Piperidine derivative and preparation method and pharmaceutical use thereof

Patent metadata

Field	Value
Publication number	US-10087191-B2
Application number	US-201615736898-A
Country	US
Kind code	B2
Filing date	May 27, 2016
Priority date	Jun 16, 2015
Publication date	Oct 2, 2018
Grant date	Oct 2, 2018

Abstract

The present invention relates to a piperidine derivative and the preparation method and a pharmaceutical use thereof. In particular, the present invention relates to the piperidine derivative as shown by general formula (I) and the preparation method thereof and a pharmaceutical composition containing the same, and the use thereof as an estrogen receptor modulator in the treatment of estrogen receptor mediated or dependent diseases or conditions, the diseases preferably being breast cancer. In the abstract, the definition of each substituent of the general formula (I) is the same as that in the description.

First claim

What is claimed is:

1. A compound of formula (I):

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
ring A is selected from the group consisting of:

R is selected from the group consisting of hydrogen, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted by one or more groups selected from the group consisting of halogen, amino, cyano, hydroxy, alkoxy, carboxy, cycloalkyl, aryl and heteroaryl;
each R 1 is identical or different and each is independently selected from the group consisting of hydrogen, alkyl, halogen, cyano and alkoxy, wherein the alkyl and alkoxy are each optionally substituted by one or more groups selected from the group consisting of halogen, amino, cyano and hydroxy;
R 2 is selected from the group consisting of alkyl, haloalkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted by one or more groups selected from the group consisting of halogen, amino, cyano, hydroxy, alkoxy, carboxy, cycloalkyl, aryl and heteroaryl;
R 3 is selected from the group consisting of hydrogen, alkyl and cycloalkyl, wherein the alkyl and cycloalkyl are each optionally substituted by one or more groups selected from the group consisting of alkyl, halogen, amino, cyano, hydroxy, alkoxy, carboxy and cycloalkyl;
each R 4 is identical or different and each is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkoxy, amino, halogen, cyano, carboxy, alkenyl, alkynyl, heterocyclyl, aryl, heteroaryl, —OR 5 , —NHC(O)OR 5 and —NHC(O)NR 6 R 7 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, alkoxy, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of R c , alkyl, haloalkyl, hydroxyalkyl, halogen, amino, nitro, cyano, hydroxy, oxo, hydroxyalkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R c is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 5 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and —C(O)NR 6 R 7 ;
R 6 and R 7 are identical or different and each is independently selected from the group consisting of hydrogen, alkyl, hydroxy, halogen, cyano, amino, nitro, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R a and R b are identical or different and each is independently selected from the group consisting of hydrogen, alkyl, hydroxy, halogen, cyano, amino, nitro, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, —OR 5 , aryl and heteroaryl;
m is 0, 1, 2, 3 or 4; and
n is 0, 1, 2, 3 or 4.

2. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein ring A is selected from the group consisting of:

wherein:
R 4 , R a , R b and m are as defined in claim 1 .

3. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein n is 2.

4. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is halogen.

5. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is alkyl, and the alkyl is optionally substituted by one or more groups selected from the group consisting of halogen, amino, cyano, hydroxy, alkoxy, carboxy and cycloalkyl.

6. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is alkyl.

7. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , wherein R is hydrogen or alkyl.

8. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , being selected from the group consisting of a compound of formula (I-A), formula (I-B) and formula (I-C):

or a tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein:
ring B is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl;
R d is selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, oxo, amino, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R f is selected from the group consisting of hydrogen, alkyl, halogen, haloalkyl, hydroxyalkyl, hydroxyalkyl, amino, cyano, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substituted by one or more groups selected from the group consisting of alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; and
R to R 5 , m and n are as defined in claim 1 .

9. The compound of formula (I), or the tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or the pharmaceutically acceptable salt thereof according to claim 1 , being selected from the group consisting of a compound of formula (II), formula (III) and formula (IV):

Assignees

• Jiangsu Hengrui Medicine Co
• Shanghai hengrui pharmaceutical co ltd

Inventors

• Yu Shanghai
• Yang Fanglong
• Chen Lei
• Yan Jingjing
• Zhang Xiqian
• Xie Zhichao
• Chen Lingxiang
• He Mingxun

Classifications

• A61P43/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title