Biaryl derivative useful as diacylglycerol acyltransferase 2 inhibitor, and use thereof

Patent metadata

Field	Value
Publication number	US-12459915-B2
Application number	US-202118043947-A
Country	US
Kind code	B2
Filing date	Sep 3, 2021
Priority date	Sep 4, 2020
Publication date	Nov 4, 2025
Grant date	Nov 4, 2025

Abstract

The present invention relates to a biaryl derivative compound, which exhibits the activity of a diacylglycerol acyltransferase 2 (DGAT2) inhibitor and is represented by chemical formula (1), a pharmaceutical composition comprising same as an active ingredient, and a use thereof.

First claim

The invention claimed is:

1 . A compound of the following Formula (1), or a pharmaceutically acceptable salt or isomer thereof:

wherein
A, D and E are each independently CH or N;
R 1 is alkyl, cycloalkyl or haloalkyl; and
R 2 is-G-J-L;
wherein G is —C(═O)— or a direct bond;
J is alkylene, alkenylene, alkylene-arylene, alkenylene-arylene, alkoxyene-arylene, arylene, heteroarylene-heterocycloalkylene, heteroarylene-arylene or heteroarylene-oxy-cycloalkylene; and
L is hydrogen, halo, amino, nitro, carboxy (—COOH), carboxyalkyl, carboxyalkoxy, cycloalkyl or aryl; and
wherein the alkyl, alkylene, carboxyalkyl, carboxyalkoxy or aryl is optionally substituted with one or more substituents selected from hydroxy, halo, alkyl and alkoxy; and
the heterocycloalkylene or heteroarylene includes one or more heteroatoms selected from N, O and S.

2 . The compound, or a pharmaceutically acceptable salt or isomer thereof according to claim 1 , wherein
R 1 is C 1 -C 7 alkyl, C 3 -C 10 cycloalkyl or halo-C 1 -C 7 alkyl; and R 2 is-G-J-L; wherein J is C 1 -C 7 alkylene, C 2 -C 7 alkenylene, C 1 -C 7 alkylene-C 6 -C 10 arylene, C 2 -C 7 alkenylene-C 6 -C 10 arylene, C 1 -C 7 alkoxyene-C 6 -C 10 arylene, C 6 -C 10 arylene, 5- to 12-membered heteroarylene-5- to 12-membered heterocycloalkylene, 5- to 12-membered heteroarylene-C 6 -C 10 arylene or 5- to 12-membered heteroarylene-oxy-C 3 -C 10 cycloalkylene; and L is hydrogen, halo, amino, nitro, carboxy, carboxy-C 1 -C 7 alkyl, carboxy-C 1 -C 7 alkoxy, C 3 -C 10 cycloalkyl or C 6 -C 10 aryl; and wherein the alkyl, alkylene, carboxyalkyl, carboxyalkoxy or aryl is optionally substituted with 1 to 4 substituents selected from hydroxy, halo, C 1 -C 7 alkyl and C 1 -C 7 alkoxy; and the heterocycloalkylene or heteroarylene includes 1 to 4 heteroatoms selected from N, O and S.

3 . The compound, or a pharmaceutically acceptable salt or isomer thereof according to claim 1 , wherein the compound is selected from the following group:
N-(6-(5-(2-ethoxyphenoxy)pyridin-3-yl) pyrazin-2-yl)-3-phenylpropanamide; methyl 2-(4-(2-((6-(5-(2-ethoxyphenoxy)pyridin-3-yl) pyrazin-2-yl)amino)-2-oxoethyl)phenyl)acetate; 2-(4-(2-((6-(5-(2-ethoxyphenoxy)pyridin-3-yl) pyrazin-2-yl)amino)-2-oxoethyl)phenyl) acetic acid; 2-(4-(3-((6-(5-(2-ethoxyphenoxy)pyridin-3-yl) pyrazin-2-yl)amino)-3-oxopropyl)phenyl) acetic acid; methyl 2-(4-(3-((6-(5-(2-ethoxyphenoxy)pyridin-3-yl) pyrazin-2-yl)amino)-3-oxopropyl)phenyl)-2-methylpropanoate; ethyl 2-(4-(2-((6-(5-(2-ethoxyphenoxy)pyridin-3-yl) pyrazin-2-yl)amino)-2-oxoethyl)phenyl)-2,2-difluoroacetate; 3-(4-(2-((6-(5-(2-ethoxyphenoxy)pyridin-3-yl) pyrazin-2-yl)amino)-2-oxoethyl)phenyl)-2,2-dimethylpropanoic acid; (R)-1-(2-((6-(5-(2-ethoxyphenoxy)pyridin-3-yl) pyrazin-2-yl)amino) pyrimidin-4-yl) piperidine-3-carboxylic acid; 3-(3-(6-((6-(5-(2-ethoxyphenoxy)pyridin-3-yl) pyrazin-2-yl)amino) pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid; N-(6-(3-(2-ethoxyphenoxy)phenyl) pyrazin-2-yl)-3-phenylpropanamide; 2-(4-(2-((6-(3-(2-ethoxyphenoxy)phenyl) pyrazin-2-yl)amino)-2-oxoethyl)phenyl) acetic acid; 2-(4-(3-((6-(3-(2-ethoxyphenoxy)phenyl) pyrazin-2-yl)amino)-3-oxopropyl)phenyl) acetic acid; 2-(4-(3-((6-(3-(2-ethoxyphenoxy)phenyl) pyrazin-2-yl)amino)-3-oxopropyl) phenoxy)-2-methylpropanoic acid; 2-(4-(2-((6-(3-(2-ethoxyphenoxy)phenyl) pyrazin-2-yl)amino)-2-oxoethyl)phenyl-2,2-difluoroacetic acid; 3-(4-(2-((6-(3-(2-ethoxyphenoxy)phenyl) pyrazin-2-yl)amino)-2-oxoethyl)phenyl)-2,2-dimethylpropanoic acid; 2-(4-(3-((6-(3-(2-ethoxyphenoxy)phenyl) pyrazin-2-yl)amino)-3-oxopropyl)phenyl)-2-methylpropanoic acid; (E)-2-(4-(3-((6-(3-(2-ethoxyphenoxy)phenyl) pyrazin-2-yl)amino)-3-oxopro-1-phen-1-yl)phenyl)-2-methylpropanoic acid; 3-(4-(1-((6-(3-(2-ethoxyphenoxy)phenyl) pyrazin-2-yl)amino)-2-methyl-1-oxopropan-2-yl)phenyl)-2,2-dimethylpropanoic acid; 2-(4-(2-((6-(3-(2-ethoxyphenoxy)phenyl) pyrazin-2-yl)amino)-2-oxoethyl) phenoxy-2-methylpropanoic acid; 2-(4-(2-((6-(3-(2-ethoxyphenoxy)phenyl) pyrazin-2-yl)amino) pyrimidin-4-yl)phenyl) acetic acid; (1r,4r)-4-((2-((6-(3-(2-ethoxyphenoxy)phenyl) pyrazin-2-yl)amino) pyrimidin-4-yl)oxy) cyclohexane-1-carboxylic acid; N-(6-(6-(2-ethoxyphenoxy)pyridin-2-yl) pyrazin-2-yl)-3-phenylpropanamide; 3-(4-(2-((6-(6-(2-ethoxyphenoxy)pyridin-2-yl) pyrazin-2-yl)amino)-2-oxoethyl)phenyl)-2,2-dimethylpropanoic acid; (R)-1-(2-((6-(6-(2-ethoxyphenoxy)pyridin-2-yl) pyrazin-2-yl)amino) pyrimidin-4-yl) piperidine-3-carboxylic acid; 3-(3-(6-((6-(6-(2-ethoxyphenoxy)pyridin-2-yl) pyrazin-2-yl)amino) pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid; 2-(4-(3-((6-(3-((3-ethoxypyridin-2-yl)oxy) phenyl) pyrazin-2-yl)amino)-3-oxopropyl)phenyl)-2-methylpropanoic acid; 3-(4-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy) phenyl) pyrazin-2-yl)amino)-2-oxoethyl)phenyl)-2,2-dimethylpropanoic acid; 2-(4-(3-((6-(3-((3-ethoxypyridin-2-yl)oxy) phenyl) pyrazin-2-yl)amino)-3-oxopropyl) phenoxy)-2-methylpropanoic acid; 3-(4-(1-((6-(3-((3-ethoxypyridin-2-yl)oxy) phenyl) pyrazin-2-yl)amino)-2-methyl-1-oxopropane-2-yl)phenyl)-2,2-dimethylpropanoic acid; 2-(4-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy) phenyl) pyrazin-2-yl)amino)-2-oxoethyl) phenoxy)-2-methylpropanoic acid; (R)-1-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy) phenyl) pyrazin-2-yl)amino) pyrimidin-4-yl) piperidine-3-carboxylic acid; 3-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy) phenyl) pyrazin-2-yl)amino) pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid; and (1r,4r)-4-((2-((6-(3-((3-ethoxypyridin-2-yl)oxy) phenyl) pyrazin-2-yl)amino) pyrimidin-4-yl)oxy) cyclohexane-1-carboxylic acid.

4 . A pharmaceutical composition for the treatment of diseases associated with diacylglycerol acyltransferase 2 (DGAT2) comprising the compound of Formula (1), or a pharmaceutically acceptable salt or isomer thereof as defined in claim 1 as an active ingredient, together with a pharmaceutically acceptable carrier.

5 . The pharmaceutical composition according to claim 4 , wherein the disease associated with DGAT2 is selected from the group consisting of fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), diabetes, obesity, hyperlipidemia, atherosclerosis and hypercholesterolemia.

6 . A pharmaceutical composition for the treatment of diseases associated with diacylglycerol acyltransferase 2 (DGAT2) comprising the compound of Formula (1), or a pharmaceutically acceptable salt or isomer thereof as defined in claim 2 as an active ingredient, together with a pharmaceutically acceptable carrier.

7 . The pharmaceutical composition according to claim 6 , wherein the disease associated with DGAT2 is selected from the group consisting of fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), diabetes, obesity, hyperlipidemia, atherosclerosis and hypercholesterolemia.

8 . A pharmaceutical composition for the treatment of diseases associated with diacylglycerol acyltransferase 2 (DGAT2) comprising the compound of Formula (1), or a pharmaceutically acceptable salt or isomer thereof as defined in claim 3 as an active ingredient, together with a pharmaceutically acceptable carrier.

9 . The pharmaceutical composition according to claim 8 , wherein the disease associated with DGAT2 is selected from the group consisting of fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), diabetes, obesity, hyperlipidemia, atherosclerosis and hypercholesterolemia.

Assignees

• Lg Chemical Ltd

Inventors

• Yoon Seung Hyun
• Joo Hyun Woo
• Seo Bo Kyung
• Lee Eun Jin
• Jung Jin Young
• Yoon Su Young
• Cho Woo Young

Classifications

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/12

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

• C07D241/20

  Nitrogen atoms (nitro radicals C07D241/16) · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• C07D241/16

  Halogen atoms; Nitro radicals · CPC title