Fused tricyclic compounds and uses thereof in medicine

Patent metadata

Field	Value
Publication number	US-10966970-B2
Application number	US-201816611778-A
Country	US
Kind code	B2
Filing date	Jun 2, 2018
Priority date	Jun 1, 2017
Publication date	Apr 6, 2021
Grant date	Apr 6, 2021

Abstract

A fused tricyclic compound and use thereof as a medicament, in particular as a medicament for the treatment and/or prevention of hepatitis B. Specifically, 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 each variate is as defined in specification. The compound also includes a Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof as a medicament, especially as a medicament for the treatment and/or prevention of hepatitis B.

First claim

What is claimed is:

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

X is N or —CR 6a —;
Y is a single bond, —CH 2 — or —C(═O)—;
Q is a single bond, —O— or —N(R 9 )—;
R 1 is H, deuterium, F, Cl, Br, I, OH, —COOH, 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, R 2 —S(═O) 2 —, R 12 —(CR e R f ) n — or R a R b N—, wherein each of the 5- to 6-membered heterocyclyl, 5- to 6-membered heteroaryl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl and C 3-7 cycloalkyl is independently unsubstituted or substituted with 1, 2, 3 or 4 R v ;
R 9 is H, deuterium, C 1-6 alkyl or C 1-6 haloalkyl; or, R 9 and R 1 , together with the nitrogen atom to which they are attached, form a 3- to 12-membered heterocyclyl, wherein each of the C 1-6 alkyl, C 1-6 haloalkyl and 3- to 12-membered heterocyclyl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents selected from —COOH, ═O, tetrazolyl or C 1-6 alkyl-O—C(═O)—;
each of R 4 and R 5 is independently H, deuterium, C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl or 3- to 12-membered heterocyclyl, wherein each of the C 1-6 alkyl, C 1-6 alkylamino, C 1-6 alkoxy, C 2-6 alkynyl, C 2-6 alkenyl, C 3-7 cycloalkyl and 3- to 12-membered heterocyclyl is independently unsubstituted or substituted with 1, 2, 3 or 4 R 1 ;
R 6 is H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl or Ret-C(═O)—O—(CR e R f ) q —, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R z ;
R 6a is H, deuterium, F, Cl, Br, CN, OH, C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl or R 17 —C(═O)—O—(CR e R f ) q —, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 3-7 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R z ;
R 2 is pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiapyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, furyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, phenyl, or naphthyl, wherein each of the pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiapyranyl, piperidyl, morpholinyl, thiomorpholinyl, piperazinyl, pyrrolyl, pyridyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, 1,3,5-triazinyl, thiazolyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, phenyl and naphthyl is independently unsubstituted or substituted with 1, 2, 3 or 4 R w ;
each of R 3 , R 7 and R 8 is independently H, deuterium, F, Cl, Br, hydroxy, cyano, C 1-12 alkyl, C 3-7 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, R 13 —(CR e R f ) m —, R 13 —(CR e R f ) m —O—, R 13 —C(═O)—(CR e R f ) m —, R 13 —C(═O)—N(R g )—(CR e R f ) m —, R 13 —O—C(═O)—(CR e R f ) m —, R 13 —O—C(═O)—N(R g )—(CR e R f ) m —, R e —C(═O)—(CR e R f ) m —O—C(═O)—,

R 14 —S(═O) 2 —(CR e R f ) m —, R 14 —S(═O) 2 —N(R g )—(CR e R f ) m —, R 14 —S(═O) 2 —N(R g )—C(═O)—, R a R b N—, R c C(═O)—, R a R b NC(═O)—, R d OC(═O)— or R 10 O—, wherein each of the C 1-12 alkyl, C 3-7 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R w ;
R 10 is H, deuterium, C 1-12 alkyl, C 2-12 alkynyl, C 3-7 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl, 5- to 10-membered heteroaryl, R 15 —(CR e R f ) g —, R 15 —O—(CR e R f ) g —, R 15 —C(═O)—(CR e R f ) g —, R 15 O—C(═O)—(CR e R f ) g —, R 15 —O—C(═O)—N(R g )—(CR e R f ) g —, R 16 —S(═O) 2 —(CR e R f ) g — or R 16 —S(═O) 2 —N(R g )—(CR e R f ) g —, wherein each of the C 1-12 alkyl, C 2-12 alkynyl, C 3-7 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R x ;
each R 12 and R 17 is independently C 3-7 cycloalkyl, C 6-10 aryl, C 1-6 alkoxy, amino or C 1-6 alkylamino, wherein each of the C 3-7 cycloalkyl, C 6-10 aryl, C 1-6 alkoxy, amino and C 1-6 alkylamino is independently unsubstituted or substituted with 1, 2, 3 or 4 R j ;
each R 13 , R 14 , R 15 and R 16 is independently C 1-12 alkyl, C 1-12 alkoxy, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl or C 6-10 aryl, wherein each of the C 1-12 alkyl, C 1-12 alkoxy, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl and C 6-10 aryl is independently unsubstituted or substituted with 1, 2, 3 or 4 R h ;
R 13a is methyl, C 2-12 alkyl, C 1-12 alkoxy, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 12-membered heterocyclyl or C 6-10 aryl, wherein each of the methyl and C 6-10 aryl is independently substituted with 1, 2, 3 or 4 R h , and wherein C 2-12 alkyl, C 1-12 alkoxy, C 3-7 cycloalkyl, 5- to 10-membered heteroaryl and 3- to 12-membered heterocyclyl is independently unsubstituted or substituted with 1, 2, 3 or 4 R h ;
each R a , R b , R c , R d , R e , R f , R g , R k , R i , and R m is independently H, deuterium, OH, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 3- to 12-membered heterocyclyl or 5- to 10-membered heteroaryl, wherein each of the C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-6 cycloalkyl, C 6-10 aryl, 3- to 12-membered heterocyclyl and 5- to 10-membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, CN, OH, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
or, R a and R b , together with the nitrogen atom to which they are attached, form a 3- to 8-membered heterocyclyl or 5- to 8-membered heteroaryl, wherein each of the 3- to 8-membered heterocyclyl and 5- to 8-membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, CN, OH, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
each R v , R w , R x , R y , R z , R j and R h is independently F, Cl, Br, CN, OH, —COOH, amino, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxy, C 1-12 haloalkoxy, C 1-12 alkylthio, C 1-12 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl or 5- to 10-membered heteroaryl, wherein each of the amino, C 1-12 alkyl, C 1-12 haloalkyl, C 1-12 alkoxy, C 1-12 haloalkoxy, C 1-12 alkylthio, C 1-12 alkylamino, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, 3- to 12-membered heterocyclyl, C 6-10 aryl and 5- to 10-membered heteroaryl is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from F, Cl, Br, CN, OH, ═O, —COOH, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkylthio, C 1-6 haloalkoxy, C 1-12 alkylamino, C 2-6 alkenyl, C 2-6

Assignees

• Sunshine Lake Pharma Co Ltd
• North & South Brother Pharmacy Investment Co Ltd

Inventors

• Liu Xinchang
• Ren Qingyun
• Huang Jianzhou
• Xiong Zhimin
• Xiong Jinfeng
• Li You
• Liu Yang
• Zou Zhifu
• Yan Guanghua
• Goldmann Siegfried
• Zhang Yingjun

Classifications

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/4375

  the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine · CPC title

• A61P1/16

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

• A61P31/20

  for DNA viruses · CPC title

• C07D455/06

  containing benzo [a] quinolizine ring systems · CPC title