Influenza virus replication inhibitor and use thereof

Patent metadata

Field	Value
Publication number	US-11104689-B2
Application number	US-201816646072-A
Country	US
Kind code	B2
Filing date	Sep 18, 2018
Priority date	Sep 18, 2017
Publication date	Aug 31, 2021
Grant date	Aug 31, 2021

Abstract

Disclosed are a compound as shown in formula (I) as an influenza virus replication inhibitor and a preparation method therefor, a pharmaceutical composition comprising the compound and the use of the compound and pharmaceutical composition thereof in the treatment of influenza.

First claim

What is claimed is:

1. A compound having Formula (I), a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof,

wherein,
U 1 is N or CH;
U 2 is N or CH;
Y 1 is CR 1a R 1b , S or O;
Y 2 is CR 2a R 2b , S or O;
Y 3 is CR 3a R 3b , S or O;
each Y 4 is independently CR 4a R 4b , S or O;
each R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a and R 4b is independently H, deuterium, F, Cl, Br, I, CN, NO 2 , OR b , R b O—C 1-4 alkylene, R d R c N—C 1-4 alkylene, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 carbocyclyl, 3-8 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl; wherein each C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 carbocyclyl, 3-8 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
or optionally two R 1a , R 1b , R 2a , R 2b , R 3a , R 3b , R 4a , R 4b together with the carbon atom to which they are attached, form a C 3-8 carbocyclic ring or 3-8 membered heterocyclic ring; wherein each C 3-8 carbocyclic ring and 3-8 membered heterocyclic ring is unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 alkylamino;
ring A is one of the following sub-formulae:

wherein,
each X 1 is independently S, S(═O), S(═O) 2 , O, NH, CH 2 or absent;
each X 2 is independently CH or N;
each X 3 is independently CH or N;
each X 4 is independently S, O, NH or CH 2 ;
each A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , and A 8 is independently C or N;
B 1 is —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 — or O;
ring C is benzocyclohexane, benzocyclopentane, naphthalene, benzoimidazole, benzopyrazole, benzothiophene, benzopyrimidine, indole, purine, quinoline, isoquinoline, bicyclic [2.2.2]octane, or benzobicyclic [2.2.2] octane;
ring D is C 3-8 carbocyclic ring, 3-8 membered heterocyclic ring, C 6-10 aromatic ring, C 11 aromatic ring, C 12 aromatic ring, or 5-10 membered heteroaromatic ring;
each q is independently 0, 1, 2, 3, 4, 5, or 6;
each t is independently 0, 1, 2, or 3;
each R is independently H, deuterium, F, Cl, Br, I, CN, NO 2 , oxo(═O), —C(═O)R a , —C(═O)OR b , —C(═O)NR c R d , —OR b , —NR c R d , R b O—C 1-4 alkylene, R d R c N—C 1-4 alkylene, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkylene, 3-8 membered heterocyclyl, (3-8 membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5-10 membered heteroaryl, or (5-10 membered heteroaryl)-C 1-4 alkylene; wherein each C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, C 3-8 cycloalkyl-C 1-4 alkylene, 3-8 membered heterocyclyl, (3-8 membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5-10 membered heteroaryl and (5-10 atomic heteroaryl)-C 1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, CN, NO 2 , —OR b , —NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, R b O—C 1-4 alkylene or R d R c N—C 1-4 alkylene;
or optionally two R together with carbon atom or nitrogen atom to which they are attached form a C 3-8 carbocyclic ring, 3-8 membered heterocyclic ring, C 6-10 aromatic ring or a 5-10 membered heteroaryl ring; wherein the C 3-8 carbocyclic ring, 3-8 membered heterocyclic ring, C 6-10 aromatic ring, and 5-10 membered heteroaryl ring is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, CN, NO 2 , —OR b , —NR c R d , C 1-6 alkyl, C 1-6 haloalkyl, R b O—C 1-4 alkylene or R d R c N—C 1-4 alkylene;
P is H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 carbocyclyl, C 3-8 carbocyclyl-C 14 alkylene, 3-8 membered heterocyclyl, (3-8 member heterocyclyl)-C 14 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-C 1-4 alkylene, —C(═O)—R Pa , —C(═O)-L-R Pe , —C(═O)-L-O—R Pb , —C(═O)-L-O-L-O—R Pb , —C(═O)-L-O—C(═O)—R Pa , —C(═O)—NR Pf R Pd , —C(═O)—O—R Pb , —S(═O) 2 —R Pk , —P(═O)—(R Pg )(R Ph ), —C(═O)—O-L-O—R Pb , —C(═N + R Pi R Pj )(—NR Pc R Pd ), R Pb —O—C 1-4 alkylene, R Pb —O-L-O—C 1-4 alkylene, R Pa —(C═O)—O—C 1-4 alkylene, R Pb —O—(C═O)—C 1-4 alkylene, R Pb —O—(C═O)—NR Pf —C 1-4 alkylene, R Pb —O—(C═O)—O—C 1-4 alkylene, NR Pf R Pd —O—(C═O)—O—C 1-4 alkylene, R Pb —O-L-O—(C═O)—O—C 1-4 alkylene, NR Pe R Pd -L-O—(C═O)—O—C 1-4 alkylene, R Pb —O-L-NR Pf —(C═O)—O—C 1-4 alkylene, NR Pe R Pd -L-N(R Pf )—(C═O)—O—C 1-4 alkylene, R Pb —O-L-O-L-O—(C═O)—O—C 1-4 alkylene, (HO) 2 P(═O)—C 1-4 alkylene, (BnO) 2 P(═O)—C 1-4 alkylene or R Pa —(C═O)—NR Pf -L-O—(C═O)—O—C 1-4 alkylene, wherein each of C 1-6 alkyl, C 2-6 alkenyl, C 3-8 carbocyclyl, C 3-8 carbocyclyl-C 1-4 alkylene, 3-8 membered heterocyclyl, (3-8 membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5-10 membered heteroaryl and (5-10 membered heterocyclyl)-C 1-4 alkylene is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, oxo(═O), CN, NO 2 , —OR b , —NR c R d , —C(═O)R a , —O(C═O)R a , —C(═O)OR b , C 1-6 alkyl, R b O—C 1-4 alkylene, —NR d R c C(═O)R a or R d R c N—C 1-4 alkylene;
each L is independently C 1-6 alkylene or C 2-6 alkenylene;
each R Pf is independently H or C 1-6 alkyl;
each R Pa , R Pb , R Pc , R Pd , R Pe , R Pi , R Pj and R Pk is independently C 1-6 alkyl, C 3-8 carbocyclyl, C 3-8 carbocyclyl-C 1-4 alkylene, 3-8 membered heterocyclyl, (3-8 membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-C 1-4 alkylene, C 1-6 alkylamino, C 1-6 alkylthio or C 1-6 alkylsilyl, wherein each C 1-6 alkyl, C 3-8 carbocyclyl, C 3-8 carbocyclyl-C 1-4 alkylene, 3-8 membered heterocyclyl, (3-8 membered heterocyclyl)-C 1-4 alkylene, C 6-10 aryl, C 6-10 aryl-C 1-4 alkylene, 5-10 membered heteroaryl, (5-10 membered heteroaryl)-C 1-4 alkylene, C 1-6 alkylamino and C 1-6 alkylthio is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, oxo(═O), CN, NO 2 , —OR b , —NR c R d , —C(═O)R a , —O(C═O)R a , —C(═O)OR b , C 1-6 alkyl, R b O—C 1-4 alkylene, —NR d R c C(═O)R a or R d R c N—C 1-4 alkylene;
each R Pg and R Ph is independently C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 carbocyclyloxy, C 3-8 carbocyclylamino, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylamino, C 6-10 aryloxy, C 6-10 arylamino, 5-10 membered heteroaryloxy or 5-10 membered heteroarylamino, wherein each of C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 carbocyclyloxy and C 3-8 carbocyclylamino, 3-8 membered heterocyclyloxy, 3-8 membered heterocyclylamino, C 6-10 aryloxy, C 6-10 arylamino, 5-10 membered heteroaryloxy and 5-10 membered heteroarylamino is independently unsubstituted or substituted with 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, oxo(═O), CN, NO 2 , —OR b , —NR c

Assignees

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

Inventors

• Tang Changhua
• Ren Qingyun
• Luo Huichao
• Yin Junjun
• Yi Kai
• Lei Yibo
• Wang Yejun
• Zhang Yingjun

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D513/14 Primary

  Ortho-condensed systems · CPC title

• C07D491/22

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

• A61K31/7056

  containing five-membered rings with nitrogen as a ring hetero atom · CPC title

• A61K31/7012

  Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid (gluconic acid A61K31/191; ascorbic acid A61K31/375) · CPC title