C 3-10 cycloalkyl, C 3-10 cycloalkylamino, C 3-10 cycloalkyloxy, C 3-10 cycloalkyl acyl, C 3-10 cycloalkoxycarbonyl, C 3-10 cycloalkylsulfonyl, C 3-10 cycloalkylsulfinyl, C 3-10 cycloalkyl-C 1-5 alkyl;
or substituents of R 2 and R 3 are linked with each other by a covalent bond to form a five-, six- or seven-membered saturated ring with a substituent R 03 or without substituents;
R 03 is selected from C 1-6 alkyl or halogen;
R 4 is selected from H, halogen, C 1-6 alkyl, C 3-10 cycloalkoxy, phenyl substituted C 1-6 alkyl, phenyl substituted C 2-6 alkenyl, phenyl, C 1-6 alkyl substituted phenyl, C 3-6 cycloalkyl;
R 5 is selected from H, cyano, carboxyl, C 1-6 alkoxyacyl, C 1-7 alkylaminocarbonyl, halo C 1-6 alkylaminocarbonyl, C 1-6 alkoxy-C 1-6 alkylaminocarbonyl, N,N-di(C 1-6 alkyl)amino-C 1-6 alkylaminocarbonyl, aminocarbonyl, hydroxy C 1-6 alkylaminocarbonyl, hydroxyl-substituted halo C 1-6 alkyl, nitrile group-substituted amidino, or selected from C 3-10 cycloalkyl, C 3-10 cycloalkenyl, or a 5- to 10-membered aromatic ring optionally substituted with one or more R 05 ;
R 05 is selected from C 1-6 alkyl, C 3-10 cycloalkyl.

2. The compound, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 , R 2 and R 3 are each independently selected from hydrogen, C 1-10 alkyl, hydroxyl C 1-10 alkyl, C 3-10 cycloalkyl, C 1-6 alkoxy-C 1-6 alkyl, halo C 1-10 alkyl, C 1-6 alkylsulfonyl-C 1-6 alkyl, C 1-6 alkylamido-C 1-6 alkyl, N,N-di(C 1-6 alkyl)aminoacyl-C 1-6 alkyl, N,N-di(C 1-6 alkyl)amino-C 1-6 alkanoyl, morpholinyl-C 1-6 alkanoyl, C 3-10 cycloalkyl-C 1-5 alkyl, or the substituents of R 2 and R 3 are linked with each other by a covalent bond to form a five-, six- or seven-membered saturated ring with a substituent R 03 or without substituents.

3. The compound, or the pharmaceutically acceptable salt thereof according to claim 2 , wherein R 1 is selected from hydrogen, C 1-6 alkyl, hydroxyl C 1-6 alkyl, C 3-10 cycloalkyl, C 1-4 alkoxy-C 1-4 alkyl, halo C 1-4 alkyl, C 1-4 alkylsulfonyl-C 1-4 alkyl, C 1-4 alkylamido-C 1-4 alkyl, N,N-di(C 1-4 alkyl)aminoacyl-C 1-4 alkyl, N,N-di(C 1-4 alkyl)amino-C 1-4 alkanoyl, morpholinyl-C 1-4 alkanoyl, C 3-6 cycloalkyl-C 1-5 alkyl; R 2 and R 3 are selected from hydrogen or methyl; or the substituents of R 2 and R 3 are linked with each other by a covalent bond to form a five-, six- or seven-membered saturated ring without substituents.

4. The compound, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 4 is selected from H, C 1-6 alkyl, phenyl substituted C 1-6 alkyl, halogen, C 3-6 cycloalkyl.

5. The compound, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 5 is selected from cyano, C 1-6 alkylaminocarbonyl, halo C 1-4 alkylaminocarbonyl, C 1-4 alkoxy-C 1-4 alkylaminocarbonyl, N,N-di(C 1-4 alkyl)amino-C 1-4 alkylaminocarbonyl, aminocarbonyl, hydroxy C 1-4 alkylaminocarbonyl, hydroxyl-substituted halo C 1-4 alkyl, nitrile group-substituted amidino, or selected from a 5- to 6-membered nitrogen-containing heteroaromatic ring optionally substituted with one or more R 05 ;
wherein R 05 is selected from C 1-6 alkyl.

6. The compound, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 5 is selected from

R 04 is selected from H, C 1-6 alkyl, halo C 1-4 alkyl, C 1-4 alkoxy-C 1-4 alkyl, N,N-di(C 1-4 alkyl)amino-C 1-4 alkyl, hydroxy C 1-4 alkyl.

7. The compound, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the structural unit

is selected from

8. The compound, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the structural unit

is selected from

R 01 and R 02 are each independently selected from H, halogen, C 1-10 alkyl, C 3-10 cycloalkyl, C 1-10 alkyl substituted with C 3-10 cycloalkyl.

9. The compound, or the pharmaceutically acceptable salt thereof according to claim 8 , wherein

is selected from

10. The compound, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the structural unit

is selected from

n 01 and n 02 are selected from 0, 1, 2 or 3, the sum of n 01 and n 02 is 2, 3 or 4, and R 2 and R 3 are not linked to form a ring.

11. The compound, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the structural unit

is selected from

wherein n=1 or 2.

12. The compound, or the pharmaceutically acceptable salt the

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd

Inventors

• Chen Shuhui
• Ding Charles Z
• Yan Xiaobing
• Huang Wei
• Hu Guoping
• Li Jian
• Zhang Xiquan
• Yang Ling
• Xu Hongjiang

Classifications

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P25/28

  for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia · CPC title

• A61P25/16

  Anti-Parkinson drugs · CPC title