Benzothiophene derivative regulator, preparation method therefor and use thereof

Patent metadata

Field	Value
Publication number	US-12459931-B2
Application number	US-202017755711-A
Country	US
Kind code	B2
Filing date	Nov 5, 2020
Priority date	Nov 5, 2019
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

Abstract

A nitrogen-containing ring derivative regulator, a preparation method therefor and use thereof. In particular, the present invention relates to a compound as represented by general formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and use thereof as a G protein-coupled receptor regulator in the treatment or prevention of central nervous system diseases and/or mental diseases.

First claim

What is claimed is:

1 . A compound of formula (IV-A), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:

wherein:
is selected from the group consisting of single bond and a double bond;
R 2 is selected from the group consisting of hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl;
or, two R 2 on the same or different carbon atoms are bonded to form a C 3-8 cycloalkyl or 3 to 8 membered heterocyclyl, wherein the C 3-8 cycloalkyl or 3 to 8 membered heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of deuterium, C 1-6 alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3-8 alkoxy, C 3-8 haloalkoxy and C 3-8 hydroxyalkyl;
R 3 is selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, hydroxy, cyano, C 2-6 alkenyl and C 2-6 alkynyl;
R 4 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R 5 is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl, 5 to 14 membered heteroaryl, —(CH 2 ) n1 R aa , —C(O)R aa , —C(O)NR aa R bb , —C(O)(CH 2 ) n1 R aa , —C(O)NR aa (CH 2 ) n1 R bb , —S(O) 2 R aa , —(CH 2 ) n1 S(O)(═NR aa )R bb , —S(O) m1 NR aa R bb and —C(O)OR aa , wherein the C 1-6 alkyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl and 5 to 14 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of cyano, halogen, C 1-6 alkyl and C 1-6 alkoxy;
or, R 4 and R 5 are bonded to form a 3 to 8 membered heterocyclyl or 5 to 14 membered heteroaryl, which is optionally further substituted by one or more substituents selected from the group consisting of C 1-6 alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3-8 alkoxy, C 3-8 haloalkoxy, C 3-8 hydroxyalkyl, —C(O)R cc and —C(O)NR cc R dd ;
R aa and R bb are each independently selected from the group consisting of hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl and 5 to 14 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl and 5 to 14 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl and 5 to 14 membered heteroaryl;
or, R aa and R bb together with the adjacent nitrogen atom are bonded to form a 4 to 10 membered heterocyclyl, which is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 hydroxyalkyl;
R cc and R dd are each independently selected from the group consisting of hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl and 5 to 14 membered heteroaryl, wherein the amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl and 5 to 14 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 alkoxy;
y is 0, 1, 2, 3 or 4;
z is 0, 1, 2, 3 or 4;
m is 1 or 2; and
n1 is 0, 1, 2 or 3;

wherein the compound of formula (IV-A) does not comprise compounds

2 . The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound is further shown as formula (IX-B):

R 2 is selected from the group consisting of hydrogen, cyano, halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 3-6 cycloalkyl;
R 3 is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 haloalkoxy;
R 3 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R 4 is selected from the group consisting of hydrogen and C 1-6 alkyl;
R 5 is selected from the group consisting of C 1-6 alkyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl, 5 to 14 membered heteroaryl, —(CH 2 ) n1 R aa , —C(O)R aa , —C(O)NR aa R bb , —C(O)(CH 2 ) n1 R aa , —C(O)NR aa (CH 2 ) n1 R bb , —S(O) 2 R aa , —(CH 2 ) n1 S(O)(═NR aa )R bb , —S(O) m1 NR aa R bb and —C(O)OR aa , wherein the C 1-6 alkyl, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl and 5 to 14 membered heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of cyano, halogen, C 1-6 alkyl and C 1-6 alkoxy;
or, R 4 and R 5 are bonded to form a 3 to 8 membered heterocyclyl or 5 to 10 membered heteroaryl, which is optionally further substituted by one or more substituents selected from the group consisting of C 1-6 alkyl, halogen, amino, oxo, thioxo, cyano, hydroxy, C 3-8 alkoxy, C 3-8 haloalkoxy and C 3-8 hydroxyalkyl,
R aa and R bb are each independently selected from the group consisting of hydrogen, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl and 5 to 10 membered heteroaryl containing 1 to 2 heteroatom selected from the group consisting of N, O and S, which are each optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-8 cycloalkyl, 3 to 8 membered heterocyclyl, C 6-14 aryl and 5 to 14 membered heteroaryl;
or, R aa and R bb together with the adjacent nitrogen atom are bonded to form a 4 to 6 membered heterocyclyl, which is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy and C 1-6 hydroxyalkyl.

3 . The compound, a stereoisomer thereof or a pharmaceutically acceptable salt thereof according to claim 1 , wherein
R 2 is selected from the group consisting of hydrogen, cyano, halogen, C 1-3 alkyl, C 1-3 haloalkyl and C 3-6 cycloalkyl; R 3 is selected from the group consisting of hydrogen, halogen and C 1-3 alkyl, R 4 is selected from the group consisting of hydrogen and C 1-3 alkyl; R 5 is selected from the group consisting of —(CH 2 ) n1 R aa , —C(O)R aa , —C(O)NR aa R bb , —S(O) 2 R aa and —S(O) m1 NR aa R bb ; R aa and R bb are each independently selected from the group consisting of hydrogen, amino, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy, C 3-6 cycloalkyl and 5 to 6 membered heteroaryl containing 1 to 2 heteroatom selected from the group consisting of N, O and S, which are each optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, cyano, oxo, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 alkoxy and C 3-6 cycloalkyl; or, R aa and R bb together with the adjacent nitrogen atom are bonded to form a 4 to 6 membered nitrogen-containing heterocyclyl, which is optionally further substituted by one or more substituents selected from the group consisting of halogen, hydroxy, C 1-3 alkyl, C 1-3 haloalkyl

Assignees

• Shanghai Hansoh Biomedical Co Ltd
• Jiangsu Hansoh Pharmaceutical Group Co Ltd

Inventors

• Su Yidong
• Li Song
• Chen Xiaopo
• Wang Jun

Classifications

• C07D413/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D409/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · CPC title