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CA-3189681-C - NOVEL BIARYL DERIVATIVE USEFUL AS DIACYLGLYCEROL ACYLTRANSFERASE 2 INHIBITOR, AND USE THEREOF

CA3189681CCA 3189681 CCA3189681 CCA 3189681CCA-3189681-C

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.

Inventors

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

Assignees

  • LG CHEM, LTD.

Dates

Publication Date
20260505
Application Date
20210903
Priority Date
20200904

Claims (5)

  1. CLAIMS 1. A compound of the following Formula (1), or a pharmaceutically acceptable salt or stereoisomer thereof: [Formula (1)] wherein A, D and E are each independently CH or N; R1 is alkyl, cycloalkyl or haloalkyl; R2 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; L is hydrogen, halo, amino, nitro, carboxy (-COOH), carboxyalkyl, carboxyalkoxy, cycloalkyl or aryl; 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. 2. The compound, or a pharmaceutically acceptable salt or stereoisomer thereof according to Claim 1, wherein A, D and E are each independently CH or N; R1 is C1-C7 alkyl, C3-C10 cycloalkyl or halo-C1-C7 alkyl; R2 is -G-J-L; wherein G is -C(=O)- or a direct bond; J is C1-C7 alkylene, C2-C7 alkenylene, C1-C7 alkylene-C6-C10 arylene, C2-C7 alkenylene-C6-C10 arylene, C1-C7 alkoxyene-C6-C10 arylene, C6-C10 arylene, 5- to 12-- 76 - membered heteroarylene-5- to 12- membered heterocycloalkylene, 5- to 12-membered heteroarylene-C6-C10 arylene or 5- to 12-membered heteroarylene-oxy-C3-C10 cycloalkylene; L is hydrogen, halo, amino, nitro, carboxy, carboxy-C1-C7 alkyl, carboxy-C1-C7 alkoxy, C3-C10 cycloalkyl or C6-C10 aryl; wherein the alkyl, alkylene, carboxyalkyl, carboxyalkoxy or aryl is optionally substituted with 1 to 4 substituents selected from hydroxy, halo, C1-C7 alkyl and C1-C7 alkoxy; and the heterocycloalkylene or heteroarylene includes 1 to 4 heteroatoms selected from N, O and S.
  3. 3. The compound, or a pharmaceutically acceptable salt or stereoisomer 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; - 77 - 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; - 78 - 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. 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 stereoisomer thereof as defined in any one of Claims 1 to 3 as active ingredient, together with a pharmaceutically acceptable carrier.
  5. 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. - 79 -

Description

CA 03189681 2023-2-15 PCT/KR2021 /011906 English translation DESCRIPTION TITLE OF INVENTION NOVEL BIARYL DERIVATIVE USEFUL AS DIACYLGLYCEROL ACYLTRANSFERASE 2 INHIBITOR, AND USE THEREOF TECHNICAL FIELD The present invention relates to a biaryl derivative compound represented by Formula (1) showing inhibitory activity against diacylglycerol acyltransferase 2 (DGAT2), a pharmaceutical composition comprising the same as an active ingredient, and use thereof. BACKGROUND ART The improvement of living standards according to economic development, frequent consumption of instant foods, and changes to meat-based dietary habits caused excessive accumulation of caloric energy in the body. These changes in the dietary life of modern people have also led to a reduction in caloric energy consumption due to lack of exercise, leading to a serious prevalence of metabolic diseases such as obesity, hyperlipidemia, diabetes, cardiovascular disease and coronary artery disease. Specifically, obesity is one of the rapidly increasing diseases and is reported to be the cause of metabolic diseases such as diabetes. The development of therapeutic agents for metabolic diseases by controlling the functions of enzymes involved in the biosynthetic pathway of triglycerides-which is the main cause of obesity-is drawing attention. - I - CA 03189681 2023-2-15 PCT/KR2021 /011906 English translation Neutral fats, such as triglycerides (TG), play a very important role in the storage function as an energy source in the body. However, when neutral fats are excessively accumulated in organs or tissues, they cause obesity, hypertriglyceridemia, fatty liver, etc., thereby causing serious diseases such as diabetes, arteriosclerosis, metabolic abnormalities and hypofunction of organs. Diacylglycerol acyltransferasewhich is a crucial enzyme in the biosynthesis of triglycerides-is found in various tissues of mammals, and is an enzyme that synthesizes TG by binding fatty acyl-CoA to the hydroxyl group of diacylglycerol in the final step of the glycerol phosphate pathway which is the main pathway for triglyceride synthesis. At present, two isoformsDGATl and DGAT2-are known. Although their biochemical functions are similar, there is a difference in that DGATl is mainly expressed in the small intestine and adipose tissue, and DGAT2 is mainly expressed in the liver and adipose tissue. In addition, with respect to the gene family, DGATl belongs to the ACAT family, and DGAT2 belongs to the MGAT family. As such, it is expected that their role in TG biosynthesis is also different. Several studies, including animal studies, have shown that DGAT2 primarily contributes to the biosynthesis of TG in vivo. Unlike DGAT2 knockout mice-which hardly synthesize TG and die shortly after birth due to an abnormal skin layer, DGATl knockout mice showed a slight decrease in TG levels and no problems with the survival of the mice (Stone SJ et al., 2000. Nat. Genet. 25: 87-90). In addition, as a result of reducing the expression level of DGATl or DGAT2 by using antisense oligonucleotide (ASO) in an animal model of fatty liver, fatty liver symptoms were alleviated and the rate of glucose production in the liver was significantly reduced only when the amount of DGAT2 was reduced (Choi CS et al., 2007. Hepatology. 45: 1366-74). CA 03189681 2023-2-15 PCT/KR2021 /011906 English translation The underlying molecular mechanisms have not been fully elucidated, but it has been thought that the inhibition of DGAT2 results in down-regulation of the expression of multiple genes encoding proteins involved in lipid production, such as sterol regulatory element-binding proteins 1 c (SREBP 1 c) and stearoyl CoA-desaturase 1 (SCD 1 ). At the same time, it has been thought that the oxidative pathway was induced by an increase in genes such as carnitine palmitoyltransferase 1 ( CPTl ). This change in turn leads to a decrease in hepatic DAG and TAG lipid levels, and thus improved insulin responsiveness in the liver. In addition, the inhibition of DGAT2 inhibited hepatic VLDL TAG secretion and reduced circulating cholesterol levels. Finally, plasma apolipoprotein B (APOB) levels were suppressed, which was thought to be due to the reduced supply of TAG in the lipidation of the newly synthesized APOB protein. That is, when DGAT2 is inhibited, beneficial effects on both glycemic control and plasma cholesterol profile showed, which means that the inhibition of DGAT2 can be applied to the treatment of metabolic disorders. DISCLOSURE OF INVENTION TECHNICAL PROBLEM An object of the present invention is to provide a novel biaryl derivative compound represented by Formula (1) showing inhibitory activity against diacylglycerol acyltransferase 2 (DGAT2). Another object of the present invention is to provide a method of preparing the biaryl derivative compound. Still another object of the present invention is to provide a pharmaceutical CA 03189681 2023-2-15 PCT/KR2021 /011906 English translation composition for