Steroid derivative regulators, method for preparing the same, and uses thereof

Patent metadata

Field	Value
Publication number	US-2025051387-A1
Application number	US-202418903464-A
Country	US
Kind code	A1
Filing date	Oct 1, 2024
Priority date	Feb 11, 2018
Publication date	Feb 13, 2025
Grant date	—

Abstract

Steroid derivative regulators, a method for preparing the same, and uses thereof are described. Specifically, a compound of formula (I), a preparation method therefor, a pharmaceutical composition containing the compound, and uses thereof as a regulator the of GABAA receptor for treating depression, convulsion, Parkinson's disease, and nervous system diseases are described, wherein the substituents of the formula (I) are as defined in the description.

First claim

1 .- 26 . (canceled)

27 . A compound of formula (IV), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof:

wherein:
Z is selected from the group consisting of —CR 23 R 24 —, —(CH 2 ) n1 NR 23 — and —CH 2 O—;
ring A is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n1 R 25 , —(CH 2 ) n1 OR 25 , —(CH 2 ) n1 SR 25 , —(CH 2 ) n1 C(O)R 25 , —(CH 2 ) n1 C(O)OR 25 , —(CH 2 ) n1 S(O) m1 R 25 , —(CH 2 ) n1 NR 25 R 26 , —(CH 2 ) n1 C(O)NR 25 R 26 , —(CH 2 ) n1 C(O)NHR 25 , —(CH 2 ) n1 NR 25 C(O)R 26 and —(CH 2 ) n1 NR 25 S(O) m1 R 26 ;
each R a is identical or different and each is selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n1 R 23 , —(CH 2 ) n1 OR 23 , —(CH 2 ) n1 SR 23 , —(CH 2 ) n1 C(O)R 23 , —(CH 2 ) n1 C(O)OR 23 , —(CH 2 ) n1 S(O) m1 R 23 , —(CH 2 ) n1 S(O)(NR 23 )R 24 , —(CH 2 ) n1 NR 23 R 24 , —(CH 2 ) n1 C(O)NR 23 R 24 , —(CH 2 ) n1 NR 23 C(O)R 23 and —(CH 2 ) n1 NR 23 S(O) m1 R 24 , wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n1 R 25 , —(CH 2 ) n1 OR 25 , —(CH 2 ) n1 SR 25 , —(CH 2 ) n1 C(O)R 25 , —(CH 2 ) n1 C(O)OR 25 , —(CH 2 ) n1 S(O) m1 R 25 , —(CH 2 ) n1 NR 25 R 26 , —(CH 2 ) n1 C(O)NR 25 R 26 , —(CH 2 ) n1 C(O)NHR 25 , —(CH 2 ) n1 NR 25 C(O)R 26 and —(CH 2 ) n1 NR 25 S(O) m1 R 26 ;
R 15a is selected from the group consisting of alkyl, haloalkyl, alkoxy, halogen, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n1 R 23 , —(CH 2 ) n1 OR 23 , —(CH 2 ) n1 SR 23 , —(CH 2 ) n1 S(O) m1 R 23 and —(CH 2 ) n1 NR 23 R 24 , wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
R 16a is selected from the group consisting of hydrogen atom, alkyl, haloalkyl, alkoxy, halogen, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n1 R 23 , —(CH 2 ) n1 OR 23 , —(CH 2 ) n1 SR 23 , —(CH 2 ) n1 S(O) m1 R 23 and —(CH 2 ) n1 NR 23 R 24 ;
or, R 15a and R 16a form a cycloalkyl or heterocyclyl, wherein the cycloalkyl or heterocyclyl is optionally further substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, and R 15a and R 16a are not hydrogen at the same time;
R 23 and R 24 are each selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n1 R 25 , —(CH 2 ) n1 OR 25 , —(CH 2 ) n1 SR 25 , —(CH 2 ) n1 C(O)R 25 , —(CH 2 ) n1 C(O)OR 25 , —(CH 2 ) n1 S(O) m1 R 25 , —(CH 2 ) n1 NR 25 R 26 , —(CH 2 ) n1 C(O)NR 25 R 26 , —(CH 2 ) n1 C(O)NHR 25 , —(CH 2 ) n1 NR 25 C(O)R 26 and —(CH 2 ) n1 NR 25 S(O) m1 R 26 ;
R 25 and R 26 are identical or different and are each independently selected from the group consisting of hydrogen atom, deuterium atom, alkyl, deuterated alkyl, haloalkyl, hydroxy, amino, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, halogen, hydroxy, amino, oxo, nitro, cyano, alkenyl, alkynyl, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
x is an integer of 0, 1, 3, 4 or 5;
m 1 is an integer of 0, 1 or 2; and
n 1 is an integer of 0, 1, 2, 3, 4 or 5.

28 . The compound of formula (IV), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 27 , being a compound of formula (IV-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

R 15a is selected from the group consisting of alkyl, haloalkyl, alkoxy, halogen, amino, hydroxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) n1 R 23 , —(CH 2 ) n1 OR 23 , —(CH 2 ) n1 SR 23 , —(CH 2 ) n1 S(O) m1 R 23 and —(CH 2 ) n1 NR 23 R 24 , wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally further substituted by one or more substituents selected from the group consisting of deuterium atom, alkyl, haloalkyl, halogen, amino, oxo, nitro, cyano, hydroxy, alkenyl, alkynyl, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;
ring A, Z, R a , R 23 —R 24 , m 1 , n 1 and x are as defined in claim 27 .

29 . The compound of formula (IV), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 27 , being a compound of formula (V), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:
R 15a , R 16a , R a and x are as defined in claim 27 .

30 . The compound of formula (IV), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 27 , being a compound of formula (V-A), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

wherein:
R 15a , R 16a , R a and x are as defined in claim 27 .

31 . The compound of formula (IV), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 27 , wherein the ring A is selected from the group consisting of:

32 . The compound of formula (IV), the stereoisomer thereof, or the pharmaceutically acceptable salt thereof according to claim 27 , wherein
Z is selected from the group consisting of —CH 2 —, —CH 2 NH—, —CH 2 O—, —NH— and —NHSO 2 —; R a is selected from the group consisting of hydrogen atom, halogen, am

Assignees

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

Inventors

• Su Yidong
• Deng Haining
• Chen Xiaopo
• Bao Rudi
• Zhang Fujun

Classifications

• C07J41/0094

  containing nitrile radicals, including thiocyanide radicals · CPC title

• C07J9/00

  Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane · CPC title

• C07J7/009

  by only one oxygen atom doubly bound · CPC title

• C07J1/00

  Normal steroids containing carbon, hydrogen, halogen or oxygen, not substituted in position 17 beta by a carbon atom, e.g. estrane, androstane · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title