Title of the invention: Novel amide derivatives useful as diacylglycerol acyltransferase 2 inhibitors and uses thereof
technical field
[One]
The present invention relates to an amide derivative compound represented by Formula (1) that exhibits diacylglycerol acyltransferase 2 (DGAT2) inhibitory activity, a pharmaceutical composition comprising the same as an active ingredient, and uses thereof.
background
[2]
The improvement of living standards according to economic development, frequent consumption of instant food, and changes in eating habits centered on meat caused excessive accumulation of calorie energy in the body. These changes in modern people's eating habits also add to the reduction in calorie and energy consumption due to lack of exercise, and the prevalence of metabolic diseases such as obesity, hyperlipidemia, diabetes, cardiovascular disease, and coronary artery disease has reached a serious level. In particular, obesity is one of the diseases that are rapidly increasing and is reported to be the cause of metabolic diseases such as diabetes. This is drawing attention.
[3]
Triglycerides (TG), such as triglycerides, play a very important role in the storage function as an energy source in the body. It causes serious diseases such as hardening, metabolic abnormalities, and organ dysfunction. Diacylglycerol acyltransferase, which is a crucial enzyme in the biosynthesis of triglycerides, is found in various tissues of mammals, and in the last step of the glycerol phosphate pathway, which is the main pathway of triglyceride synthesis, diacylglycerol (diacylglycerol) It is an enzyme that synthesizes TG by binding fatty acyl-CoA to the hydroxyl group of Currently, two isoforms, DGAT1 and DGAT2, are known, and their biochemical functions are similar, but DGAT1 is mainly expressed in the small intestine and adipose tissue, and DGAT2 is mainly expressed in the liver and adipose tissue. Archipelago DGAT1 was of the ACAT family, and DGAT2 was of the MGAT family, so it was expected that the role for TG biosynthesis would also be different.
[4]
Several studies, including animal experiments, have shown that DGAT2 mainly contributes to the biosynthesis of TG in vivo. Unlike DGAT2 knockout mice that synthesize little TG and die shortly after birth due to an abnormal skin layer, DGAT1 knockout mice show only 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 DGAT1 or DGAT2 in an animal model of fatty liver using antisense oligonucleotide (ASO), only when the amount of DGAT2 was decreased, fatty liver symptoms were alleviated and the glucose production rate in the liver was significantly reduced. (Choi CS et al. 2007. Hepatology. 45: 1366-74).
[5]
Although the molecular mechanism underlying it has not been fully elucidated, inhibition of DGAT2 is linked to sterol regularoty element-binding proteins 1c (SREBP1c) and strearoyl CoA-desaturase 1 1, was thought to down-regulate the expression of multiple genes encoding proteins involved in lipogenesis, including SCD1). At the same time, it was thought that the oxidative pathway was derived from an increase in genes such as carnitine palmitoyl transferase 1 (CPT1). These changes in turn lead to a decrease in hepatic DAG and TAG lipid levels, and thus improved insulin responsiveness in the liver. In addition, inhibition of DGAT2 inhibited hepatic VLDL TAG secretion and decreased circulating cholesterol levels. Finally, plasma apolipoprotein B (APOB) levels are suppressed, which was thought to be due to the decreased supply of TAG in the lipidation of newly synthesized APOB protein. That is, when DGAT2 was inhibited, beneficial effects were shown on both glycemic control and plasma cholesterol profile, suggesting that DGAT2 inhibition could be applied to the treatment of metabolic diseases.
DETAILED DESCRIPTION OF THE INVENTION
technical challenge
[6]
It is an object of the present invention to provide a novel amide derivative compound represented by Formula (1) that exhibits diacylglycerol acyltransferase 2 (DGAT2) inhibitory activity.
[7]
Another object of the present invention is to provide a method for preparing the amide derivative compound.
[8]
Another object of the present invention is to provide a pharmaceutical composition for the treatment of metabolic diseases related to DGAT2, comprising the amide derivative compound as an active ingredient, and a method for preparing the same.
[9]
Another object of the present invention is to use the amide derivative compound as an active ingredient to improve physical and chemical properties compared to conventional compounds, thereby improving efficacy in disease animal models as well as improving efficacy and improving efficacy in metabolic diseases related to DGAT2 in a subject It is to provide convenience of administration and a method of treatment.
means of solving the problem
[10]
In order to achieve the above object, the present invention provides a compound of formula (1), or a pharmaceutically acceptable salt or isomer thereof:
[11]
[Formula (1)]
[12]

[13]
[14]
In the above formula (1),
[15]
A, B and E are each independently CH or N;
[16]
D is N, CH or C-haloalkyl;
[17]
R 1 is alkyl, cycloalkyl or haloalkyl;
[18]
R 2 is hydrogen or alkyl;
[19]
R 3 is -GJL;
[20]
wherein G is -NH- or a direct bond;
[21]
J is alkylene, alkenylene, alkylene-arylene, alkylene-amino-arylene, alkylene-aryloxylene-alkylene, alkylene-cycloalkyl, alkenylene-cycloalkyl, alkoxyene-arylene, arylene, cycloalkyl, aryl, aryl-alkyl, heterocycloalkylene, heterocycloalkylene-arylene, heterocycloalkylene-heteroarylene or heterocycloalkyl;
[22]
L is hydrogen, halo, amino, nitro, carboxy (-COOH), aminocarbonylalkyl, carboxyalkyl, carboxyalkoxy, carboxyalkyl-aryl, cycloalkyl, aryl, aryloxy, heterocycloalkyl or heteroaryl; or
[23]
R 2 and R 3 together with the nitrogen to which they are attached may form a heterocycloalkyl;
[24]
said alkyl, alkylene, alkylene-arylene, alkenyl, alkenylene, cycloalkyl, carboxyalkyl, carboxyalkoxy, alkoxyalkyl, aminocarbonyl, aryl, aryl-alkyl, arylene, aryloxy, heterocycloalkyl or Heteroaryl may be optionally substituted, the substituents being hydroxy, halo, oxo, nitro, -COOH, -CH 2 COOH, alkyl, alkenyl, alkoxy, haloalkyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl and at least one selected from heteroaryl-alkyl;
[25]
Said heterocycloalkylene, heterocycloalkyl, heteroarylene or heteroaryl comprises one or more heteroatoms selected from N, O and S.
[26]
[27]
The compounds of formula (1) according to the present invention may form pharmaceutically acceptable salts. Pharmaceutically acceptable salts include acids that form non-toxic acid addition salts containing pharmaceutically acceptable anions, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, and the like; organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and the like; and acid addition salts formed with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and the like. In addition, pharmaceutically acceptable salts of carboxylic acids include, for example, alkali metal or alkaline earth metal salts formed by lithium, sodium, potassium, calcium, magnesium and the like; amino acid salts such as lysine, arginine, and guanidine; organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, and the like. The compound of formula (1) according to the present invention can be converted into its salt by a conventional method.
[28]
On the other hand, since the compounds according to the present invention may have an asymmetric carbon center and an asymmetric axis or an asymmetric plane, they may exist as E or Z isomers, R or S isomers, racemates, diastereomeric mixtures and individual diastereomers, All these isomers and mixtures are included within the scope of the present invention.
[29]
In the present specification, unless otherwise specified for convenience, the compound of formula (1) is used in the meaning including the compound of formula (1), pharmaceutically acceptable salts and isomers thereof.
[30]
In defining the compound of Formula (1) throughout this specification, the concepts defined for the following substituents are used.
[31]
The term "halogen" or "halo" denotes fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
[32]
The term “alkyl” or “alkylene” is a straight-chain or branched hydrocarbon, which may contain single, double or triple bonds, and is C 1 -C 10 alkyl or C 1 -C 10 alkylene, or C 1 -C 7 alkyl or C 1 -C 7 alkylene is preferred. For example, the alkyl includes, but is not limited to, methyl, ethyl, n -propyl, i -propyl, n -butyl, i -butyl, tert -butyl, acetylene, vinyl, trifluoromethyl, and the like.
[33]
The term “alkenyl” or “alkenylene” is a branched or unbranched hydrocarbon having at least one carbon-carbon double bond, which is C 2 -C 10 alkenyl or C 2 -C 10 alkenylene, or C 2 -C 7 alkenyl or C 2 -C 7 alkenylene is preferred. For example, the alkenyl includes, but is not limited to, vinyl, allyl, butenyl, isopropenyl, or isobutenyl.
[34]
The term “cycloalkyl” is a partially or fully saturated mono- or fused-ring cyclic hydrocarbon, with C 3 -C 10 cycloalkyl being preferred. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
[35]
The term "alkoxy", unless otherwise defined, means alkyloxy having from 1 to 10 carbon atoms.
[36]
The term "cycloalkoxy", unless otherwise defined, means cycloalkyloxy having from 3 to 10 carbon atoms.
[37]
The term “aryl” or “arylene” means an aromatic hydrocarbon, preferably C 5 -C 12 aryl or C 5 -C 12 arylene, more preferably C 6 -C 10 aryl or C 6 -C 10 is arylene. For example, the aryl includes, but is not limited to, phenyl, naphthyl, and the like.
[38]
The term “heteroaryl” or “heteroarylene” refers to a single or fused ring that contains one or more heteroatoms selected from N, O and S as a reducing agent and can be fused with benzo or C 3 -C 8 cycloalkyl. It means a 3 to 12 membered aromatic hydrocarbon, more preferably a 5 to 12 membered aromatic hydrocarbon. For example, the heteroaryl is pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, oxadiazolyl, isoxadiazolyl, tetrazolyl, triazolyl, indolyl, indazolyl, isoxazolyl, oxazolyl, thia Zolyl, isothiazolyl, furanyl, benzofuranyl, imidazolyl, thiophenyl, benzthiazole, benzimidazole, quinolinyl, indolinyl, 1,2,3,4-tetrahydroisoquinolyl, 3 , 4-dihydroisoquinolyl, thiazolopyridyl, 2,3-dihydrobenzofuran, 2,3-dihydrothiophene, 2,3-dihydroindole, benzo [1,3] dioxane, chroman , thiochroman, 1,2,3,4-tetrahydroquinoline, 4 H -benzo [1,3] dioxin, 2,3-dihydrobenzo [1,4] dioxin, 6,7-dihydro-5 H -cyclopenta[ d ]pyrimidine, and the like.
[39]
The term “heterocycloalkyl” or “heterocycloalkylene” refers to a partially or completely saturated hydrocarbon comprising at least one hetero atom selected from N, O and S as a reducing agent and forming a single or fused ring, 3 to 12 won or 5 to 12 won is preferable. Examples include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, imidazolinyl, piperazinyl, tetrahydrofuran, tetrahydrothiofuran, and the like.
[40]
Aryl-alkyl, alkyl-aryl and heteroaryl-alkyl refer to a group formed by combining aryl and alkyl or heteroaryl and alkyl as defined above, and include, for example, benzyl, thiophenmethyl, pyrimidinemethyl, and the like. , but is not limited thereto.
[41]
[42]
According to one embodiment of the present invention, in the formula (1)
[43]
A, B and E are each independently CH or N;
[44]
D is N, CH or C-halo-C 1 -C 7 alkyl;
[45]
R 1 is C 1 -C 7 alkyl, C 3 -C 10 cycloalkyl or halo-C 1 -C 7 alkyl;
[46]
R 2 is hydrogen or C 1 -C 7 alkyl;
[47]
R 3 is -GJL;
[48]
wherein G is -NH- or a direct bond;
[49]
J is C 1 -C 7 alkylene, C 2 -C 7 alkenylene, C 1 -C 7 alkylene -C 6 -C 10 arylene, C 1 -C 7 alkylene-amino-C 6 -C 10 aryl ene, C 1 -C 7 alkylene -C 6 -C 10 aryloxylene-C 1 -C 7 alkylene, C 1 -C 7 alkylene -C 3 -C 10cycloalkyl, C 2 -C 7 alkenylene -C 3 -C 10 cycloalkyl, C 1 -C 7 alkoxyene -C 6 -C 10 arylene, C 6 -C 10 arylene, C 3 -C 10 cycloalkyl , C 6 -C 10 aryl, C 6 -C 10 aryl -C 1 -C 7 alkyl, 5-12 membered heterocycloalkylene, 5-12 membered heterocycloalkylene-C 6 -C 10arylene, 5-12 membered heterocycloalkylene-5-12 membered heteroarylene or 5-12 membered heterocycloalkyl;
[50]
L is hydrogen, halo, amino, nitro, carboxy (-COOH), aminocarbonyl-C 1 -C 7 alkyl, carboxy-C 1 -C 7 alkyl, carboxy-C 1 -C 7 alkoxy, carboxy -C 1 - C 7 alkyl -C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, 5 to 12 membered heterocycloalkyl or 5 to 12 membered heteroaryl; or
[51]
R 2 and R 3 together with the nitrogen to which they are attached may form a 5 to 12 membered heterocycloalkyl;
[52]
said alkyl, alkylene, alkylene-arylene, alkenyl, alkenylene, cycloalkyl, carboxyalkyl, carboxyalkoxy, alkoxyalkyl, aminocarbonyl, aryl, aryl-alkyl, arylene, aryloxy, heterocycloalkyl or Heteroaryl may be optionally substituted, the substituents being hydroxy, halo, oxo, nitro, -COOH, -CH 2 COOH, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 1 -C 7 alkoxy, halo -C 1 -C 7 alkyl, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkoxycarbonyl and 5-12 membered heteroaryl-C 1 -C 71 to 4 selected from alkyl;
[53]
The heterocycloalkylene, heterocycloalkyl, heteroarylene or heteroaryl contains 1 to 5 heteroatoms selected from N, O and S.
[54]
[55]
Representative of the compounds of formula (1) according to the present invention may include, but are not limited to, the following compounds:
[56]
( R )-1-(3,5-bis(trifluoromethyl)phenyl)-3-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl ) urea;
[57]
((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl) -L -phenylalanine;
[58]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)morpholine-4-carboxamide;
[59]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)pyrrolidine-1-carboxamide;
[60]
1-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)pyrrolidine-3-carboxylic acid;
[61]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzamide;
[62]
( R )-4-chloro- N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzamide;
[63]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-3-methoxybenzamide;
[64]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4-methoxybenzamide;
[65]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4-nitrobenzamide;
[66]
( R )-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)benzoic acid;
[67]
( R )-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)phenyl)acetic acid;
[68]
( R )-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)phenyl)-2-methylpropanoic acid;
[69]
( R )-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)phenoxy)-2-methylpropanoic acid ;
[70]
( R ) -N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-1-(methylsulfonyl)piperidine-4- carboxa mid;
[71]
( R )-1-acetyl- N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)piperidine-4-carboxamide;
[72]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-1-(isopropylsulfonyl)piperidine-4-car copymide;
[73]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-1-(5-ethylpyrimidin-2-yl)piperidin din-4-carboxamide;
[74]
( R )-4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-4-oxobutanoic acid;
[75]
(1 R )-2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)cyclopentane-1-carboxylic acid;
[76]
( R )-4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)bicyclo[2.2.2]octane-1- carboxylic acid;
[77]
( R )-4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2,2-dimethyl-4-oxobutanoic acid ;
[78]
( R )-1-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-3,3-dimethylpyrrolidin-2,5-da ion;
[79]
( R )-5-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2,2-dimethyl-5-oxopentanoic acid ;
[80]
( R )-5-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3,3-dimethyl-5-oxopentanoic acid ;
[81]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-2-(3-trifluoromethyl)phenyl)acetamide;
[82]
( R )-2-(3,5-bis(trifluoromethyl)phenyl) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl ) acetamide;
[83]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-2-phenylacetamide;
[84]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-3-phenylpropanamide;
[85]
( R )-2-(3-chlorophenyl) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)acetamide;
[86]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-2-methyl-2-phenylpropanamide;
[87]
( R )-4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl)benzoic acid;
[88]
( R )-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl)benzoic acid;
[89]
( R )-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl)phenyl ) acetic acid;
[90]
( R )-2-(4-(2-amino-2-oxoethyl)phenyl- N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl ) acetamide;
[91]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-2-(4-hydroxyphenyl)acetamide;
[92]
( R )-4-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl)phenoxy C) butanoic acid;
[93]
( R )-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino-2-oxoethyl)phenoxy -2-methylpropanoic acid;
[94]
( R )-2-(4-(1-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-methyl-1- oxopropan-2-yl)phenyl)-2-methylpropanoic acid;
[95]
( R )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)benzoic acid;
[96]
( R , E )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxoprop-1- en-1-yl)benzoic acid;
[97]
( R , E )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-methyl-3-oxo prop-1-en-1-yl)benzoic acid;
[98]
4-(3-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-methyl-3-oxopropyl) benzoic acid;
[99]
( R )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)-2-fluoro robenzoic acid;
[100]
( R )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)-2-methyl benzoic acid;

Claims
[Claim 1]
A compound of Formula (1), or a pharmaceutically acceptable salt or isomer thereof: [Formula (1)] In Formula (1), A, B and E are each independently CH or N; D is N, CH or C-haloalkyl; R 1 is alkyl, cycloalkyl or haloalkyl; R 2 is hydrogen or alkyl; R 3 is -GJL; wherein G is -NH- or a direct bond; J is alkylene, alkenylene, alkylene-arylene, alkylene-amino-arylene, alkylene-aryloxylene-alkylene, alkylene-cycloalkyl, alkenylene-cycloalkyl, alkoxyene-arylene, arylene, cycloalkyl, aryl, aryl-alkyl, heterocycloalkylene, heterocycloalkylene-arylene, heterocycloalkylene-heteroarylene or heterocycloalkyl; L is hydrogen, halo, amino, nitro, carboxy (-COOH), aminocarbonylalkyl, carboxyalkyl, carboxyalkoxy, carboxyalkyl-aryl, cycloalkyl, aryl, aryloxy, heterocycloalkyl or heteroaryl; or R 2 and R 3can form a heterocycloalkyl with the nitrogen to which they are attached; said alkyl, alkylene, alkylene-arylene, alkenyl, alkenylene, cycloalkyl, carboxyalkyl, carboxyalkoxy, alkoxyalkyl, aminocarbonyl, aryl, aryl-alkyl, arylene, aryloxy, heterocycloalkyl or Heteroaryl may be optionally substituted, the substituents being hydroxy, halo, oxo, nitro, -COOH, -CH 2 COOH, alkyl, alkenyl, alkoxy, haloalkyl, alkylsulfonyl, alkylcarbonyl, alkoxycarbonyl and at least one selected from heteroaryl-alkyl; Said heterocycloalkylene, heterocycloalkyl, heteroarylene or heteroaryl comprises one or more heteroatoms selected from N, O and S.
[Claim 2]
The method of claim 1 , wherein A, B and E are each independently CH or N; D is N, CH or C-halo-C 1 -C 7 alkyl; R 1 is C 1 -C 7 alkyl, C 3 -C 10 cycloalkyl or halo-C 1 -C 7 alkyl; R 2 is hydrogen or C 1 -C 7 alkyl; R 3 is -GJL; wherein G is -NH- or a direct bond; J is C 1 -C 7 alkylene, C 2 -C 7 alkenylene, C 1 -C 7 alkylene -C 6-C 10 arylene, C 1 -C 7 alkylene-amino-C 6 -C 10 arylene, C 1 -C 7 alkylene -C 6 -C 10 aryloxylene-C 1 -C 7 alkylene, C 1 -C 7 alkylene -C 3 -C 10 cycloalkyl, C 2 -C 7 alkenylene -C 3 -C 10 cycloalkyl, C 1 -C 7 alkoxyene -C 6 -C 10 arylene, C 6 -C 10 arylene, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryl -C 1 -C 7 alkyl, 5 to 12 membered heterocycloalkylene, 5 to 12 membered heterocycloalkylene-C 6 -C 10 arylene, 5 to 12 membered heterocycloalkylene-5 to 12 membered heteroarylene or 5 to 12 membered heterocycloalkyl; L is hydrogen, halo, amino, nitro, carboxy (-COOH), aminocarbonyl-C 1 -C 7 alkyl, carboxy-C 1 -C 7 alkyl, carboxy-C 1 -C 7alkoxy, carboxy-C 1 -C 7 alkyl -C 6 -C 10 aryl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxy, 5 to 12 membered heterocycloalkyl or 5 to 12 membered heteroaryl; or R 2 and R 3 together with the nitrogen to which they are attached may form a 5 to 12 membered heterocycloalkyl; said alkyl, alkylene, alkylene-arylene, alkenyl, alkenylene, cycloalkyl, carboxyalkyl, carboxyalkoxy, alkoxyalkyl, aminocarbonyl, aryl, aryl-alkyl, arylene, aryloxy, heterocycloalkyl or Heteroaryl may be optionally substituted, the substituents being hydroxy, halo, oxo, nitro, -COOH, -CH 2 COOH, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 1 -C 7 alkoxy, halo -C 1 -C 7 alkyl, C 1 -C 7 alkylsulfonyl, C 1 -C 7 alkylcarbonyl, C 1 -C 7 alkoxycarbonyl and 1 to 4 selected from 5 to 12 membered heteroaryl-C 1 -C 7 alkyl; The heterocycloalkylene, heterocycloalkyl, heteroarylene or heteroaryl is a compound comprising 1 to 5 heteroatoms selected from N, O and S, or a pharmaceutically acceptable salt or isomer thereof.
[Claim 3]
2. The compound of claim 1 selected from: ( R )-1-(3,5-bis(trifluoromethyl)phenyl)-3-(6-(3-(2-ethoxyphenoxy)p peridin-1-yl)pyrazin-2-yl)urea; ((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl) -L -phenylalanine; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)morpholine-4-carboxamide; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)pyrrolidine-1-carboxamide; 1-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)pyrrolidine-3-carboxylic acid; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzamide; ( R )-4-chloro- N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzamide; ( R )- N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-3-methoxybenzamide; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4-methoxybenzamide; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4-nitrobenzamide; ( R )-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)benzoic acid; ( R )-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)phenyl)acetic acid; ( R )-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)phenyl)-2-methylpropanoic acid; ( R )-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)phenoxy)-2-methylpropanoic acid ; ( R ) -N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-1-(methylsulfonyl)piperidine-4- carboxa mid; ( R )-1-Acetyl- N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)piperidine-4-carboxamide; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-1-(isopropylsulfonyl)piperidine-4-car copymide; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-1-(5-ethylpyrimidin-2-yl)piperidin din-4-carboxamide; ( R )-4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-4-oxobutanoic acid; (1 R )-2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)cyclopentane-1-carboxylic acid; ( R )-4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)bicyclo[2.2.2]octane-1- carboxylic acid; ( R )-4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2,2-dimethyl-4-oxobutanoic acid ; ( R )-1-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-3,3-dimethylpyrrolidin-2,5-da ion; ( R)-5-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2,2-dimethyl-5-oxopentanoic acid; ( R )-5-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3,3-dimethyl-5-oxopentanoic acid ; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-2-(3-trifluoromethyl)phenyl)acetamide; ( R )-2-(3,5-bis(trifluoromethyl)phenyl) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl ) acetamide; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-2-phenylacetamide; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-3-phenylpropanamide; ( R )-2-(3-chlorophenyl) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)acetamide; ( R ) -N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-2-methyl-2-phenylpropanamide; ( R )-4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl)benzoic acid; ( R )-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl)benzoic acid; ( R )-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl)phenyl ) acetic acid; ( R )-2-(4-(2-amino-2-oxoethyl)phenyl- N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl )acetamide;( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-2-(4-hydroxyphenyl)acetamide ( R )-4-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl) Phenoxy)butanoic acid;( R )-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino-2 -oxoethyl)phenoxy-2-methylpropanoic acid; ( R)-2-(4-(1-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-methyl-1-oxopropane -2-yl)phenyl)-2-methylpropanoic acid; ( R )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)benzoic acid; ( R , E )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxoprop-1- en-1-yl)benzoic acid; ( R , E )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-methyl-3-oxo prop-1-en-1-yl)benzoic acid; 4-(3-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-methyl-3-oxopropyl) benzoic acid; ( R )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)-2-fluoro robenzoic acid; ( R )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)-2-methyl benzoic acid; ( R)-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)-2-methoxybenzoic acid ; ( R )-2-chloro-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl) benzoic acid; ( R )-3-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)benzoic acid; ( R )-2-(4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)phenyl ) acetic acid; ( R )-3-(4-(2-amino-2-oxoethyl)phenyl- N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl )propanamide;( R )-2-(4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3- oxopropyl)phenyl)-2-methylpropanoic acid;( R )-1-(4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine-2 -yl)amino)-3-oxopropyl)phenyl)cyclopropane-1-carboxylic acid;( R )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidine-1) -yl)pyrazin-2-yl)amino)-3-oxopropyl)-2,6-difluorobenzoic acid ;)-2,6-dichloro-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl ) benzoic acid; ( R )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)-2,6 -dimethylbenzoic acid; ( R )-1-(4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)phenyl ) piperidine-4-carboxylic acid; ( R )-1-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl-2,6-difluorophenyl) piperidine-4-carboxylic acid;( R )-2-(1-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carba Moyl-2,6-difluorophenyl)piperidin-4-yl)acetic acid;( R )-4-(4-((6-(3-(2-ethoxyphenoxy)piperidine-1) -yl)pyrazin-2-yl)carbamoyl)piperidin-1-yl)benzoic acid;( R )-2-(4-(3-((6-(3-(2-ethoxyphenoxy)p) Peridin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)phenoxy)-2-methylpropanoic acid;( R )-3-(4-(3-((6-(3-) (2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)phenyl)propanoic acid ;)-4-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)phenoxy)benzoic acid; ( R )-3-(4-(3-((6-( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxo ethyl)phenyl)-2-methylpropanoic acid; ( S )-3-(4-(3-((6-( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxo ethyl)phenyl)-2-methylpropanoic acid; ( R )-3-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl)phenyl )-2,2-dimethylpropanoic acid; ( R )-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyridin-2-yl)amino)-2-oxoethyl)phenyl ) acetic acid; ( R )-2-(4-(3-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)ureido)phenyl)acetic acid; ( R )-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyridin-2-yl)amino)-2-oxoethyl)phenyl )-2-methylpropanoic acid; ( R )-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl)phenyl )-2-methylpropanoic acid; ( R )-2-(4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyridin-2-yl)amino)-3-oxopropyl)phenyl) -2-methylpropanoic acid; ( R )-3-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyridin-2-yl)amino-2-oxoethyl)phenyl- 2,2-dimethylpropanoic acid;( R )-3-(4-(2-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)-6-(trifluoro) Rhomethyl)pyrimidin-2-yl)amino-2-oxoethyl)phenyl)-2,2-dimethylpropanoic acid;( R )-3-(4-(1-((6-(3-(2) -ethoxyphenoxy )piperidin-1-yl)pyrazin-2-yl)amino)-2-methyl-1-oxopropan-2-yl)phenyl)propanoic acid ; ((2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)allyl)amino)phenyl)propanoic acid ; 2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)piperidin-1-yl)pyrimidin-5 -carboxylic acid: 3-(3-(( R )-3-((6-(( R )-3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine- 2-yl)carbamoyl)piperidin-1-yl)phenyl-2,2-dimethylpropanoic acid ;)-3-(4-(1-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-2-yl)amino)-2-methyl-1- oxopropan-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(1-((4-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)amino) -2-methyl-1-oxopropan-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-2-(4-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)piperidine-1 -yl)phenyl)acetic acid; ( R )-2-(4-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)piperidin-1- yl)phenyl)-2-methylpropanoic acid; ( R )-2-(6-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)piperidin-1- yl)pyridin-3-yl)-2-methylpropanoic acid; ( R )-2-(5-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)piperidine-1 -yl)-2H - tetrazol-2-yl)acetic acid; ( R )-4-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)piperidin-1-yl)- 4-oxobutanoic acid; ( R)-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)piperidin-1-yl)acetic acid; 3-(3-(( R )-3-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)piperidin din-1-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-1-(4-(1-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-methyl-1- oxopropan-2-yl)phenyl)piperidine-4-carboxylic acid; 6-(3-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)pyrrolidin-1-yl)nicotinic acid ; N- (6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-3-methylpyrrolidine-3-carboxamide; 6-(3-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)-3-methylpyrrolidin-1 -yl) nicotinic acid; ( R )-2-(4-(2-((6-(3-(2-isopropoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl) phenyl)acetic acid; ( R)-2-(4-(3-((6-(3-(2-methoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)phenyl)- 2-methylpropanoic acid; ( R )-2-methyl-2-(4-(3-oxo-3-((6-(3-(2-(trifluoromethoxy)phenoxy)piperidin-1-yl)pyrazine-2) -yl)amino)propyl)phenyl)propanoic acid; ( R )-2-(4-(3-((6-(3-(2-(2-fluoroethoxy)phenoxy)piperidin-1-yl)pyrazin-2-yl)amino)- 3-oxopropyl)phenyl)-2-methylpropanoic acid; ( R )-3-(4-(2-((6-(3-(2-(2-fluoroethoxy)phenoxy)piperidin-1-yl)pyrazin-2-yl)amino)- 2-oxoethyl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(2-((6-(3-(2-cyclopropoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl) phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(2-((6-(3-(2-cyclobutoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl) phenyl)-2,2-dimethylpropanoic acid; ( R )-2-(4-(3-((6-(3-(2-cyclopropoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl) phenyl)-2-methylpropanoic acid; ( R)-2-(4-(3-((6-(3-(2-cyclobutoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)phenyl) -2-methylpropanoic acid; ( R )-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino-2-oxoethyl)phenoxy )acetic acid;( R )-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxo ethoxy)phenyl)acetic acid;2-(4-(2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino) -2-oxoethoxy)phenyl)propanoic acid;( R )-3-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine-2) -yl)amino)-2-oxoethyl)phenoxy-2,2-dimethylpropanoic acid;( R )-2-(4-(2-((6-(( R )-3-(2-to) oxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl)phenoxy)propanoic acid;( S )-2-(4-(2-((6-(() R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl)phenoxy)propanoic acid ;)-2-(4-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)-2- oxoethyl)phenoxy)-2-methylpropanoic acid; ( R )-2-(4-(2-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-2-oxoethyl) phenoxy)-2-methylpropanoic acid; ( R )-2-(4-((4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2- oxoethyl)phenoxy)methyl)phenyl)-2-methylpropanoic acid; ( R )-2-(4-(3-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)- 3-oxopropyl)phenoxy)-2-methylpropanoic acid; ( R )-2-(4-(3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-3-oxopropyl) phenoxy)-2-methylpropanoic acid; ( R )-3-(4-(1-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-methyl-1- oxopropan-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-2-(4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2,2-dimethyl -3-oxopropyl)phenyl)-2-methylpropanoic acid; ( R)-3-(4-(2-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-2-oxoethyl)phenyl) -2,2-dimethylpropanoic acid; ( R )-3-(4-(2-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-2-yl)amino)-2-oxoethyl) phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(2-((4-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)amino) -2-oxoethyl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(2-((2-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrimidin-4-yl)amino) -2-oxoethyl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)- 2-oxoethyl)phenyl)-2,2-dimethylpropanoic acid; ( R )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)bicyclo[2.2 .2]octane-1-carboxylic acid; ( R )-4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-oxoethyl)bicyclo[2.2 .2]octane-1-carboxylic acid; ( R)-4-(3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-3-oxopropyl)bicyclo[2.2. 2]octane-1-carboxylic acid; ( R )-4-(3-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxo propyl)bicyclo[2.2.2]octane-1-carboxylic acid; ( R , E )-4-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxoprop-1 -en-1-yl)bicyclo[2.2.2]octane-1-carboxylic acid; ( R )-2-(4-(3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-3-oxopropyl) phenyl)-2-methylpropanoic acid; ( R )-2-(4-(3-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)- 3-oxopropyl)phenyl)-2-methylpropanoic acid; ( R )-3-(4-(1-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)-2-methyl-1 -oxopropan-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(1-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)- 2-methyl-1-oxopropan-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R)-3-(4-(1-((6-(3-(2-cyclobutoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-2-methyl-1-oxo propan-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-oxopropyl)phenyl )-2,2-dimethylpropanoic acid; ( R )-3-(3-(3-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)- 3-oxopropyl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3'-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)-[1,1'-bi phenyl]-3-yl)-2,2-dimethylpropanoic acid; and ( R )-3-(3′-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamoyl)-[1,1′- Biphenyl]-4-yl)-2,2-dimethylpropanoic acid, or a pharmaceutically acceptable salt or isomer thereof.
[Claim 4]
A diacylglycerol acyl comprising a pharmaceutically acceptable carrier together with a compound of formula (1), or a pharmaceutically acceptable salt or isomer thereof, as defined in any one of claims 1 to 3 as an active ingredient. A pharmaceutical composition for the treatment of transferase 2 (DGAT2) related diseases.
[Claim 5]
5. The method of claim 4, wherein the DGAT2-related disease is selected from the group consisting of fatty liver, nonalcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), diabetes, obesity, hyperlipidemia, atherosclerosis, and hypercholesterolemia. which will be, a pharmaceutical composition.