Heterocyclic compounds, process for preparation of the same and use thereof

Patent metadata

Field	Value
Publication number	US-10174011-B2
Application number	US-201515124264-A
Country	US
Kind code	B2
Filing date	Mar 9, 2015
Priority date	Mar 7, 2014
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

The present invention provides a heterocyclic compound represented by the formula (I), its stereoisomers, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions thereof, and their use in preparing a medicament for the prevention and/or treatment of central nervous system disease.

First claim

The invention claimed is:

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

wherein,
A is C, B and D and are each independently C or N;
represents a single or double bond;
E is CH, N or C; when E is CH or N, the bond connected to E represents a single bond; and when E is C, the bond connected to E represents a double bond;
R 1 is hydrogen or 1 to 4 substituents each independently selected from the group consisting of halogen, hydroxy, mercapto, oxo(═O), thioxo(═S), C1-C6 alkoxy, halogenated C1˜C6 alkoxy, C1˜C6 alkylthio, C1˜C6 alkyl, halogenated C1˜C6 alkyl, nitro, amino, C1˜C6 alkyl-substituted amino, cyano, carboxyl, aldehyde group, amino C1˜C6 alkyl, hydroxyl C1˜C6 alkyl, cyano C1˜C6 alkyl, C1˜C6 alkanoyl, halogenated C1˜C6 alkanoyl, sulfonic group(—SO 2 OH), aminosulfonyl(—SO 2 NH 2 ), carbamoyl(—CONH 2 ), C1˜C6 alkyl-substituted carbamoyl, carboxyl C1˜C6 alkyl, C1˜C6 alkylsulfonyl, halogenated C1˜C6 alkylsulfonyl, C1˜C6 alkyl-substituted amino C1˜C6 alkyl, carbamoyl C1˜C6 alkyl and C1˜C6 alkyl-substituted carbamoyl C1˜C6 alkyl;
R 2 does not exist, or is 1 to 3 substituents each independently selected from the group consisting of halogen, hydroxy, mercapto, C1˜C6 alkoxy, halogenated C1˜C6 alkoxy, C1˜C6 alkylthio, C1˜C6 alkyl, halogenated C1˜C6 alkyl, nitro, amino, C1˜C6 alkyl-substituted amino, cyano, carboxyl, aldehyde group, amino C1˜C6 alkyl, hydroxyl C1˜C6 alkyl, cyano C1˜C6 alkyl, C1˜C6 alkanoyl, halogenated C1˜C6 alkanoyl, sulfonic group(—SO 2 OH), aminosulfonyl(—SO 2 NH 2 ), carbamoyl(—CONH 2 ), C1˜C6 alkyl-substituted carbamoyl, carboxy C1˜C6 alkyl, C1˜C6 alkylsulfonyl, halogenated C1˜C6 alkylsulfonyl, C1˜C6 alkyl-substituted amino C1˜C6 alkyl, carbamoyl C1˜C6 alkyl and C1˜C6 alkyl-substituted carbamoyl C1˜C6 alkyl;
R 3 is hydrogen or 1 to 4 substituents each independently selected from the group consisting of hydroxyl and C1˜C6 alkyl;
L does not exist or is C1˜C5 alkylene;
ring G is a heteromonocyclic or heterobicyclic group, wherein the heterobicyclic group is a phenyl-fused heteromonocyclic group, a cyclohydrocarbyl-fused heteromonocyclic group or a heteromonocycle-fused heteromonocyclic group, wherein the heteromonocyclic group contains at least one heteroatom selected from the group consisting of N, S and O;
ring G is connected to L through a carbon atom on ring G; and
ring G is optionally substituted with one or more substituents which are identical or different,
the substituent on the ring G is selected from the group consisting of halogen, C1˜C6 alkyl, halogenated C1˜C6 alkyl, C1˜C6 alkoxy, halogenated C1˜C6 alkoxy, nitro, cyano, hydroxy, mercapto, amino, C1˜C6 alkyl-substituted amino, azido, C1˜C6 alkanoyl, halogenated C1˜C6 alkanoyl, C2˜C6 alkenyl, C2˜C6 alkynyl, carboxy C1˜C6 alkyl, cyano C1˜C6 alkyl, C2˜C6 alkenyloxy, C2˜C6 alkynyloxy, carbamoyl(—CONH 2 ), C1˜C6 alkyl-substituted carbamoyl, carboxyl, hydroxyl C1˜C6 alkyl, oxo(═O), thioxo(═S), aminosulfonyl(—SO 2 NH 2 ), C1˜C6 alkylthio, C1˜C6 alkylsulfonyl, halogenated C1˜C6 alkylsulfonyl, sulfonic group(—SO 2 OH), aldehyde group, amino C1˜C6 alkyl, C1˜C6 alkyl-substituted amino C1˜C6 alkyl, carbamoyl C1˜C6 alkyl, C1˜C6 alkyl-substituted carbamoyl C1˜C6 alkyl, C3˜C10 cyclohydrocarbyl, C3˜C10 cyclohydrocarbyl C1˜C6 alkyl, C3˜C10 cyclohydrocarbylformamido, furanyl, thienyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, triazolyl, triazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, pyranyl, pyrazinyl, piperazinyl, pyridazinyl, pyridyl, piperidinyl, pyrimidinyl, imidazolyl, C3˜C10 cyclohydrocarbyl C1˜C6 alkoxy, furanyl C1˜C6 alkyl, furanyl C1˜C6 alkoxy, thienyl C1˜C6 alkyl, thienyl C1˜C6 alkoxy, pyrrolyl C1˜C6 alkyl, pyrrolyl C1˜C6 alkoxy, pyrrolidinyl C1˜C6 alkyl, pyrrolidinyl C1˜C6 alkoxy, pyrazolyl C1˜C6 alkyl, pyrazolyl C1˜C6 alkoxy, triazolyl C1˜C6 alkyl, triazolyl C1˜C6 alkoxy, thiazolyl C1˜C6 alkyl, thiazolyl C1˜C6 alkoxy, isothiazolyl C1˜C6 alkyl, isothiazolyl C1˜C6 alkoxy, oxazolyl C1˜C6 alkyl, oxazolyl C1˜C6 alkoxy, isoxazolyl C1˜C6 alkyl, isoxazolyl C1˜C6 alkoxy, pyrazinyl C1˜C6 alkyl, pyrazinyl C1˜C6 alkoxy, pyridazinyl C1˜C6 alkyl, pyridazinyl C1˜C6 alkoxy, pyridyl C1˜C6 alkyl, pyridyl C1˜C6 alkoxy, pyrimidinyl C1˜C6 alkyl, pyrimidinyl C1˜C6 alkoxy, phenyl, phenoxy, phenylsulfonyl, phenyl C1˜C6 alkyl, phenyl C1˜C6 alkoxy, phenyl C1˜C6 alkanoyl, and phenyl C1˜C6 alkanoyloxy; said C3˜C10 cyclohydrocarbyl, C3˜C10 cyclohydrocarbyl C1˜C6 alkyl, furanyl, thienyl, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, triazolyl, triazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, pyranyl, pyrazinyl, piperazinyl, pyridazinyl, pyridyl, piperidinyl, pyrimidinyl, imidazolyl, C3˜C10 cyclohydrocarbyl C1˜C6 alkoxy, furanyl C1˜C6 alkyl, furanyl C1˜C6 alkoxy, thienyl C1˜C6 alkyl, thienyl C1˜C6 alkoxy, pyrrolyl C1˜C6 alkyl, pyrrolyl C1˜C6 alkoxy, pyrrolidinyl C1˜C6 alkyl, pyrrolidinyl C1˜C6alkoxy, pyrazolyl C1 ˜C6 alkyl, pyrazolyl C1˜C6 alkoxy, triazolyl C1˜C6 alkyl, triazolyl C1˜C6 alkoxy, thiazolyl C1˜C6 alkyl, thiazolyl C1˜C6 alkoxy, isothiazolyl C1˜C6 alkyl, isothiazolyl C1˜C6 alkoxy, oxazolyl C1˜C6 alkyl, oxazolyl C1˜C6 alkoxy, isoxazolyl C1˜C6 alkyl, isoxazolyl C1˜C6 alkoxy, pyrazinyl C1˜C6 alkyl, pyrazinyl C1˜C6 alkoxy, pyridazinyl C1˜C6 alkyl, pyridazinyl C1˜C6 alkoxy, pyridyl C1˜C6 alkyl, pyridyl C1˜C6 alkoxy, pyrimidinyl C1˜C6 alkyl, pyrimidinyl C1˜C6 alkoxy, phenyl, phenoxy, phenylsulfonyl, phenyl C1˜C6alkyl, phenyl C1˜C6alkoxy, phenyl C1˜C6alkanoyl and phenyl C1˜C6alkanoyloxy are optionally substituted with one or more substituents selected from the group consisting of halogen, C1˜C6 alkyl, halogenated C1˜C6 alkyl, C1˜C6 alkoxy, C1˜C6 alkoxycarbonyl, halogenated C1˜C6 alkoxy, nitro, cyano, hydroxy, amino, C1˜C6alkanoyl, halogenated C1˜C6alkanoyl, carbamoyl, and carboxyl;
provided that the following compounds are excluded:
1-(2-(4-(2-cyano-7-fluorobenzo[b]thiophen-4-yl)-2-methylpiperazin- 1-yl)ethyl)isochroman-6-carboxamide; and
1-(2-(4-(7-fluorobenzo[b]thiophen-4-yl)-2-methylpiperazin-1-yl)ethyl)isochroman-6-carboxamide.

2. The heterocyclic compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1 , wherein ring G is a 3- to 10-membered heteromonocyclic group, a phenyl-fused 3- to 10-membered heteromonocyclic group, a C3˜C10 cyclohydrocarbyl-fused 3- to 10-membered heteromonocyclic group or a 3- to 10-membered heteromonocycle-fused 3- to 10-membered heteromonocyclic group.

3. The heterocyclic compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 2 , wherein ring G is a 5- b 4 to 7-membered heteromonocyclic group, a phenyl-fused 5- to 7-membered heteromonocyclic group, a C5-C7 cyclohydrocarbyl-fused 5- to 7-membered heteromonocyclic group or a 5- to 7-membered heteromonocycle-fused 5- to 7-membered heteromonocyclic group.

4. The heterocyclic compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 3 , wherein ring G is a heterocyclic group selected from the group consisting of furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, dihydrothienyl, tetrahydrothienyl, pyrrolyl, dihydro-pyrrolyl, pyrrolidinyl, pyrazolyl, dihydro-pyrazolyl, pyrazolidinyl, triazolyl, dihydrotriazole, triazolidinyl, thiazolyl, dihydro-thiazolyl, thiazolidinyl, isothiazolyl, dihydro-isothiazolyl, isothiazolidinyl, oxazolyl, dihydro-oxazolyl, oxazolidinyl, isoxazolyl, dihydro-isoxazolyl, isoxazolidinyl, pyranyl, dihydro-pyranyl, tetrahydropyranyl, pyrazinyl, dihydro-pyrazinyl, tetrahydro-pyrazinyl, piperazinyl, pyridazinyl, dihydro-pyridazinyl, tetrahydro-pyridazinyl,

Assignees

• Shanghai Inst Materia Medica Cas
• Suzhou Vigonvita Life Sciences Co Ltd
• Topharman Shandong Co Ltd

Inventors

• Jiang Hualiang
• Wang Zhen
• Li Jianfeng
• Zhang Rongxia
• He Yang
• Liu Yongjian
• Bi Minghao
• Liu Zheng
• Tian Guanghui
• Chen Weiming
• Yang Feipu
• Wu Chunhui
• Wang Yu
• Jiang Xiangrui
• Yin Jingjing
• Wang Guan
• Shen Jingshan

Classifications

• A61P43/00

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

• A61P25/24

  Antidepressants · CPC title

• A61P25/22

  Anxiolytics · CPC title

• A61P25/20

  Hypnotics; Sedatives · CPC title