N-heterocyclic five-membered ring-containing capsid protein assembly inhibitor, pharmaceutical composition thereof, and use thereof

Patent metadata

Field	Value
Publication number	US-12116356-B2
Application number	US-202318106103-A
Country	US
Kind code	B2
Filing date	Feb 6, 2023
Priority date	Mar 30, 2018
Publication date	Oct 15, 2024
Grant date	Oct 15, 2024

Abstract

A N-heterocyclic five-membered ring-containing capsid protein assembly inhibitor, and a pharmaceutical composition and use thereof, specifically relating to a compound as represented by formula I, a stereoisomer, a tautomer, a geometrical isomer, a solvate, an active metabolite, a hydrate, a prodrug or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and a medical use thereof. The medical use comprises the use in treating diseases benefiting from the capsid protein assembly inhibitor, and in particular, diseases caused by hepatitis B virus infection.

First claim

What is claimed:

1. A compound of Formula I, a stereoisomer, a tautomer, a geometric isomer, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof,

wherein,
X and Y each independently represent CR 7 , and said R 7 is independently selected from the group consisting of hydrogen, C 3-4 cycloalkyl, —CN, fluoro, chloro, bromo and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with one or more fluoro;
ring A is selected from the group consisting of phenyl and 5- to 10-membered heteroaryl;
R 1 , R 2 and R 3 are each independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, —CHF 2 , —CH 2 F, —CF 3 , —CN, and C 1-3 alkyl;
R 4 is selected from the group consisting of hydrogen, C 1-3 alkyl and C 3-4 cycloalkyl;
R 5 is selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered cycloalkyl and 3- to 7-membered heterocycloalkyl, wherein said C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 3- to 7-membered cycloalkyl and 3- to 7-membered heterocycloalkyl are optionally substituted with the group(s) selected from the group consisting of halo, 3- to 4-membered cycloalkyl, 3- to 4-membered heterocycloalkyl, —OR 8 , oxo, —CN, —C(O)OR 8 , —SO 2 R 8 , —C(O)N(R 8 ) 2 , and C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with one or more groups selected from the group consisting of fluoro, —CN and —OH; and
each R 8 is independently selected from the group consisting of hydrogen and C 1-3 alkyl.

2. The compound of Formula I, a stereoisomer, a tautomer, a geometric isomer, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein:
X and Y each independently represent CR 7 , and said R 7 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more fluoro;
alternatively, R 7 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, and C 1-3 alkyl;
alternatively, R 7 is independently selected from the group consisting of hydrogen, fluoro, chloro, bromo, and methyl; and
alternatively, R 7 is independently selected from the group consisting of hydrogen, chloro, bromo, and methyl.

3. The compound of Formula I, a stereoisomer, a tautomer, a geometric isomer, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein:
ring A is selected from the group consisting of phenyl, 5-membered heteroaryl, 6-membered heteroaryl, 7-membered heteroaryl, 8-membered heteroaryl, 9-membered heteroaryl and 10-membered heteroaryl;
alternatively, ring A is selected from the group consisting of phenyl and 6-membered heteroaryl;
alternatively, ring A is selected from phenyl; and
alternatively, the “heteroaryl” in the above definitions of ring A contains 1 or 2 N atoms.

4. The compound of Formula I, a stereoisomer, a tautomer, a geometric isomer, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein:
R 1 is selected from the group consisting of hydrogen, fluoro, chloro, —CHF 2 , —CN, —CF 3 and methyl; and
alternatively, R 1 is selected from the group consisting of hydrogen and fluoro.

5. The compound of Formula I, a stereoisomer, a tautomer, a geometric isomer, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein:
R 2 is selected from the group consisting of hydrogen, fluoro, chloro, and bromo; and
alternatively, R 2 is selected from the group consisting of hydrogen and fluoro.

6. The compound of Formula I, a stereoisomer, a tautomer, a geometric isomer, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein:
R 3 is selected from the group consisting of hydrogen, fluoro, chloro, —CHF 2 , —CN, —CF 3 , and methyl;
alternatively, R 3 is selected from the group consisting of hydrogen, fluoro, chloro, —CN, and methyl.

7. The compound of Formula I, a stereoisomer, a tautomer, a geometric isomer, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein:
R 1 is selected from the group consisting of hydrogen, fluoro, chloro, —CHF 2 , —CN, —CF 3 and methyl, and at least one of R 1 and R 3 is fluoro or hydrogen.

8. The compound of Formula I, a stereoisomer, a tautomer, a geometric isomer, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein:
one of R 1 and R 3 is selected from the group consisting of hydrogen and fluoro, and the other is selected from the group consisting of hydrogen, fluoro, chloro, —CHF 2 , —CN, —CF 3 , and methyl;
alternatively, one of R 1 and R 3 is hydrogen, and the other is selected from the group consisting of fluoro, chloro, —CHF 2 , —CN, —CF 3 and methyl;
alternatively, R 2 is fluoro, and one of R 1 and R 3 is hydrogen, and the other is selected from the group consisting of fluoro, chloro and —CN;
alternatively, R 2 is fluoro, R 1 is hydrogen, and R 3 is —CN or chloro; and
alternatively, R 2 is fluoro, R 1 is hydrogen, and R 3 is —CN.

9. The compound of Formula I, a stereoisomer, a tautomer, a geometric isomer, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein:
R 4 is selected from the group consisting of hydrogen and C 1-3 alkyl; and/or R 8 is selected from the group consisting of hydrogen and methyl;
alternatively, R 4 is methyl or hydrogen; and
alternatively, R 4 is methyl.

10. The compound of Formula I, a stereoisomer, a tautomer, a geometric isomer, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof according to claim 1 , wherein:
R 5 is selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 6-membered cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl is optionally substituted with the group(s) selected from the group consisting of halo, 3- to 4-membered cycloalkyl, 3- to 4-membered heterocycloalkyl, —OR 8 , oxo, —CN, —C(O)OR 8 , —SO 2 R 8 , —C(O)N(R 8 ) 2 , and C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with one or more groups selected from the group consisting of fluoro, —CN and —OH;
alternatively, R 5 is selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 4- to 6-membered cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 4- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl is optionally substituted with the group(s) selected from the group consisting of halo, 3- to 4-membered cycloalkyl, 3- to 4-membered heterocycloalkyl, —OR 8 , oxo, —CN, —C(O)OR 8 , —SO 2 R 8 , —C(O)N(R 8 ) 2 , and C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with one or more groups selected from the group consisting of fluoro, —CN and —OH;
alternatively, R 5 is selected from the group consisting of C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 6-membered cycloalkyl and 4- to 6-membered heterocycloalkyl, wherein said C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, 3- to 6-membered cycloalkyl or 4- to 6-membered heterocycloalkyl is optionally substituted with the group(s) selected from the group consisting of halo, oxo, —OH, —CN, —C(O)OR 8 , —C(O)N(R 8 ) 2 , and C 1-3 alkyl, wherein C 1-3 alkyl is optionally substituted with on

Assignees

• Chia Tai Tianqing Pharmaceutical Group Co Ltd

Inventors

• Zhang Yinsheng
• Ao Wangwei
• Li Yuan
• Wang Hui
• Shen hangzhou
• Ni Jie
• Zhang Huan
• Wu Jie
• Zhang Li
• Cao Kai
• Lu Peng
• Liu Xushi
• Wang Jie
• Zhao Tianxiao
• Ge Xingfeng
• Lu Dandan
• Chen Shuo
• Ma Xueqin
• Shi Wei
• Wang Xiaojin
• Xu Hongjiang

Classifications

• C07D409/12 Primary

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

• C07D405/12

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

• C07D207/34 Primary

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D401/12 Primary

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

• C07D403/12

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