Title of the Invention: Novel amino aryl derivatives useful as diacylglycerol acyltransferase 2 inhibitors and uses thereof
technical field
[One]
The present invention relates to an amino aryl 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 diet 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 caloric 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 attracting 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 associated with sterol regulatory element-binding proteins 1c (SREBP1c) and stearoyl 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 induced from an increase in genes such as carnitine palmitoyltransferase 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 decreased TAG supply 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]
An object of the present invention is to provide a novel amino aryl 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 amino aryl derivative compound.
[8]
Another object of the present invention is to provide a pharmaceutical composition for the treatment of metabolic diseases related to DGAT2, and a method for preparing the same, comprising the amino aryl derivative compound as an active ingredient.
[9]
Another object of the present invention is to use the amino aryl 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 in metabolic diseases related to DGAT2 in a subject and to provide a method of treatment with convenience of administration.
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 and D are each independently CH or N;
[16]
B and E are each independently CH, C-halogen, C-haloalkyl or N;
[17]
R 1 is alkyl, cycloalkyl or haloalkyl;
[18]
R 2 is hydrogen, halogen or alkyl;
[19]
R 3 is -GJ;
[20]
wherein G is aryl, arylene, arylene-alkylene, heteroaryl or heteroarylene;
[21]
J is hydrogen, amino, aminocarbonyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-oxy, heterocycloalkyl, aryl, aryl-oxy, aryl-alkoxy, heteroaryl, heteroaryl-amino, carboxyalkyl, carboxyalkenyl , carboxyalkyl-aryl, carboxyalkoxy-aryl, carboxyalkyl-heterocycloalkyl, carboxyalkenyl-heterocycloalkyl, carboxyalkoxy-heterocycloalkyl, carboxyalkyl-amino-aryl, carboxyalkyl-aryl-oxy or carboxyalkyl- heteroaryl;
[22]
wherein said alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl or heteroarylene may be optionally substituted, the substituents being from halo, -COOH, alkyl, alkoxy, haloalkyl, alkylsulfonyl and heteroaryl-alkyl. one or more selected;
[23]
The heterocycloalkyl, heteroaryl or heteroarylene comprises one or more heteroatoms selected from N, O and S.
[24]
[25]
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.
[26]
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.
[27]
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.
[28]
In defining the compound of Formula (1) throughout this specification, the concepts defined for the following substituents are used.
[29]
The term "halogen" or "halo" denotes fluorine (F), chlorine (Cl), bromine (Br) or iodine (I).
[30]
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.
[31]
The term “alkenyl” is a branched or unbranched hydrocarbon having at least one carbon-carbon double bond, preferably C 2 -C 10 alkenyl or C 2 -C 7 alkenyl. For example, the alkenyl includes, but is not limited to, vinyl, allyl, butenyl, isopropenyl, or isobutenyl.
[32]
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.
[33]
The term "alkoxy", unless otherwise defined, means alkyloxy having from 1 to 10 carbon atoms.
[34]
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.
[35]
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 Jolyl, 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, 4H-benzo [1,3] dioxin, 2,3-dihydrobenzo [1,4] dioxin, 6,7-dihydro-5H- cyclopenta[d]pyrimidine and the like.
[36]
The term “heterocycloalkyl” refers to a partially or fully 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 or 5 to 12 membered. This is preferable. Examples include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, imidazolinyl, piperazinyl, tetrahydrofuran, tetrahydrothiofuran, and the like.
[37]
Aryl-alkoxy, alkyl-aryl and heteroaryl-alkyl and alkyl-heteroaryl refer to a group formed by combining aryl or heteroaryl as defined above with alkyl or alkoxy, for example, benzyl, methoxyphenyl, thiophene methyl, pyrimidinemethyl, and the like.
[38]
[39]
According to one embodiment of the present invention, in the formula (1)
[40]
A and D are each independently CH or N;
[41]
B and E are each independently CH, C-halogen, C-halo-C 1 -C 7 alkyl or N;
[42]
R 1 is C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl or halo-C 1 -C 7 alkyl;
[43]
R 2 is hydrogen, halogen or C 1 -C 7 alkyl;
[44]
R 3 is -GJ;
[45]
wherein G is C 6 -C 10 aryl, C 6 -C 10 arylene, C 6 -C 10 arylene -C 1 -C 7 alkylene, 5 to 12 membered heteroaryl or 5 to 12 membered heteroarylene;
[46]
J is hydrogen, amino, aminocarbonyl, C 1 -C 7 alkoxy -C 1 -C 7 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl-oxy, 5 to 12 membered heterocycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryl-oxy, C 6 -C 10 aryl -C 1 -C 7 alkoxy, 5-12 membered heteroaryl, 5-12 membered heteroaryl-amino, carboxy-C 1 -C 7 alkyl, carboxy-C 2 -C 7alkenyl, carboxy-C 1 -C 7 alkyl -C 6 -C 10 aryl, carboxy-C 1 -C 7 alkoxy -C 6 -C 10 aryl, carboxy-C 1 -C 7 alkyl-5 to 12 membered heterocyclo alkyl, carboxy-C 2 -C 7 alkenyl-5 to 12 membered heterocycloalkyl, carboxy-C 1 -C 7 alkoxy-5 to 12 membered heterocycloalkyl, carboxy-C 1 -C 7 alkyl-amino-C 6 -C 10 aryl, carboxy-C 1 -C 7alkyl -C 6 -C 10 aryl-oxy or carboxy-C 1 -C 7 alkyl-5 to 12 membered heteroaryl;
[47]
Said alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl or heteroarylene may be optionally substituted, the substituents being halo, -COOH, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, halo- 1 to 4 selected from C 1 -C 7 alkyl, C 1 -C 7 alkylsulfonyl and 5 to 12 membered heteroaryl-C 1 -C 7 alkyl;
[48]
The heterocycloalkyl, heteroaryl or heteroarylene contains 1 to 5 heteroatoms selected from N, O and S.
[49]
[50]
Representative of the compounds of formula (1) according to the present invention may include, but are not limited to, the following compounds:
[51]
( R )-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)thiazole-5-carboxylic acid;
[52]
( R ) -N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4,5-dimethylthiazol-2-amine ;
[53]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)thiazol-2-amine;
[54]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4-phenylthiazol-2-amine;
[55]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[ d ]thiazol-2-amine;
[56]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-6-methoxybenzo[ d ]thiazol-2-amine;
[57]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-6-(methanesulfonyl)benzo[ d ]thiazole-2 -amines;
[58]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-3-(1-(2-methoxyethoxy)-2 -methylpropan-2-yl)isoxazol-5-amine;
[59]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2yl)-4-phenyloxazol-2-amine;
[60]
( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[ d ]oxazol-2-amine;
[61]
( R )-5-chloro- N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[ d ]oxazol-2-amine;
[62]
( R )-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[ d ]oxazol-5-yl ) acetic acid;
[63]
( R )-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2yl)amino)benzo[ d ]oxazol-5-yl) -2-methylpropanoic acid;
[64]
( R )-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2yl)amino)benzo[ d ]oxazol-5-yl) -2,2-dimethylpropanoic acid;
[65]
( R,E )-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[ d ]oxazole-5 -yl) acrylic acid;
[66]
( R )-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[ d ]oxazol-5-yl ) propanoic acid;
[67]
( R )-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[ d ]oxazol-6-yl )-2-methylpropanoic acid;
[68]
( R )-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[ d ]oxazol-6-yl ) propanoic acid;
[69]
( R )-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N- ( 1 H -pyrazol-3-yl)pyrazin-2-amine;
[70]
( R )-2-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H - pyrazol-1-yl ) acetic acid;
[71]
( R )-3-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H - pyrazol-1-yl )-2,2-dimethylpropanoic acid;
[72]
( R )-3-(3-(6-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoropyrimidin-2-yl)amino)pyridine -2-yl)phenyl)-2,2-dimethylpropanoic acid;
[73]
( R )-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N- ( 1-methyl- 1H -tetrazol-5-yl)pyrazin-2-amine;
[74]
( R ) -N -6-(3-(2-ethoxyphenoxy)piperidin-1-yl) -N -phenylpyrazin-2-amine;
[75]
( R ) -N- (4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)methanesulfonamide;
[76]
( R )-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-N- ( pyridin-4- ylmethyl)acetamide;
[77]
( R )-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-2-methylpropanoic acid;
[78]
( R )-2-(4-((6-(3-(2-ethoxyphenoxy)pyridin-1-yl)pyrazin-2-yl)amino)phenyl)-2-methylpropanoic acid;
[79]
( R )-2-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-2-methylpropanoic acid;
[80]
( R )-3-(3′-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-[1,1′-biphenyl ]-4-yl)-2,2-dimethylpropanoic acid;
[81]
( R )-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N- ( pyridin-2-yl)pyrazin-2-amine;
[82]
( R )-6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)nicotinic acid;
[83]
( R )-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)isonicotinic acid;
[84]
( R )-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)nicotinic acid;
[85]
( R )-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)-2-methyl propanoic acid;
[86]
( R )-2-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)acetic acid;
[87]
( R,E )-3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)acrylic acid;
[88]
( R )-3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)propanoic acid;
[89]
( R )-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)-2,2 -dimethylpropanoic acid;
[90]
( R )-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N- ( 5-phenylpyridin-2-yl)pyrazin-2-amine;
[91]
( R )-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N- ( 4-phenylpyridin-2-yl)pyrazin-2-amine;
[92]
( R )-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl )-2-methylpropanoic acid;
[93]
( R )-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl )-2-methylpropanoic acid;
[94]
( R )-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl )-2,2-dimethylpropanoic acid;
[95]
( R )-3-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl )-2,2-dimethylpropanoic acid;
[96]
( R )-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl ) propanoic acid;
[97]
( R )-3-(3-(5-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)phenyl )-2,2-dimethylpropanoic acid;
[98]
( R )-3-(3-(5-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl )-2,2-dimethylpropanoic acid;
[99]
( R )-2-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)phenyl)-2 -methylpropanoic acid;
[100]
( R )-2-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-2-methyl propanoic acid;

Claims
[Claim 1]
A compound of Formula (1), or a pharmaceutically acceptable salt or isomer thereof: [Formula (1)] In Formula (1), A and D are each independently CH or N; B and E are each independently CH, C-halogen, C-haloalkyl or N; R 1 is alkyl, cycloalkyl or haloalkyl; R 2 is hydrogen, halogen or alkyl; R 3 is -GJ; wherein G is aryl, arylene, arylene-alkylene, heteroaryl or heteroarylene; J is hydrogen, amino, aminocarbonyl, alkoxy-alkyl, cycloalkyl, cycloalkyl-oxy, heterocycloalkyl, aryl, aryl-oxy, aryl-alkoxy, heteroaryl, heteroaryl-amino, carboxyalkyl, carboxyalkenyl , carboxyalkyl-aryl, carboxyalkoxy-aryl, carboxyalkyl-heterocycloalkyl, carboxyalkenyl-heterocycloalkyl, carboxyalkoxy-heterocycloalkyl, carboxyalkyl-amino-aryl, carboxyalkyl-aryl-oxy or carboxyalkyl- heteroaryl; wherein said alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl or heteroarylene may be optionally substituted, the substituents being from halo, -COOH, alkyl, alkoxy, haloalkyl, alkylsulfonyl and heteroaryl-alkyl. one or more selected; The heterocycloalkyl, heteroaryl or heteroarylene comprises one or more heteroatoms selected from N, O and S.
[Claim 2]
The method of claim 1, wherein A and D are each independently CH or N; B and E are each independently CH, C-halogen, C-halo-C 1 -C 7 alkyl or N; R 1 is C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl or halo-C 1 -C 7 alkyl; R 2 is hydrogen, halogen or C 1 -C 7 alkyl; R 3 is -GJ; where G is C 6 -C 10 aryl, C 6 -C 10 arylene, C 6 -C 10 arylene -C 1-C 7 alkylene, 5-12 membered heteroaryl or 5-12 membered heteroarylene; J is hydrogen, amino, aminocarbonyl, C 1 -C 7 alkoxy -C 1 -C 7 alkyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkyl-oxy, 5 to 12 membered heterocycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryl-oxy, C 6 -C 10 aryl -C 1 -C 7 alkoxy, 5-12 membered heteroaryl, 5-12 membered heteroaryl-amino, carboxy-C 1 -C 7alkyl, carboxy-C 2 -C 7 alkenyl, carboxy-C 1 -C 7 alkyl -C 6 -C 10 aryl, carboxy-C 1 -C 7 alkoxy -C 6 -C 10 aryl, carboxy-C 1 -C 7 alkyl-5-12 membered heterocycloalkyl, carboxy-C 2 -C 7 alkenyl-5-12 membered heterocycloalkyl, carboxy-C 1 -C 7 alkoxy-5-12 membered heterocycloalkyl, carboxy-C 1 -C 7 alkyl-amino-C 6 -C 10aryl, carboxy-C 1 -C 7 alkyl -C 6 -C 10 aryl-oxy or carboxy-C 1 -C 7 alkyl-5 to 12 membered heteroaryl; Said alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl or heteroarylene may be optionally substituted, the substituents being halo, -COOH, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, halo- C 1 -C 7 alkyl, C 1 -C 7 alkylsulfonyl and 5-12 membered heteroaryl-C 1 -C 71 to 4 selected from alkyl; The heterocycloalkyl, heteroaryl or heteroarylene 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 )-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)thi azole-5-carboxylic acid; ( R ) -N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4,5-dimethylthiazol-2-amine ; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)thiazol-2-amine; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4-phenylthiazol-2-amine; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[ d ]thiazol-2-amine; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-6-methoxybenzo[ d ]thiazol-2-amine; ( R ) -N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-6-(methanesulfonyl)benzo[ d ]thiazol-2-amine; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-3-(1-(2-methoxyethoxy)-2 -methylpropan-2-yl)isoxazol-5-amine; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2yl)-4-phenyloxazol-2-amine; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[ d ]oxazol-2-amine; ( R )-5-chloro- N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[ d ]oxazol-2-amine; ( R )-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[ d ]oxazol-5-yl ) acetic acid; ( R)-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2yl)amino)benzo[ d ]oxazol-5-yl)-2 -methylpropanoic acid; ( R )-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2yl)amino)benzo[ d ]oxazol-5-yl) -2,2-dimethylpropanoic acid; ( R,E )-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[ d ]oxazole-5 -yl) acrylic acid; ( R )-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[ d ]oxazol-5-yl ) propanoic acid; ( R )-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[ d ]oxazol-6-yl )-2-methylpropanoic acid; ( R )-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[ d ]oxazol-6-yl ) propanoic acid; ( R )-6-(3-(2-ethoxyphenoxy)piperidin-1-yl) -N-(1 H -pyrazol-3-yl)pyrazin-2-amine; ( R )-2-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H - pyrazol-1-yl ) acetic acid; ( R )-3-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H - pyrazol-1-yl )-2,2-dimethylpropanoic acid; ( R )-3-(3-(6-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoropyrimidin-2-yl)amino)pyridine -2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N- ( 1-methyl- 1H -tetrazol-5-yl)pyrazin-2-amine; ( R ) -N -6-(3-(2-ethoxyphenoxy)piperidin-1-yl) -N -phenylpyrazin-2-amine; ( R ) -N-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)methanesulfonamide; ( R )-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-N- ( pyridin-4- ylmethyl)acetamide; ( R )-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-2-methylpropanoic acid; ( R )-2-(4-((6-(3-(2-ethoxyphenoxy)pyridin-1-yl)pyrazin-2-yl)amino)phenyl)-2-methylpropanoic acid; ( R )-2-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-2-methylpropanoic acid; ( R )-3-(3′-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-[1,1′-biphenyl ]-4-yl)-2,2-dimethylpropanoic acid; ( R )-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N- ( pyridin-2-yl)pyrazin-2-amine; ( R )-6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)nicotinic acid; ( R)-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)isonicotinic acid; ( R )-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)nicotinic acid; ( R )-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)-2-methyl propanoic acid; ( R )-2-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)acetic acid; ( R,E )-3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)acrylic acid; ( R )-3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)propanoic acid; ( R )-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)-2,2 -dimethylpropanoic acid; ( R )-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N- ( 5-phenylpyridin-2-yl)pyrazin-2-amine; ( R )-6-(3-(2-ethoxyphenoxy)piperidin-1-yl) -N-(4-phenylpyridin-2-yl)pyrazin-2-amine; ( R )-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl )-2-methylpropanoic acid; ( R )-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl )-2-methylpropanoic acid; ( R )-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl )-2,2-dimethylpropanoic acid; ( R )-3-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl )-2,2-dimethylpropanoic acid; ( R )-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl ) propanoic acid; ( R )-3-(3-(5-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)phenyl )-2,2-dimethylpropanoic acid; ( R )-3-(3-(5-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl )-2,2-dimethylpropanoic acid; ( R)-2-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)phenyl)-2-methyl propanoic acid; ( R )-2-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-2-methyl propanoic acid; ( R )-3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-2,2 -dimethylpropanoic acid; 1-(6-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)pyrrolidin- 3-carboxylic acid; 1-(6-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-3-methyl pyrrolidine-3-carboxylic acid; 1-(6-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidin- 3- carboxylic acid; ( R )-1-(6-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl) piperidine-3-carboxylic acid; ( R )-1-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidin- 4- carboxylic acid; ( R)-2-(1-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidine -4-yl)acetic acid; ( R )-2-(1-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)pi peridin-4-yl)-2-methylpropanoic acid; 2-((( S )-1-(6-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin- 2-yl)piperidin-3-yl)acetic acid;( R )-2-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine) -2-yl)amino)pyridin-2-yl)phenyl)-2-methylpropanoic acid;( R )-2-(4-(6-((6-(3-(2-ethoxyphenoxy)p) Peridin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2-methylpropanoic acid;( R )-2-(4-(6-((6-(3-( (3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2-methylpropanoic acid ; (3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2,2- dimethylpropanoic acid; ( R)-3-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2 -yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyridin-2-yl)amino)pyridin-2-yl)phenyl )-2,2-dimethylpropanoic acid; ( R )-3-(3-(6-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)pyridin-2-yl) phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-2-yl)amino)pyridin-2-yl) phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(6-((4-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)amino) pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H - pyrazol-1-yl )phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(6-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-(trifluoromethyl)pyrimidin-4-yl) )amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R)-3-(3-(6-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-(trifluoromethyl)pyrimidin-2-yl)amino )pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl )-2,2-dimethylpropanoic acid; ( R )-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)glycine ; ( R )-(4-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2 -yl)phenyl)glycine; ( R )-(4-(6-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)pyridin-2-yl)phenyl) glycine; ( R )-(4-(6-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)glycine ; ( R )-2-((4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl) phenyl)amino)-2-methylpropanoic acid; ( R )-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)- 4-fluorophenyl)-2,2-dimethylpropanoic acid; ( R)-3-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2 -yl)-4-fluorophenyl)-2,2-dimethylpropanoic acid; ( R )-2-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenoxy c)-2-methylpropanoic acid; ( R )-2-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridine -2-yl)phenoxy)-2-methylpropanoic acid; ( R )-2-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenoxy c)-2-methylpropanoic acid; ( R )-2-(4-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridine -2-yl)phenoxy)-2-methylpropanoic acid; ( R )-2-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)- 4-fluorophenoxy)-2-methylpropanoic acid; ( R )-2-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridine -2-yl)-4-fluorophenoxy)-2-methylpropanoic acid; ( R)-3-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl) -1H -pyrazol-1-yl)-2,2-dimethylpropanoic acid; ( R )-3-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)benzoic acid ; ( R )-3-((6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2 -yl)oxy)benzoic acid; ( R )-4-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)benzoic acid ; ( R )-4-((6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2 -yl)oxy)benzoic acid; ( R )-2-(3-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl) oxy)phenyl)-2-methylpropanoic acid; ( R )-2-(3-((6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino) pyridin-2-yl)oxy)phenyl)-2-methylpropanoic acid; ( R)-2-(4-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy) phenyl)-2-methylpropanoic acid; ( R )-2-(4-((6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino) pyridin-2-yl)oxy)phenyl)-2-methylpropanoic acid; ( R )-2-(3-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl) oxy)phenyl)acetic acid; ( R )-2-(3-((6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino) pyridin-2-yl)oxy)phenyl)acetic acid; ( R )-2-(4-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl) oxy)phenyl)acetic acid; ( R )-2-(4-((6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino) pyridin-2-yl)oxy)phenyl)acetic acid; ( R )-4-(((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy) methyl)benzoic acid; ( R )-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-5-fluoropyridine- 2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)-5 -fluoropyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-fluoropyridine- 2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)- 3-fluoropyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-2-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)- 5-fluoropyridin-2-yl)phenoxy)-2-methylpropanoic acid; ( R )-2-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)- 3-fluoropyridin-2-yl)phenoxy)-2-methylpropanoic acid; ( R )-3-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)- 3-fluoropyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-5-fluoropyridine- 2-yl)-4-fluorophenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)-5 -fluoropyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoic acid; ( R )-2-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-(trifluoro methyl)pyridin-2-yl)phenyl)-2-methylpropanoic acid; ( R )-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-4-(trifluoro methyl)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-methylpyridin-2 -yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrazin-2-yl)phenyl )-2,2-dimethylpropanoic acid; ( R ) -N- (6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)pyrimidin-2-amine; ( R )-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidine-5-carboxylic acid; ( R)-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)pyrimidin-4-yl)-2-methylpropanoic acid; ( R )-2-(2-((4-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)pyrimidin-4- yl)-2-methylpropanoic acid;(2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidine- 4-yl) -L -proline;1-(2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyri Midin-4-yl)pyrrolidine-3-carboxylic acid 1-(2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine-2- yl)amino)pyrimidin-4-yl)-3-methylpyrrolidine-3-carboxylic acid 1-(2-((6-(( R )-3-(2-ethoxyphenoxy)piperidine) -1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidine-3-carboxylic acid;( R )-1-(2-((6-(( R )-3-(2) -ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidine-3-carboxylic acid 1-(2-((6-(( R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)-3-methylpiperidine-3-carboxylic acid; ( R )-1-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidine -4-carboxylic acid; 5-(2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)bicyclo[ 2.2.1]heptane-2-carboxylic acid; ( R )-2-(1-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl) piperidin-4-yl)acetic acid; ( R )-2-(1-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl) piperidin-4-yl)-2-methylpropanoic acid; ( R )-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl) piperazin-1-yl)acetic acid; 2-(( S )-1-(2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidine- 4-yl)piperidin-3-yl)acetic acid; ( E )-3-(( S )-1-(2-((6-(( R ))-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidin-3-yl)acrylic acid; 3-(( S )-1-(2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidine- 4-yl)piperidin-3-yl)propanoic acid; 2-((( S )-1-(2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidine -4-yl)piperidin-3-yl)oxy)acetic acid; 2-((( R )-1-(2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidine -4-yl)piperidin-3-yl)oxy)acetic acid; 2-((( R )-1-(2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidine -4-yl)piperidin-3-yl)oxy)-2-methylpropanoic acid; ( R )-4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)oxy)cyclo hexane-1-carboxylic acid; (1 R, 4 r )-4-((2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)oxy)cyclohexane-1-carboxylic acid; (1 R, 4 r )-4-((2-((6-(( R )-3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine-2 -yl)amino)pyrimidin-4-yl)oxy)cyclohexane-1-carboxylic acid; (1 S, 4 s )-4-((2-((6-(( R )-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyri midin-4-yl)oxy)cyclohexane-1-carboxylic acid; (1 S, 4 s )-4-((2-((6-(( R )-3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine-2 -yl)amino)pyrimidin-4-yl)oxy)cyclohexane-1-carboxylic acid; ( R )-6-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)picolinic acid ; ( R )-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl) phenyl)acetic acid; ( R )-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl )-2-methylpropanoic acid; ( R )-2-(3-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyri midin-4-yl)phenyl)-2-methylpropanoic acid; ( R )-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl) phenyl)-2-methylpropanoic acid; ( R )-2-(4-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyri midin-4-yl)phenyl)-2-methylpropanoic acid; ( R )-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl) phenyl) propanoic acid; ( R )-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl) phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyri midin-4-yl)phenyl)-2,2-dimethylpropanoic acid; ( R)-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl) -2,2-dimethylpropanoic acid; ( R )-3-(3-(2-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)pyrimidin-4-yl )phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(3-(2-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl )phenyl)-2,2-dimethylpropanoic acid; ( R )-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl) phenyl)acetic acid; ( R )-2-(4-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyri midin-4-yl)phenyl)acetic acid; ( R )-3-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl) phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyri midin-4-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(2-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)pyrimidin-4-yl )phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(2-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl) phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(2-((4-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)amino) pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl) phenoxy)-2-methylpropanoic acid; ( R )-2-(3-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyri midin-4-yl)phenoxy)-2-methylpropanoic acid; ( R )-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl) phenoxy)-2-methylpropanoic acid; ( R )-2-((4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl )phenyl)amino)-2-methylpropanoic acid; ( R )-2-(4-((2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl )oxy)phenyl)acetic acid; ( R)-2-(4-((2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidine -4-yl)phenyl)acetic acid;( R )-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl) amino)-5-fluoropyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid;( R )-3-(3-(2-((6-(3-((3-to Toxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)phenyl)-2,2-dimethyl propanoic acid; ( R )-3-(3-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl) Amino)-6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid;( R )-3-(3-(2-((6-(3-( 2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid ( R )-2-(3-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl )phenyl)-2-methylpropanoic acid;( R )-2-(4-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl) )amino)pyrimidin-2-yl)phenyl)-2-methylpropanoic acid ;)-3-(3-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl)phenyl) -2,2-dimethylpropanoic acid; ( R )-3-(3-(4-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyri midin-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl) phenyl)-2,2-dimethylpropanoic acid; ( R )-3-(4-(4-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyri midin-2-yl)phenyl)-2,2-dimethylpropanoic acid; ( R )-2-(3-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl) phenoxy)-2-methylpropanoic acid; ( R )-2-(3-(4-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyri midin-2-yl)phenoxy)-2-methylpropanoic acid; ( R )-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl) phenoxy)-2-methylpropanoic acid; ( R)-2-(4-(6-((6-(3-(2-ethoxy-4-fluorophenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2- yl)phenoxy)-2-methylpropanoic acid; ( R )-2-(4-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl) phenoxy)-2-methylpropanoic acid; and ( R )-2-(4-(4-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino) Pyrimidin-2-yl)phenoxy)-2-methylpropanoic 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.