Fused tetracyclic compounds and uses thereof in medicine

Patent metadata

Field	Value
Publication number	US-11447498-B2
Application number	US-201917276735-A
Country	US
Kind code	B2
Filing date	Sep 27, 2019
Priority date	Sep 30, 2018
Publication date	Sep 20, 2022
Grant date	Sep 20, 2022

Abstract

A fused tetracyclic compound and application thereof in medicine, especially as a medicament for the treatment and/or prevention of hepatitis B. A compound having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, in medicine, especially as a medicament for the treatment and/or prevention of hepatitis B, wherein each variable is as defined in the specification.

First claim

What is claimed is:

1. A compound having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein R 1 is R 1a O— or R a R b N—;
X is CR 7 or N;
ring A is a heterocyclyl consisting of 5 ring atoms, a heterocyclyl consisting of 6 ring atoms or a carbocyclyl consisting of 5 to 6 carbon atoms;
R 3 is hydrogen, deuterium, F, Cl, Br, hydroxy, cyano, C 1-6 alkyl, C 2-6 alkynyl, C 3-7 cycloalkyl, heterocyclyl consisting of 3 to 10 ring atoms, C 6-10 aryl, heteroaryl of 5 to 10 ring atoms or R 10 —C 0-4 alkylene-O—, wherein each of C 1-6 alkyl, C 2-6 alkynyl, C 3-7 cycloalkyl, heterocyclyl consisting of 3 to 10 ring atoms, C 6-10 aryl, heteroaryl of 5 to 10 ring atoms and —C 0-4 alkylene- of R 10 —C 0-4 alkylene-O— is independently unsubstituted or substituted by 1, 2, 3 or 4 R g ;
R 10 is deuterium, R 11 O—, C 1-6 alkyl, C 3-7 cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, C 6-10 aryl or heteroaryl consisting of 5 to 10 ring atoms, wherein each of C 1-6 alkyl, C 3-7 cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, C 6-10 aryl and heteroaryl consisting of 5 to 10 ring atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 R j ;
each R j and R g is independently deuterium, F, Cl, Br, CN, ═O, HO—, HOOC—, R 11 O—, R 12 —S(═O) 2 —, R 13 -(C═O)—, R 14 13 S(═O) 2 —O—, R 15 13 S(═O) 2 —N(R c )-, R 16 —N(R c )—S(═O) 2 —, R 17 -(C═O)—N(R c )—S(═O) 2 —, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, heterocyclyl consisting of 3 to 10 ring atoms, C 6-10 aryl or heteroaryl consisting of 5 to 10 ring atoms, wherein each of amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, heterocyclyl consisting of 3 to 10 ring atoms, C 6-10 aryl and heteroaryl consisting of 5 to 10 ring atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 R w ;
each R 11 , R 12 , R 12a , R 13 , R 13a , R 14 , R 15 , R 16 and R 17 is independently hydrogen, deuterium, R a R b N—, C 1-6 alkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, C 6-10 aryl, C 6-10 aryl C 1-3 alkylene or heteroaryl consisting of 5 to 10 ring atoms, wherein each of C 1-6 alkyl, C 2-6 alkynyl, C 3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, C 6-10 aryl, C 6-10 aryl C 1-3 alkylene and heteroaryl consisting of 5 to 10 ring atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, HO—, ═O, HOOC—, R a R b N—S(═O) 2 —, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, heteroaryl consisting of 5 to 6 ring atoms, heterocyclyl of 3 to 6 ring atoms, C 1-6 alkoxy C 1-4 alkylene or C 1-4 alkylamino C 1-4 alkylene;
each R w is independently deuterium, F, Cl, Br, HO—, HOOC—, ═O, amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, tert-butoxycarbonyl, C 1-6 alkyl-S(═O) 2 —, C 3-6 cycloalkyl-S(═O) 2 — or C 3-7 cycloalkyl, wherein each of amino, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, tert-butoxycarbonyl, C 1-6 alkyl-S(═O) 2 —, C 3-6 cycloalkyl-S(═O) 2 — and C 3-7 cycloalkyl is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from F, Cl, Br, CN, OH, ═O, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy or C 1-6 alkylamino;
each of R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is independently hydrogen, deuterium, F, Cl, Br, R 12a 13 S(═O) 2 —, R 13a -(C═O)—, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl, phenyl, heteroaryl consisting of 5 to 6 ring atoms or heterocyclyl consisting of 3 to 10 ring atoms, wherein each of C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl, phenyl, heteroaryl consisting of 5 to 6 ring atoms and heterocyclyl consisting of 3 to 10 ring atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 R w ;
or R 6 and R 4 , together with the atom to which they are attached, form a carbocyclyl consisting of 5 to 6 ring atoms or a heterocyclyl consisting of 5 to 6 ring atoms, wherein each of carbocyclyl consisting of 5 to 6 ring atoms and heterocyclyl consisting of 5 to 6 ring atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 R w ;
each R 2 is independently hydrogen, deuterium, F, Cl, Br, ═O, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl, phenyl or heterocyclyl consisting of 3 to 6 ring atoms, wherein each of C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl, phenyl and heterocyclyl consisting of 3 to 6 ring atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 R w ;
or two R 2 linked to the same carbon atom, together with the carbon atom to which they are attached, form a C 3-6 cycloalkyl or —(C═O)—, wherein C 3-6 cycloalkyl is unsubstituted or substituted by 1, 2, 3, or 4 R w ;
each R 1a , R a , R b and R c is independently hydrogen, deuterium, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclyl consisting of 3 to 6 ring atoms or heteroaryl consisting of 5 to 10 ring atoms, wherein each of C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, heterocyclyl consisting of 3 to 6 ring atoms and heteroaryl consisting of 5 to 10 ring atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents selected from F, Cl, Br, CN, HO—, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
n is 0, 1, 2, 3, 4, or 5.

2. The compound of claim 1 having Formula (II):

wherein X 1 is —O—, —NH—, —S—, —CH 2 —O—, —O—CH 2 —, —CH 2 — or —CH 2 —CH 2 —.

3. The compound of claim 1 , wherein R 3 is hydrogen, deuterium, F, Cl, Br, hydroxy, cyano, C 1-4 alkyl, C 2-4 alkynyl, C 3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, phenyl, heteroaryl consisting of 5 ring atoms, heteroaryl consisting of 6 ring atoms or R 10 —C 0-3 alkylene-O—, wherein each of C 1-4 alkyl, C 2-4 alkynyl, C 3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, phenyl, heteroaryl consisting of 5 ring atoms, heteroaryl consisting of 6 ring atoms and —C 0-3 alkylene- of R 10 —C 0-3 alkylene-O— is independently unsubstituted or substituted by 1, 2, 3 or 4 R g ;
R 10 is deuterium, R 11 O—, C 1-4 alkyl, C 3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, phenyl, heteroaryl consisting of 5 ring atoms or heteroaryl consisting of 6 ring atoms, wherein each of C 1-4 alkyl, C 3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 ring atoms, phenyl, heteroaryl consisting of 5 ring atoms and heteroaryl consisting of 6 ring atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 R j .

4. The compound of claim 1 , wherein R 3 is hydrogen, deuterium, F, Cl, Br, hydroxy, cyano, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, ethynyl, propargyl, propynyl, but-1-yne-4-yl, but-2-yne-1-yl, but-1-yne-1-yl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, oxe

Assignees

• Sunshine Lake Pharma Co Ltd

Inventors

• Huang Jianzhou
• Ren Qingyun
• Xiong Jinfeng
• Liu Yang
• Zhang Yingjun

Classifications

• C07D491/147 Primary

  the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom · CPC title

• A61P31/12

  Antivirals · CPC title

• A61P1/16 Primary

  for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• C07D491/22

  in which the condensed system contains four or more hetero rings · CPC title