Novel aminoaryl derivatives useful as diacylglycerol acyltransferase 2 inhibitors and their use

Abstract

The present invention relates to an aminoaryl derivative compound represented by chemical formula (1) and exhibiting diacylglycerol acyltransferase 2 (DGAT2) inhibitory activity, a pharmaceutical composition comprising the compound as an active ingredient, and use thereof.

Description

Technical Field

[0001] The present invention relates to an aminoaryl derivative compound represented by formula (1) that exhibits inhibitory activity against diacylglycerol acyltransferase 2 (DGAT2), a pharmaceutical composition comprising the compound as an active ingredient, and uses thereof. Background Art

[0002] Along with economic development, the raising of living standard, the frequent consumption of instant food and the change of the eating habit based on meat have caused the excessive accumulation of heat in the body.These changes in modern people's dietary life also cause the reduction of the caloric consumption caused by lack of exercise, causing the serious prevalence of metabolic diseases such as obesity, hyperlipidemia, diabetes, cardiovascular disease, coronary artery disease.Particularly, obesity is one of rapidly increasing diseases, and is reported to be the cause of metabolic diseases such as diabetes.Developing the therapeutic agent for metabolic diseases by controlling the function of the enzyme of the biosynthetic pathway of triglyceride that participates as the main cause of obesity has aroused people's concern.

[0003] Neutral fats, such as triglycerides (TG), play a crucial role in the body's energy storage function as a source of energy. However, when neutral fats accumulate excessively in organs or tissues, they can cause obesity, hypertriglyceridemia, fatty liver disease, and other serious diseases, leading to serious illnesses such as diabetes, arteriosclerosis, metabolic abnormalities, and organ dysfunction. Diacylglycerol acyltransferase is a key enzyme in triglyceride biosynthesis. It is present in various mammalian tissues and is an enzyme that synthesizes TG by combining fatty acyl-CoA with the hydroxyl group of diacylglycerol in the final step of the phosphoglycerol pathway, the primary pathway for triglyceride synthesis. Currently, two isoforms are known: DGAT1 and DGAT2. Although their biochemical functions are similar, they differ in that DGAT1 is primarily expressed in the small intestine and adipose tissue, while DGAT2 is primarily expressed in the liver and adipose tissue. Furthermore, in terms of gene families, DGAT1 belongs to the ACAT family, while DGAT2 belongs to the MGAT family. Therefore, their roles in TG biosynthesis are expected to differ.

[0004] Several studies, including animal studies, have shown that DGAT2 contributes primarily to the biosynthesis of TG in the body. Unlike DGAT2 knockout mice, which rarely synthesize TG and die shortly after birth due to skin layer abnormalities, DGAT1 knockout mice show a slight decrease in TG levels, and the mice survive without problems (Stone SJ et al., 2000. Nat. Genet. 25: 87-90). In addition, as a result of reducing the expression level of DGAT1 or DGAT2 using antisense oligonucleotides (ASOs) in an animal model of fatty liver, fatty liver symptoms are alleviated only when the amount of DGAT2 is reduced, and the rate of glucose production in the liver is significantly reduced (Choi CS et al., 2007. Hepatology. 45: 1366-74).

[0005] The underlying molecular mechanisms have not yet been fully elucidated, but it is believed that inhibition of DGAT2 leads to downregulation of the expression of genes encoding multiple proteins involved in lipid production, such as sterol regulatory element binding protein 1c (SREBP1c) and stearoyl-CoA-desaturase 1 (SCD1). Simultaneously, it is believed that oxidative pathways are induced by increases in genes such as carnitine palmitoyltransferase 1 (CPT1). These changes, in turn, lead to a decrease in hepatic DAG and TAG lipid levels, thereby improving insulin responsiveness in the liver. Furthermore, inhibition of DGAT2 suppresses hepatic VLDL TAG secretion and lowers circulating cholesterol levels. Finally, plasma apolipoprotein B (APOB) levels are suppressed, which is believed to be caused by a reduced supply of TAG in the lipidation of newly synthesized APOB protein. That is, when DGAT2 is inhibited, beneficial effects are shown on both glycemic control and plasma cholesterol profiles, suggesting that DGAT2 inhibition may be applicable to the treatment of metabolic disorders. Summary of the Invention

[0006] Technical issues

[0007] An object of the present invention is to provide a novel aminoaryl derivative compound represented by formula (1) which exhibits inhibitory activity against diacylglycerol acyltransferase 2 (DGAT2).

[0008] Another object of the present invention is to provide a method for preparing the aminoaryl derivative compound.

[0009] Another object of the present invention is to provide a pharmaceutical composition comprising the aminoaryl derivative compound as an active ingredient for treating metabolic diseases associated with DGAT2 and a preparation method thereof.

[0010] Yet another object of the present invention is to provide a method for treating a metabolic disease associated with DGAT2 in a subject, wherein by using an aminoaryl derivative compound having improved physical and chemical properties compared to conventional compounds as an active ingredient, the efficacy in a disease animal model and the efficacy and convenience of administration in the subject are improved.

[0011] Technical Solutions

[0012] In order to achieve the above object, the present invention provides a compound of the following formula (1) or a pharmaceutically acceptable salt or isomer thereof:

[0013] [Formula (1)]

[0014]

[0015] in

[0016] A and D are each independently CH or N;

[0017] B and E are each independently CH, C-halogen, C-haloalkyl or N;

[0018] R 1 is alkyl, cycloalkyl or haloalkyl;

[0019] R 2 is hydrogen, halogen or alkyl;

[0020] R 3 Yes - GJ;

[0021] wherein G is aryl, arylene, arylene-alkylene, heteroaryl, or heteroarylene;

[0022] 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;

[0023] wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl or heteroarylene is optionally substituted with one or more substituents selected from halogen, -COOH, alkyl, alkoxy, haloalkyl, alkylsulfonyl and heteroaryl-alkyl; and

[0024] The heterocycloalkyl, heteroaryl and heteroarylene groups include one or more heteroatoms selected from N, O and S.

[0025] The compound of formula (1) according to the present invention can form a pharmaceutically acceptable salt. Pharmaceutically acceptable salts can include acid addition salts formed from the following acids: inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid and hydroiodic acid, 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 and salicylic acid, or sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, the acid forming a non-toxic acid addition salt comprising a pharmaceutically acceptable anion. In addition, pharmaceutically acceptable carboxylates include salts with alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium and magnesium, salts with amino acids such as lysine, arginine and guanidine, organic salts such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, diethanolamine, choline and triethanolamine. The compound of formula (1) according to the present invention can be converted into their salts by conventional methods.

[0026] Meanwhile, since the compounds of formula (1) according to the present invention may have an asymmetric carbon center and an asymmetric axis or plane, they may exist as E- or Z-isomers, R- or S-isomers, racemic mixtures or diastereomeric mixtures and each diastereoisomer, all of which are within the scope of the present invention.

[0027] Herein, unless otherwise indicated, the term "compound of formula (1)" is used to refer to all compounds of formula (1), including pharmaceutically acceptable salts and isomers thereof.

[0028] Herein, the compounds of formula (1) are defined using the following concepts for the definition of substituents.

[0029] The term "halogen" or "halo" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0030] The term "alkyl" or "alkylene" refers to a straight or branched chain hydrocarbon, which may contain single, double or triple bonds, and is preferably C1-C 10 Alkyl or C1-C 10 Alkylene or C1-C7 alkyl or C1-C7 alkylene. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, ethynyl, vinyl, trifluoromethyl, etc.

[0031] The term "alkenyl" refers to a straight or branched chain hydrocarbon having at least one carbon-carbon double bond, and is preferably C2-C 10 Examples of alkenyl groups include, but are not limited to, vinyl, allyl, butenyl, isopropenyl, isobutenyl, and the like.

[0032] The term "cycloalkyl" refers to a partially or fully saturated monocyclic or fused cyclic hydrocarbon, and is preferably C3-C 10- Cycloalkyl. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0033] Unless otherwise defined, the term "alkoxy" refers to an alkoxy group having 1 to 10 carbon atoms.

[0034] The term "aryl" or "arylene" refers to an aromatic hydrocarbon, preferably a C5-C 12 Aryl or C5-C 12 Arylene, more preferably C6-C 10 Aryl or C6-C 10 Arylene, and includes but is not limited to phenyl, naphthyl, and the like.

[0035] The term "heteroaryl" or "heteroarylene" refers to a 3- to 12-membered, more preferably 5- to 12-membered aromatic hydrocarbon that forms a monocyclic or fused ring (which may be fused to a benzene ring or a C3-C8 cycloalkyl ring) including one or more heteroatoms selected from N, O and S as ring members. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, Oxazolyl, iso Oxazolyl, tetrazolyl, triazolyl, indolyl, indazolyl, iso Azolyl, oxazolyl, thiazolyl, isothiazolyl, furyl, benzofuranyl, imidazolyl, thiophenyl, benzothiazole, benzimidazole, quinolinyl, indolyl, 1,2,3,4-tetrahydroisoquinolinyl, 3,4-dihydroisoquinolinyl, thiazolopyridyl, 2,3-dihydrobenzofuran, 2,3-dihydrothiophene, 2,3-dihydroindole, benzo[1,3]diol Chroman, thiochroman, 1,2,3,4-tetrahydroquinoline, 4H-benzo[1,3]diol oxadiazole, 2,3-dihydrobenzo[1,4] ... English, 6,7-dihydro-5H-cyclopenta[d]pyrimidine, etc.

[0036] The term "heterocycloalkyl" refers to a partially or fully saturated hydrocarbon that forms a monocyclic or condensed ring including one or more heteroatoms selected from N, O and S, and is preferably a 3- to 12-membered heterocycloalkyl or a 5- to 12-membered heterocycloalkyl. Examples of heterocycloalkyl include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, imidazolinyl, piperazinyl, tetrahydrofuran, tetrahydrothiofuran, and the like.

[0037] Aryl-alkoxy, alkyl-aryl, heteroaryl-alkyl and alkyl-heteroaryl refer to groups formed by combining the above aryl or heteroaryl groups with alkyl or alkoxy groups. Examples include, but are not limited to, benzyl, methoxyphenyl, thienylmethyl, pyrimidinylmethyl and the like.

[0038] According to one embodiment of the present invention, in the above formula (1)

[0039] A and D are each independently CH or N;

[0040] B and E are each independently CH, C-halogen, C-halo-C1-C7 alkyl or N;

[0041] R 1 is C1-C7 alkyl, C3-C7 cycloalkyl or halo-C1-C7 alkyl;

[0042] R 2 is hydrogen, halogen or C1-C7 alkyl;

[0043] R 3 Yes - GJ;

[0044] Where G is C6-C 10 Aryl, C6-C 10 Arylene, C6-C 10 Arylene-C1-C7 alkylene, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroarylene;

[0045] J is hydrogen, amino, aminocarbonyl, C1-C7 alkoxy-C1-C7 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl-oxy, 5- to 12-membered heterocycloalkyl, C6-C 10 Aryl, C6-C 10 Aryl-oxy, C6-C 10 Aryl-C1-C7 alkoxy, 5- to 12-membered heteroaryl, 5- to 12-membered heteroaryl-amino, carboxyl-C1-C7 alkyl, carboxyl-C2-C7 alkenyl, carboxyl-C1-C7 alkyl-C6-C 10 Aryl, carboxyl-C1-C7 alkoxy-C6-C 10 Aryl, carboxyl-C1-C7 alkyl-5 to 12-membered heterocycloalkyl, carboxyl-C2-C7 alkenyl-5 to 12-membered heterocycloalkyl, carboxyl-C1-C7 alkoxy-5 to 12-membered heterocycloalkyl, carboxyl-C1-C7 alkyl-amino-C6-C 10 Aryl, carboxyl-C1-C7 alkyl-C6-C 10 Aryl-oxy or carboxyl-C1-C7 alkyl-5- to 12-membered heteroaryl;

[0046] wherein the alkyl, alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl or heteroarylene is optionally substituted with 1 to 4 substituents selected from halogen, -COOH, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkyl, C1-C7 alkylsulfonyl and 5- to 12-membered heteroaryl-C1-C7 alkyl; and

[0047] The heterocycloalkyl, heteroaryl and heteroarylene groups include 1 to 5 heteroatoms selected from N, O and S.

[0048] Representative compounds of formula (1) according to the present invention include but are not limited to the following compounds:

[0049] (R)-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)thiazole-5-carboxylic acid;

[0050] (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4,5-dimethylthiazol-2-amine;

[0051] (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)thiazol-2-amine;

[0052] (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4-phenylthiazol-2-amine;

[0053] (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[d]thiazol-2-amine;

[0054] (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-6-methoxybenzo[d]thiazol-2-amine;

[0055] (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-6-(methylsulfonyl)benzo[d]thiazol-2-amine;

[0056] (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-3-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)isothiazolin-1-yl Azol-5-amine;

[0057] (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4-phenyl Azol-2-amine;

[0058] (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[d] Azol-2-amine;

[0059] (R)-5-Chloro-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[d] Azol-2-amine;

[0060] (R)-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-5-yl)acetic acid;

[0061] (R)-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-5-yl)-2-methylpropionic acid;

[0062] (R)-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-5-yl)-2,2-dimethylpropanoic acid;

[0063] (R,E)-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-5-yl)acrylic acid;

[0064] (R)-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-5-yl)propionic acid;

[0065] (R)-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-6-yl)-2-methylpropionic acid;

[0066] (R)-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-6-yl)propionic acid;

[0067] (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(1H-pyrazol-3-yl)pyrazin-2-amine;

[0068] (R)-2-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H-pyrazol-1-yl)acetic acid;

[0069] (R)-3-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H-pyrazol-1-yl)-2,2-dimethylpropanoic acid;

[0070] (R)-3-(3-(6-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0071] (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(1-methyl-1H-tetrazol-5-yl)pyrazin-2-amine;

[0072] (R)-N-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-phenylpyrazin-2-amine;

[0073] (R)-N-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)methanesulfonamide;

[0074] (R)-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-N-(pyridin-4-ylmethyl)acetamide;

[0075] (R)-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-2-methylpropanoic acid;

[0076] (R)-2-(4-((6-(3-(2-ethoxyphenoxy)pyridin-1-yl)pyrazin-2-yl)amino)phenyl)-2-methylpropanoic acid;

[0077] (R)-2-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-2-methylpropanoic acid;

[0078] (R)-3-(3'-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-[1,1'-biphenyl]-4-yl)-2,2-dimethylpropanoic acid;

[0079] (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(pyridin-2-yl)pyrazin-2-amine;

[0080] (R)-6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)nicotinic acid;

[0081] (R)-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)isonicotinic acid;

[0082] (R)-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)nicotinic acid;

[0083] (R)-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)-2-methylpropanoic acid;

[0084] (R)-2-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)acetic acid;

[0085] (R,E)-3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)acrylic acid;

[0086] (R)-3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)propanoic acid;

[0087] (R)-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)-2,2-dimethylpropanoic acid;

[0088] (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(5-phenylpyridin-2-yl)pyrazin-2-amine;

[0089] (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(4-phenylpyridin-2-yl)pyrazin-2-amine;

[0090] (R)-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl)-2-methylpropanoic acid;

[0091] (R)-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl)-2-methylpropanoic acid;

[0092] (R)-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl)-2,2-dimethylpropanoic acid;

[0093] (R)-3-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl)-2,2-dimethylpropanoic acid;

[0094] (R)-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl)propanoic acid;

[0095] (R)-3-(3-(5-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)phenyl)-2,2-dimethylpropanoic acid;

[0096] (R)-3-(3-(5-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0097] (R)-2-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)phenyl)-2-methylpropanoic acid;

[0098] (R)-2-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-2-methylpropanoic acid;

[0099] (R)-3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-2,2-dimethylpropanoic acid;

[0100] 1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)pyrrolidine-3-carboxylic acid;

[0101] 1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-3-methylpyrrolidine-3-carboxylic acid;

[0102] 1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidine-3-carboxylic acid;

[0103] (R)-1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidine-3-carboxylic acid;

[0104] (R)-1-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidine-4-carboxylic acid;

[0105] (R)-2-(1-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid;

[0106] (R)-2-(1-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidin-4-yl)-2-methylpropanoic acid;

[0107] 2-(((S)-1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidin-3-yl)acetic acid;

[0108] (R)-2-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2-methylpropanoic acid;

[0109] (R)-2-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2-methylpropanoic acid;

[0110] (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;

[0111] (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0112] (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;

[0113] (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyridin-2-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0114] (R)-3-(3-(6-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0115] (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-2-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0116] (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;

[0117] (R)-3-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H-pyrazol-1-yl)phenyl)-2,2-dimethylpropanoic acid;

[0118] (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;

[0119] (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;

[0120] (R)-3-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0121] (R)-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)glycine;

[0122] (R)-(4-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)glycine;

[0123] (R)-(4-(6-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)pyridin-2-yl)phenyl)glycine;

[0124] (R)-(4-(6-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)glycine;

[0125] (R)-2-((4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)amino)-2-methylpropanoic acid;

[0126] (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoic acid;

[0127] (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;

[0128] (R)-2-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenoxy)-2-methylpropanoic acid;

[0129] (R)-2-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenoxy)-2-methylpropanoic acid;

[0130] (R)-2-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenoxy)-2-methylpropanoic acid;

[0131] (R)-2-(4-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenoxy)-2-methylpropanoic acid;

[0132] (R)-2-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-4-fluorophenoxy)-2-methylpropanoic acid;

[0133] (R)-2-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-4-fluorophenoxy)-2-methylpropanoic acid;

[0134] (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;

[0135] (R)-3-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)benzoic acid;

[0136] (R)-3-((6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)benzoic acid;

[0137] (R)-4-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)benzoic acid;

[0138] (R)-4-((6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)benzoic acid;

[0139] (R)-2-(3-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)phenyl)-2-methylpropanoic acid;

[0140] (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;

[0141] (R)-2-(4-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)phenyl)-2-methylpropanoic acid;

[0142] (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;

[0143] (R)-2-(3-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)phenyl)acetic acid;

[0144] (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;

[0145] (R)-2-(4-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)phenyl)acetic acid;

[0146] (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;

[0147] (R)-4-(((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)methyl)benzoic acid;

[0148] (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-5-fluoropyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0149] (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;

[0150] (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-fluoropyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0151] (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;

[0152] (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;

[0153] (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;

[0154] (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;

[0155] (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-5-fluoropyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoic acid;

[0156] (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;

[0157] (R)-2-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methylpropanoic acid;

[0158] (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-4-(trifluoromethyl)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0159] (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-3-methylpyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0160] (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrazin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0161] (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)pyrimidin-2-amine;

[0162] (R)-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidine-5-carboxylic acid;

[0163] (R)-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)pyrimidin-4-yl)-2-methylpropanoic acid;

[0164] (R)-2-(2-((4-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrimidin-2-yl)pyrimidin-4-yl)-2-methylpropanoic acid;

[0165] (2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)-L-proline;

[0166] 1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid;

[0167] 1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)-3-methylpyrrolidine-3-carboxylic acid;

[0168] 1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidine-3-carboxylic acid;

[0169] (R)-1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidine-3-carboxylic acid;

[0170] 1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)-3-methylpiperidine-3-carboxylic acid;

[0171] (R)-1-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidine-4-carboxylic acid;

[0172] 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;

[0173] (R)-2-(1-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidin-4-yl)acetic acid;

[0174] (R)-2-(1-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidin-4-yl)-2-methylpropanoic acid;

[0175] (R)-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperazin-1-yl)acetic acid;

[0176] 2-((S)-1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidin-3-yl)acetic acid;

[0177] (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;

[0178] 3-((S)-1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidin-3-yl)propanoic acid;

[0179] 2-(((S)-1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidin-3-yl)oxy)acetic acid;

[0180] 2-(((R)-1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidin-3-yl)oxy)acetic acid;

[0181] 2-(((R)-1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidin-3-yl)oxy)-2-methylpropanoic acid;

[0182] (R)-4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)oxy)cyclohexane-1-carboxylic acid;

[0183] (1R,4r)-4-((2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)oxy)cyclohexane-1-carboxylic acid;

[0184] (1R,4r)-4-((2-((6-((R)-3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)oxy)cyclohexane-1-carboxylic acid;

[0185] (1S,4s)-4-((2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)oxy)cyclohexane-1-carboxylic acid;

[0186] (1S,4s)-4-((2-((6-((R)-3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)oxy)cyclohexane-1-carboxylic acid;

[0187] (R)-6-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)picolinic acid;

[0188] (R)-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)acetic acid;

[0189] (R)-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)-2-methylpropanoic acid;

[0190] (R)-2-(3-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)-2-methylpropanoic acid;

[0191] (R)-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)-2-methylpropanoic acid;

[0192] (R)-2-(4-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)-2-methylpropanoic acid;

[0193] (R)-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)propanoic acid;

[0194] (R)-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid;

[0195] (R)-3-(3-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid;

[0196] (R)-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyridin-2-yl)amino)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid;

[0197] (R)-3-(3-(2-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid;

[0198] (R)-3-(3-(2-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid;

[0199] (R)-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)acetic acid;

[0200] (R)-2-(4-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)acetic acid;

[0201] (R)-3-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid;

[0202] (R)-3-(4-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid;

[0203] (R)-3-(4-(2-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid;

[0204] (R)-3-(4-(2-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-2-yl)amino)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid;

[0205] (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;

[0206] (R)-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenoxy)-2-methylpropanoic acid;

[0207] (R)-2-(3-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenoxy)-2-methylpropanoic acid;

[0208] (R)-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenoxy)-2-methylpropanoic acid;

[0209] (R)-2-((4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)amino)-2-methylpropanoic acid;

[0210] (R)-2-(4-((2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)oxy)phenyl)acetic acid;

[0211] (R)-2-(4-((2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenyl)acetic acid;

[0212] (R)-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-5-fluoropyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid;

[0213] (R)-3-(3-(2-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoic acid;

[0214] (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;

[0215] (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;

[0216] (R)-2-(3-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl)phenyl)-2-methylpropanoic acid;

[0217] (R)-2-(4-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl)phenyl)-2-methylpropanoic acid;

[0218] (R)-3-(3-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0219] (R)-3-(3-(4-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0220] (R)-3-(4-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0221] (R)-3-(4-(4-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl)phenyl)-2,2-dimethylpropanoic acid;

[0222] (R)-2-(3-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl)phenoxy)-2-methylpropanoic acid;

[0223] (R)-2-(3-(4-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl)phenoxy)-2-methylpropanoic acid;

[0224] (R)-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)phenoxy)-2-methylpropanoic acid;

[0225] (R)-2-(4-(6-((6-(3-(2-ethoxy-4-fluorophenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenoxy)-2-methylpropanoic acid;

[0226] (R)-2-(4-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-2-yl)phenoxy)-2-methylpropanoic acid; and

[0227] (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.

[0228] Unless otherwise specified, the terms and abbreviations used herein retain their original meanings.

[0229] The present invention also provides a method for preparing a compound of formula (1). Hereinafter, the method for preparing the compound of formula (1) will be explained on the basis of exemplary reactions to illustrate the present invention. However, those skilled in the art can prepare the compound of formula (1) by various different methods based on the structure of formula (1), and such methods should be interpreted as being within the scope of the present invention. That is, the compound of formula (1) can be prepared by the methods described herein or by combining various different methods disclosed in the prior art, and these methods should be interpreted as being within the scope of the present invention. Therefore, the method for preparing the compound of formula (1) is not limited to the following method.

[0230] As shown in the following Reaction Scheme 1, the compound of formula (1) can be prepared by directly introducing a substituted amine group into compound (2) or by introducing it into compound (3) through a cross-coupling reaction using a palladium catalyst, wherein the compound (3) is prepared by introducing a protected amine into compound (2) and removing the protecting group.

[0231] [Reaction Scheme 1]

[0232]

[0233] Compound (2) can be prepared according to the method of the following Reaction Scheme 2 from tert-butyl 3-hydroxypiperidine-1-carboxylate as a starting material.

[0234] [Reaction Scheme 2]

[0235]

[0236] X=OH or Cl

[0237]

[0238] Alternatively, compound (3) can be prepared according to the method of the following reaction scheme 3.

[0239] [Reaction Scheme 3]

[0240]

[0241] In addition, aminoaryl intermediates can be synthesized by introducing amino groups into compounds obtained by cross-coupling reactions of dioxaborolane core intermediates with various types of chloroaryl compounds. For example, methyl 2-(4-(2-aminopyrimidin-4-yl)phenyl)-2-methylpropanoate can be prepared by using methyl 2-(4-bromophenyl)-2-methylpropanoate as a starting material according to the method of the following reaction scheme 4.

[0242] [Reaction Scheme 4]

[0243]

[0244] Compounds not specifically described in the production methods of the present specification are known compounds or compounds that can be easily synthesized from known compounds by known synthesis methods or similar methods.

[0245] The compound of formula (1) obtained by the above-mentioned method can be isolated or purified from the reaction product by a conventional method such as recrystallization, iontophoresis, silica gel column chromatography or ion exchange chromatography.

[0246] As explained above, the compounds according to the present invention, the starting materials or intermediates used to prepare them can be prepared by a variety of different methods, which should be interpreted as being within the scope of the present invention with respect to the preparation of the compounds of formula (1).

[0247] The compound of formula (1) according to the present invention exhibits inhibitory activity against diacylglycerol acyltransferase 2 (DGAT2). Therefore, the present invention provides a pharmaceutical composition for treating a disease associated with DGAT2, comprising the compound of formula (1) or a pharmaceutically acceptable salt or isomer thereof, and a pharmaceutically acceptable carrier. Various types of prodrugs that are converted in vivo to the compound of formula (1) are also within the scope of the present invention.

[0248] Exemplary diseases associated with DGAT2 that can be treated by the pharmaceutical composition of the present invention include, but are not limited to, diseases selected from the group consisting of fatty liver, non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), diabetes, obesity, hyperlipidemia, atherosclerosis, and hypercholesterolemia.

[0249] In the present invention, in addition to the active ingredient of the present invention, a "pharmaceutical composition" may also include other components such as carriers, diluents, excipients, etc. Therefore, if necessary, the pharmaceutical composition may include a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof. The pharmaceutical composition facilitates administration of the compound to the body. Various methods of administering the compound include, but are not limited to, oral, injection, aerosol, parenteral, and topical administration.

[0250] As used herein, "carrier" refers to a compound that facilitates the addition of a compound to cells or tissues. For example, dimethyl sulfoxide (DMSO) is a common carrier that facilitates the administration of many organic compounds into living cells or tissues.

[0251] As used herein, a "diluent" refers to a compound that not only stabilizes the biologically active form but also dilutes the compound in the solvent in which it is dissolved. Salts dissolved in buffers are used as diluents in the art. One commonly used buffer is phosphate-buffered saline, which simulates the salt forms found in body fluids. Because buffer solutions can control the pH of the solution at low concentrations, buffer diluents rarely alter the biological activity of the compound.

[0252] As used herein, "pharmaceutically acceptable" refers to properties that do not impair the biological activity and physical properties of the compound.

[0253] The compounds according to the present invention can be formulated into various pharmaceutical dosage forms. In the preparation of the pharmaceutical composition of the present invention, the active ingredient, specifically the compound of formula (1) or its pharmaceutically acceptable salt or isomer, is mixed with a pharmaceutically acceptable carrier selected in consideration of the dosage form to be prepared. For example, if desired, the pharmaceutical composition of the present invention can be formulated into an injection, an oral preparation, etc.

[0254] The compounds of the present invention can be formulated using known pharmaceutical carriers and excipients by conventional methods and inserted into unit or multi-unit containers. The formulation can be a solution, suspension or emulsion in an oil or aqueous solvent and contain conventional dispersants, suspending agents or stabilizers. In addition, the compound can be, for example, in the form of a dry powder, which is dissolved in sterilized pyrogen-free water before use. The compounds of the present invention can be formulated into suppositories using conventional suppository bases such as cocoa butter or other glycerides. Solid forms for oral administration include capsules, tablets, pills, powders and granules. Capsules and tablets are preferred. Tablets and pills are preferably enteric coated. The solid form is prepared by mixing the compound of the present invention with at least one carrier selected from an inert diluent such as sucrose, lactose or starch, a lubricant such as magnesium stearate, a disintegrant, a binder, etc.

[0255] If necessary, the compounds according to the present invention or pharmaceutical compositions containing them can be administered in combination with other drugs such as other metabolic disorder therapeutic agents.

[0256] The dosage of the compound of formula (1) of the present invention is determined by the prescription given by the doctor according to the patient's weight, age and disease condition. According to the frequency and intensity of administration, the typical dosage of an adult is in the scope of about 0.3 to 500mg every day. The typical daily dose of an adult's intramuscular or intravenous administration is about 1 to 300mg every day, which can be administered in a divided unit dose. Some patients need a higher daily dose.

[0257] As used herein, the term "treat" is used to mean preventing, delaying, or ameliorating the progression of a disease in a subject exhibiting symptoms of the disease.

[0258] Beneficial effects

[0259] The novel aminoaryl derivative compounds of formula (1) according to the present invention exhibit excellent inhibitory activity against diacylglycerol acyltransferase 2 (DGAT2) and are therefore useful for preventing, alleviating, or treating metabolic disorders associated with DGAT2. Furthermore, the novel aminoaryl derivative compounds of formula (1) according to the present invention exhibit increased lipophilicity and liver selectivity, thereby improving efficacy by increasing exposure to the liver. Furthermore, due to their relatively long half-life in disease animal models and clinical practice, they are expected to have the advantage of being easy to administer. DETAILED DESCRIPTION

[0260] Hereinafter, the present invention will be described in more detail through preparation examples and examples. However, these examples are merely illustrative, and the scope of the present invention is not limited thereto.

[0261] In the following examples, M represents molar concentration and N represents normal concentration. In addition, the abbreviations and terms used in the reaction schemes, preparation examples and examples are described as follows:

[0262] DCM: dichloromethane

[0263] DIPEA: diisopropylethylamine

[0264] DME: dimethoxyethane

[0265] DMF: N,N-dimethylformamide

[0266] HCl: hydrochloric acid

[0267] Pd / C: Palladium / Charcoal

[0268] TEA: triethylamine

[0269] TFA: trifluoroacetic acid

[0270] THF: Tetrahydrofuran

[0271] Preparation Example 1: (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine

[0272]

[0273] Step 1: (R)-tert-Butyl 3-(2-ethoxyphenoxy)piperidine-1-carboxylate

[0274] (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (30.0 g, 149 mmol), 2-ethoxyphenol (20.6 g, 149 mmol), and triphenylphosphine (43.8 g, 167 mmol) were dissolved in 500 ml of toluene and stirred at room temperature. Diethylazodicarboxylic acid (30.4 ml) was diluted in 50 ml of toluene and slowly added dropwise to the reaction mixture. After stirring at room temperature for 15 hours, it was filtered, washed with 300 ml of diethyl ether, washed with 100 ml of 3N sodium hydroxide solution, and the organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 47%) was obtained by purification on a silica gel column (ethyl acetate: hexane = 1:6).

[0275] 1 H NMR (300 MHz, chloroform-D): δ 6.89-6.95 (m, 4H), 4.07 (m, 3H), 3.9 (bs, 1H), 3.66 (bs, 1H), 3.16 (m, 2H), 2.07 (bs, 1H), 1.76-1.83 (m, 2H), 1.45 (m+s, 3H)

[0276] Step 2: (R)-3-(2-ethoxyphenoxy)piperidine hydrochloride

[0277] tert-Butyl (R)-3-(2-ethoxyphenoxy)piperidine-1-carboxylate (10.0 g, 31.1 mmol) obtained in Step 1 was dissolved in 100 ml of dichloromethane, and a 4 M hydrochloric acid solution was added dropwise at room temperature. After stirring at room temperature for 4 hours, TLC confirmed the completion of the reaction, and the organic solvent was removed under reduced pressure. After dilution with ethyl acetate and washing with aqueous sodium bicarbonate, the organic solvent was dehydrated over magnesium sulfate, and the crude compound obtained by distillation under reduced pressure was used in the next reaction without further purification.

[0278] m / z(M+H) + C 13 H 19 The calculated value of NO2 is 221, and the measured value is 222

[0279] Step 3: (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine

[0280] The (R)-3-(2-ethoxyphenoxy)piperidine hydrochloride obtained in step 2, 2,6-dichloropyrazine (5.10 g, 34.2 mmol) and triethylamine (13 ml, 93 mmol) were mixed with 100 ml of ethanol and stirred at room temperature. After stirring at room temperature for 24 hours, the reaction was confirmed to be complete by TLC experiment, and the organic solvent was removed under reduced pressure, dissolved in ethyl acetate and washed with salt water. The organic solvent was dehydrated on magnesium sulfate and the organic solvent was removed under reduced pressure. The desired product (yield 91%) was obtained by purification with a silica gel column.

[0281] 1 H-NMR (500MHz, chloroform-D) δ7.93(s,1H),7.74(s,1H),7.04-6.93(m,2H),6.92-6.80(m,2H),4.35-4.24(m,1H),4.07-3.89(m,3H),3.82-3. 68(m,1H),3.67-3.46(m,2H),2.09(q,J=4.3Hz,1H),2.02-1.97(m,1H),1.93(q,J=4.3Hz,1H),1.68-1.58(m,1H),1.38(t,J=7.0Hz,3H)

[0282] Preparation Example 2: (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-amine

[0283]

[0284] Step 1: (R)-tert-Butyl(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamate

[0285] After (R) -2-chloro-6- (3- (2-ethoxyphenoxy) piperidin-1-yl) pyrazine (1.41 g, 4.22 mmol), tert-butyl carbamate (0.55 g, 4.65 mmol), cesium carbonate (3.44 g, 10.56 mmol), 4,5-bis (diphenylphosphine) -9,9- dimethylxanthine (220 mg, 0.38 mmol) and tris (dibenzylidene acetone) dipalladium (0) (232 mg, 0.25 mmol) obtained in Preparation Example 1 were dissolved in 50 ml of 1,4-dioxane, dissolved oxygen was removed by bubbling with nitrogen under stirring, and the inflow of external air was blocked in a sealed container. The reaction was stirred at 110 ° C for 5 hours and then cooled to room temperature. After filtering through a diatomaceous earth pad and removing the organic solvent under reduced pressure, the reaction was dissolved in ethyl acetate and washed with brine. The organic solvent was dehydrated on magnesium sulfate and the organic solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 3:1) to obtain the desired product (yield 89%).

[0286] 1 H-NMR (500 MHz, chloroform-D) δ8.40 (s, 1H), 7.78 (s, 1H), 6.96 (t, J = 7.0 Hz, 2H), 6.91-6.77 (m, 2H), 6.66 (s, 1H), 4.48-4.15 (m, 1H), 4.14-3.85 (m, 3H), 3.84-3.69 (m, 1H), 3 .52-3.41(1H),3.40-3.23(m,1H),2.11(t,J=6.1Hz,1H),2.01-1.92(m,1H),1.88 (q,J=4.3Hz,1H),1.57(dt,J=13.4,4.0Hz,1H),1.52(s,9H),1.37(t,J=7.0Hz,3H)

[0287] Step 2: (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-amine

[0288] The tert-butyl (R)-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)carbamate obtained in step 1 was dissolved in 10 ml of dichloromethane, stirred, and 2 ml of trifluoroacetic acid was added dropwise. After TLC confirmed the completion of the reaction, the organic solvent was removed under reduced pressure, diluted with ethyl acetate, and washed with an aqueous sodium bicarbonate solution. The organic solvent was dehydrated over magnesium sulfate and removed under reduced pressure to obtain a crude product, which was then carried on to the next reaction without further purification.

[0289] 1 H NMR (300 MHz, chloroform-d): δ7.49 (s, 1H), 7.28 (s, 1H), 7.27 (d, 1H), 6.90-7.05 (m, 3H), 3.80-4.25 (m, 7H), 3.25 (m, 2H), 2.18 (m, 1H), 1.75-1.98 (m, 2H), 1.91 (m, 1H), 1.43 (t, 3H), 1.27 (m, 1H)

[0290] Preparation 3: (R)-2-chloro-6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine

[0291]

[0292] Step 1: 2-Chloro-3-ethoxypyridine

[0293] 2-chloropyridine-3-alcohol (10.0g, 77mmol), iodoethane (14.45g, 93mmol) and potassium carbonate (21.34g, 154mmol) are added into 77mL DMF and stirred at room temperature for 48 hours.The reaction mixture is filtered and water is added, then extracted with ethyl acetate.After washing with water and salt water, the organic layer is dehydrated on magnesium sulfate and concentrated under reduced pressure.By obtaining required product (yield 99%) with column chromatography purification.

[0294] 1 H NMR (400 MHz, chloroform-d): δ 7.96 (t, J = 3.0 Hz, 1H), 7.17 (d, J = 3.2 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H)

[0295] Step 2: (R)-tert-Butyl 3-((3-ethoxypyridin-2-yl)oxy)piperidine-1-carboxylate

[0296] To 96 mL of anhydrous DMF was added sodium hydride (3.38 g, 84 mmol), and further (R)-tert-butyl 3-hydroxypiperidine-1-carboxylate (17.00 g, 84 mmol). The temperature was raised to 60° C., stirred for 1 hour, and 2-chloro-3-ethoxypyridine (12.1 g, 77 mmol) obtained in step 1 was added, followed by stirring for 24 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. After washing with water and brine, the organic layer was dehydrated over magnesium sulfate and concentrated under reduced pressure. The desired product (yield 75%) was obtained by purification by column chromatography.

[0297] 1 H NMR (400MHz, chloroform-D): δ7.68(td,J=3.2,1.7Hz,1H),7.03(dt,J=7.8,1.4Hz,1H),6.82-6.72(m,1H),5.06(s,1H),4.03( q,J=7.0Hz,2H),3.55(d,J=100.2Hz,4H),2.16-1.96(m,1H),1.96-1.70(m,2H),1.68-1.50(m,1H),1.50-1.27(m,12H)

[0298] Step 3: (R)-2-chloro-6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine

[0299] The title compound was obtained in a similar manner to Step 3 of Preparation Example 1 using tert-butyl (R)-3-((3-ethoxypyridin-2-yl)oxy)piperidine-1-carboxylate (31.5 g, 98 mmol) obtained in Step 2, (R)-3-ethoxy-2-(piperidin-3-yloxy)pyridine hydrochloride (30 g, 116 mmol) obtained in a similar manner to Step 2 of Preparation Example 1, and 2,6-dichloropyrazine (19 g, 128 mmol) (yield 80%).

[0300] 1 H NMR (400 MHz, chloroform-d): δ 7.96 (d, J = 11.0 Hz, 1H), 7.74-7.66 (m, 2H), 7.04 (dd, J = 7.8, 1.4 Hz, 1H), 6.83 (dd, J = 7.8, 5.0 Hz, 1H), 5.24 (td, J = 7.0, 3.4 Hz, 1H), 4.05-3.83 (m, 3H), 3.83-3.70 (m, 2H), 3.67-3.53 (m, 1H), 2.22-2.09 (m, 1H), 2.07-1.93 (m, 2H), 1.75-1.60 (m, 1H), 1.35-1.27 (t, J = 7.1 Hz, 3H)

[0301] Preparation Example 4: (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyridine

[0302]

[0303] The desired product was obtained in a similar manner to Step 3 of Preparation Example 1 using (R)-3-(2-ethoxyphenoxy)piperidine hydrochloride (10 g, 45.2 mmol) and 2,6-dichloropyridine (11.37 g, 77 mmol) obtained in Step 2 of Preparation Example 1 (yield 41%).

[0304] 1 H-NMR (400 MHz, chloroform-D): δ7.44-7.29 (m, 1H), 7.17-7.05 (m, 1H), 6.94-6.86 (m, 3H), 6.73-6.49 (m, 1H), 6.49-6.32 (m, 1H), 4.30-4.17 (m, 2H), 4.04-3.96 (m, 2H), 3.95-3.78 (m, 1H), 3.35-3.18 (m, 2H), 2.22-2.07 (m, 1H), 1.97-1.75 (m, 2H), 1.64-1.52 (m, 1H), 1.40 (q, J = 6.9 Hz, 3H)

[0305] Preparation Example 5: (R)-4-chloro-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine

[0306]

[0307] The title compound was synthesized in a manner similar to Preparation Example 1 (Step 2, Step 3) using (R)-tert-butyl 3-(2-ethoxyphenoxy)piperidine-1-carboxylate (15.0 g, 46.7 mmol) and 2,4-dichloropyrimidine (13.9 g, 93 mmol) obtained in Step 1 of Preparation Example 1 (yield 19%).

[0308] 1 H-NMR (400MHz, chloroform-D): δ8.11(d,1H),7.03(m,1H),6.95(m,1H),6.89(m,2H),6.45(d,1H),4.44(dd,1H),4.22( m,1H),4.10(m,1H),4.02(m,2H),3.63(m,1H),3.51(m,1H),2.12(m,1H),1.92(m,2H),1.55(m,1H),1.40(t,3H)

[0309] Preparation Example 6: (R)-2-chloro-4-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine

[0310]

[0311] The title compound was synthesized in a manner similar to Preparation Example 1 (Step 2, Step 3) using (R)-tert-butyl 3-(2-ethoxyphenoxy)piperidine-1-carboxylate (15.0 g, 46.7 mmol) and 2,4-dichloropyrimidine (13.9 g, 93 mmol) obtained in Step 1 of Preparation Example 1 (yield 72%).

[0312] 1 H-NMR (400 MHz, chloroform-D): δ7.97 (d, 1H), 6.98 (m, 2H), 6.89 (m, 2H), 6.32 (d, 1H), 4.31 (m, 1H), 4.01 (m, 3H), 3.71 (m, 3H), 2.01 (m, 3H), 1.61 (m, 1H), 1.38 (t, 3H)

[0313] Preparation 7: (R)-2-chloro-4-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrimidine

[0314]

[0315] The desired product was obtained in a similar manner to that described in Step 3 of Preparation Example 1, using (R)-3-ethoxy-2-(piperidin-3-yloxy)pyridine hydrochloride (5.90 g, 22.80 mmol) and 2,4-dichloropyrimidine (3.74 g, 25.08 mmol) obtained in Step 3 of Preparation Example 3 (yield 26%).

[0316] 1 H-NMR (400MHz, chloroform-D): δ7.91 (d, J=6.4Hz, 1H), 7.70 (dd, J=4.8, 1.6Hz, 1H), 7.03 (dd, J=7.8, 1.4Hz, 1H), 6.82 (q, J=4.1Hz ,1H),6.32(d,J=5.9Hz,1H),5.19(s,1H),4.05-3.59(m,6H),2.25-1.90(m,3H),1.76-1.57(m,1H),1.31(t,J=6.9Hz,3H)

[0317] Preparation Example 8: (R)-2-chloro-4-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoropyrimidine

[0318]

[0319] The title compound was synthesized in a manner similar to that in step 3 of Preparation Example 1 using (R)-3-(2-ethoxyphenoxy)piperidine hydrochloride (4 g, 18.08 mmol) and 2,4-dichloro-5-fluoropyrimidine (7.54 g, 45.2 mmol) synthesized in step 2 of Preparation Example 1 (yield 81%).

[0320] 1 H-NMR (chloroform-D): δ7.96-7.83(m,1H),7.09-6.83(m,4H),4.44-4.31(m,1H),4.11(d,J=9.8Hz,1H),4.08-3.95(m, 2H),3.93(s,1H),3.82(dd,J=24.6,7.5Hz,2H),2.15-1.95(m,3H),1.63(d,J=7.9Hz,1H),1.40(q,J=6.9Hz,3H)

[0321] Preparation Example 9: (R)-4-chloro-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-(trifluoromethyl)pyrimidine

[0322]

[0323] The title compound was synthesized in a manner similar to that described in Step 3 of Preparation Example 1, using (R)-3-(2-ethoxyphenoxy)piperidine hydrochloride (1 g, 4.52 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.45 g, 11.3 mmol) synthesized in Step 2 of Preparation Example 1 (yield 38%).

[0324] 1 H-NMR (400 MHz, chloroform-d): δ8.37 (d, J=21.0 Hz, 1H), 6.96 (t, J=7.5 Hz, 2H), 6.87 (t, J=5.5 Hz, 2H), 4.28 (td, J=6.6, 3.4 Hz, 1H), 4.19 (s, 1H), 4.06-3.89 (m, 4H), 3.89-3.72 (1H), 2.16-1.88 (m, 3H), 1.67 (s, 1H), 1.62-1.48 (m, 1H), 1.48-1.30 (m, 3H)

[0325] Preparation 10: (R)-2-chloro-4-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-(trifluoromethyl)pyrimidine

[0326]

[0327] The title compound was synthesized in a manner similar to that described in Step 3 of Preparation Example 1 using (R)-3-(2-ethoxyphenoxy)piperidine hydrochloride (1 g, 4.52 mmol) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine (2.45 g, 11.3 mmol) synthesized in Step 2 of Preparation Example 1 (yield 28%).

[0328] 1 H-NMR (400MHz, chloroform-D): δ8.36(s,1H),7.12-7.01(m,1H),7.01-6.91(m,1H),6.90-6.78(m,2H),4.32(td,J=7.5,3.7Hz,1H),4.16(dd,J=13.5,3.0 Hz,1H),4.01(td,J=7.3,6.3Hz,2H),3.76(dd,J=13.5,5.7Hz,1H),3.68- 3.47(m,2H),2.19-1.84(m,4H),1.71-1.57(m,1H),1.39(t,J=7.1Hz,3H)

[0329] Preparation Example 11: 4-phenylpyridin-2-amine

[0330]

[0331] Phenylboronic acid (0.14 g, 1.16 mmol), 4-bromopyridin-2-amine (0.2 g, 1.16 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane adduct (0.09 g, 0.12 mmol) were dissolved in 3 mL of 1,2-dimethoxyethane, and a 1 M saturated aqueous sodium bicarbonate solution (3.47 ml, 3.47 mmol) was added dropwise, followed by stirring at 90°C for 5 hours. After cooling to room temperature, filtering through a pad of Celite and washing with dichloromethane, the organic solvent was dried over magnesium sulfate and removed under reduced pressure. Purification on a silica gel column (Biotage 40M column) gave the desired product (yield 97%).

[0332] 1 H-NMR (500MHz, chloroform-D) δ8.25 (d, J = 5.5Hz, 1H), 8.00-7.77 (m, 2H), 7.41 (t, J = 7.3Hz ,2H),7.36(t,J=7.3Hz,1H),7.04-6.78(m,1H),6.42(q,J=2.6Hz,1H),4.57(s,1H)

[0333] Preparation Example 12: Methyl 2-(6-aminopyridine)acetate

[0334]

[0335] Step 1: 2-(6-chloropyridin-3-yl)acetonitrile

[0336] 2-Chloro-5-(chloromethyl)pyridine (5.0 g, 30.9 mmol) was dissolved in 20 ml of ethanol and potassium cyanide (2.21 g, 33.9 mmol) was dissolved in 9 ml of water and added dropwise at 0°C. The reaction was stirred at reflux for 2 hours and then at room temperature for 18 hours. After diluting in 500 ml of dichloromethane and washing with brine, the organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 83%) was obtained by purification on a silica gel column (dichloromethane: hexane = 7:3).

[0337] 1 H-NMR (500 MHz, chloroform-D) δ 8.36 (d, J = 2.4 Hz, 1H), 7.77-7.60 (m, 1H), 7.38 (d, J = 8.6 Hz, 1H), 3.87-3.63 (2H)

[0338] Step 2: Methyl 2-(6-chloropyridin-3-yl)acetate

[0339] The 2-(6-chloropyridin-3-yl)acetonitrile (3.92 g, 25.7 mmol) obtained in step 1 was dissolved in 5 mL of concentrated hydrochloric acid and stirred at 80° C. for 24 hours. The reaction was poured into ice water, extracted with 500 mL of dichloromethane, washed with brine, and then the organic solvent was dehydrated over magnesium sulfate and removed under reduced pressure. The desired product was obtained by purification on a silica gel column (ethyl acetate: hexane = 1:1) (yield 90%).

[0340] 1 H-NMR (500 MHz, chloroform-D) δ 8.28 (d, J = 2.4 Hz, 1H), 7.61 (dd, J = 7.9, 2.4 Hz, 1H), 7.29 (d, J = 8.6 Hz, 1H), 3.71 (s, 3H), 3.61 (s, 2H)

[0341] Step 3: Methyl 2-(6-aminopyridine)acetate

[0342] The desired product was obtained in a similar manner to Preparation 2 (Step 1, Step 2) using methyl 2-(6-chloropyridin-3-yl)acetate (2.0 g, 10.8 mmol) and tert-butyl carbamate (3.8 g, 32.3 mmol) obtained in Step 2 (yield 26.8%).

[0343] 1 H-NMR (500 MHz, chloroform-D) δ 7.93 (d, J = 2.4 Hz, 1H), 7.39 (dd, J = 7.9, 2.4 Hz, 1H), 6.48 (d, J = 8.6 Hz, 1H), 4.49 (s, 2H), 3.68 (s, 3H), 3.47 (s, 2H)

[0344] Preparation Example 13: Methyl (E)-3-(6-aminopyridin-3-yl)acrylate

[0345]

[0346] To a solution of 2-amino-5-bromopyridine (2.70 g, 15.61 mmol), palladium(II) acetate (0.16 g, 0.70 mmol), tri(o-tolyl)phosphine (0.48 g, 1.56 mmol), TEA (2.61 ml, 18.73 mmol) in 30 mL of DMF was added methyl acrylate (1.48 g, 17.17 mmol), and the mixture was stirred at 100 ° C for 6 h. The reaction was quenched by adding water and the whole was extracted with ethyl acetate. The combined organic layers were washed with brine, dehydrated over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM / EA / MeOH=4:1:0 to 2:1:0 to 2:1:0.1) to give the desired product as a yellow solid (yield 83%).

[0347] 1 H-NMR (500 MHz, chloroform-D) δ 8.18 (d, J = 1.8 Hz, 1H), 7.74-7.63 (m, 1H), 7.56 (s, 1H), 6.50 (d, J = 8.6 Hz, 1H), 6.25 (d, J = 15.9 Hz, 1H), 4.73 (s, 2H), 3.78 (s, 3H)

[0348] Preparation 14: Methyl 2-(4-aminophenyl)-2-methylpropanoate

[0349]

[0350] Step 1: Methyl 2-(4-nitrophenyl)acetate

[0351] Concentrated sulfuric acid (34 ml, 0.64 mol) was added to water (34 ml), and 4-nitrophenylacetonitrile (11.8 g, 73 mmol) was added to the mixture. The reaction mixture was refluxed for 30 min, diluted with 34 mL of water and cooled to 0° C., at which time a colorless crystalline solid was isolated. The solid was filtered out, washed with ice-cold water to remove traces of acid, and dried to obtain the acid. The solid was then treated with THF / diazomethane at 0° C. The product was obtained by evaporation and column chromatography (yield 56%).

[0352] 1 H-NMR (500 MHz, chloroform-D) δ 8.18 (d, J = 8.6 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 3.73 (s, 2H), 3.71 (s, 3H)

[0353] Step 2: Methyl 2-methyl-2-(4-nitrophenyl)propionate

[0354] To a suspension of sodium hydride (60% in oil, 1.47 g, 37 mmol) in DMF (50 ml) was added 2- (4- nitrophenyl) methyl acetate (3.25 g, 16.7 mmol) obtained in step 1 at 0 ° C. The mixture was stirred at 0 ° C for 15 minutes and iodomethane (4.2 ml, 6.6 mmol) was added. The mixture was continued to stir for 5 minutes at 0 ° C and stirred at room temperature for 12 hours, then quenched with 1N aqueous hydrochloric acid solution (1 ml) and extracted with EtOAc (30x2 ml). The organic layer was washed with water (30 × 2 ml) and brine (20 ml), dehydrated on MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (EtOAc: hexane = 1: 3) to give the desired product (yield 57%).

[0355] 1 H-NMR (400 MHz, chloroform-D) δ 8.17 (d, J = 8.7 Hz, 2H), 7.49 (d, J = 8.7 Hz, 2H), 3.66 (s, 3H), 1.61 (s, 6H)

[0356] Step 3: Methyl 2-(4-aminophenyl)-2-methylpropanoate

[0357] A mixture of methyl 2-methyl-2-(4-nitrophenyl)propanoate (2.11 g, 9.45 mmol) and Pd / C (0.2 g) in MeOH (30 ml) was stirred under a H2 balloon at room temperature for 4 h, then filtered through celite to give the product (yield 95%).

[0358] 1 H-NMR (400 MHz, chloroform-D) δ 7.12 (d, J = 8.2 Hz, 2H), 6.64 (d, J = 8.7 Hz, 2H), 3.62 (s, 3H), 1.52 (d, J = 0.9 Hz, 6H)

[0359] Preparation 15: Methyl 2-(3-aminophenyl)-2-methylpropanoate

[0360]

[0361] The desired product was obtained in a similar manner to Preparation 14 using 2-(3-nitrophenyl)acetic acid (4 g, 22.08 mmol) (30% yield over 3 steps).

[0362] 1H-NMR (400 MHz, chloroform-D) δ 7.15-7.03 (m, 1H), 6.78-6.67 (m, 1H), 6.67-6.59 (1H), 6.58-6.51 (m, 1H), 3.65 (q, J = 14.9 Hz, 3H), 1.61-1.45 (m, 6H)

[0363] Preparation Example 16: 2-(2-aminobenzo[d] Methyl oxazol-5-yl)acetate

[0364]

[0365] The desired product was obtained in a similar manner to Preparation 18 (step 1, step 2, step 3, step 5, step 6) using 2-(4-hydroxyphenyl)acetic acid (20 g, 131 mmol) (yield 48% over 5 steps).

[0366] 1 H-NMR (400 MHz, chloroform-D) δ 7.27 (s, 1H), 7.21 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 5.46 (s, 2H), 3.69 (s, 3H), 3.67 (s, 2H)

[0367] Preparation Example 17: 2-(2-aminobenzo[d] Methyl 2-oxazol-5-yl)-2-methylpropanoate

[0368]

[0369] The desired product was prepared in a similar manner to Preparation 18 (step 1, step 2, step 3, step 4, step 5, step 6) using 2-(4-hydroxyphenyl)acetic acid (20 g, 131 mmol) (yield 43% over 6 steps).

[0370] 1 H-NMR (400 MHz, chloroform-D) δ 7.34 (d, J = 1.8 Hz, 1H), 7.20 (d, J = 8.7 Hz, 1H), 7.04 (dd, J = 8.7, 1.8 Hz, 1H), 5.58 (s, 2H), 3.65 (s, 3H), 1.61 (s, 6H)

[0371] Preparation Example 18: 2-(2-aminobenzo[d] Methyl oxazol-6-yl)-2-methylpropanoate

[0372]

[0373] Step 1: 2-(3-Hydroxy-4-nitrophenyl)acetic acid

[0374] 2-(3-Hydroxyphenyl)acetic acid (2 g, 13.15 mmol) and 4 mL of 70% nitric acid were stirred at room temperature for 30 minutes. After TLC confirmed that the reaction was complete, the organic solvent was removed under reduced pressure. After extraction with ethyl acetate (2 x 20 ml), it was washed with brine (20 ml), and the organic solvent was dehydrated over magnesium sulfate and removed under reduced pressure. The next reaction was carried out without additional columns.

[0375] m / z(M+H) + The calculated value for C8H7NO5 is 198, and the measured value is 198

[0376] Step 2: Methyl 2-(3-hydroxy-4-nitrophenyl)acetate

[0377] The 2-(3-hydroxy-4-nitrophenyl)acetic acid (2.59 g, 13.14 mmol) obtained in step 1 and 0.245 mL of sulfuric acid were dissolved in 50 mL of methanol and stirred at 70 ° C for 4 hours. After confirming that the reaction was complete by TLC, the organic solvent was removed under reduced pressure. After extraction with ethyl acetate (2 × 20 ml), it was washed with brine (20 ml), and the organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 26.8%) was obtained by purification with a silica gel column (ethyl acetate: hexane = 1: 9).

[0378] 1 H-NMR (400 MHz, chloroform-D) δ 10.57 (s, 1H), 8.05 (d, J = 8.7 Hz, 1H), 7.10-7.03 (m, 1H), 6.90 (dd, J = 8.7, 1.8 Hz, 1H), 3.71 (s, 3H), 3.65 (s, 2H)

[0379] Step 3: Methyl 2-(3-(benzyloxy)-4-nitrophenyl)acetate

[0380] 2-(3-hydroxy-4-nitrophenyl) methyl acetate (0.744 g, 3.52 mmol), 0.461 mL of benzyl bromide and potassium carbonate (1.315 g, 9.52 mmol) obtained in step 2 were added to 30 mL of DMF and stirred at room temperature for 15 hours. After confirming that the reaction was complete by TLC, the organic solvent was removed under reduced pressure. After extraction with ethyl acetate (2 × 20 ml), it was washed with salt water (20 ml), and the organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 30.1%) was obtained by purification with a silica gel column (ethyl acetate: hexane = 1: 9).

[0381] 1H-NMR (400 MHz, chloroform-D) δ 7.90-7.73 (m, 1H), 7.45 (dd, J = 16.5, 9.1 Hz, 2H), 7.42-7.35 (m, 2H), 7.35-7.28 (m, 1H), 7.12-7.04 (m, 1H), 6.93 (dd, J = 8.2, 1.4 Hz, 1H), 5.28-5.18 (m, 2H), 3.71-3.66 (m, 3H), 3.66-3.59 (m, 2H)

[0382] Step 4: Methyl 2-(3-(benzyloxy)-4-nitrophenyl)-2-methylpropanoate

[0383] Under nitrogen, sodium hydride (0.076 g, 3.19 mmol) was dissolved in 10.6 mL of DMF. The 2-(3-(benzyloxy)-4-nitrophenyl)acetic acid methyl ester (0.32 g, 1.062 mmol) obtained in step 3 was dissolved in DMF and slowly added dropwise, then stirred at 0° C. for 15 minutes. 0.166 mL of iodomethane was then added and stirred at room temperature for 4 hours. After confirming that the reaction was complete by TLC, the organic solvent was removed under reduced pressure. After extraction with ethyl acetate (2×20 ml), it was washed with brine (20 ml), the organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 85%) was obtained by purification with a silica gel column (ethyl acetate: hexane=1:9).

[0384] 1 H-NMR (chloroform-D) δ7.86 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 7.3 Hz, 2H), 7.42 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7. 2Hz,1H),7.07(s,1H),7.02(d,J=8.5Hz,1H),5.26(s,2H),3.69-3.58(m,3H),1.58-1.53(m,6H)

[0385] Step 5: Methyl 2-(4-amino-3-hydroxyphenyl)-2-methylpropanoate

[0386] The desired product was obtained in a similar manner to Step 3 of Preparation 94 using methyl 2-(3-(benzyloxy)-4-nitrophenyl)-2-methylpropanoate (0.297 g, 0.902 mmol) obtained in Step 4 (yield 89%).

[0387] 1 H-NMR (400 MHz, chloroform-D) δ 6.78-6.65 (m, 3H), 3.76-3.60 (m, 3H), 1.49 (d, J = 15.1 Hz, 6H)

[0388] Step 6: 2-(2-aminobenzo[d] Methyl oxazol-6-yl)-2-methylpropanoate

[0389] 2-(4-amino-3-hydroxyphenyl)-2-methylpropionic acid methyl ester (0.167g, 0.798mmol) and cyanogen bromide (0.423g, 3.99mmol) obtained in step 5 were dissolved in 5.7mL methanol and 5.7mL water, and stirred at room temperature for 6 hours. After confirming that the reaction was complete by TLC, the organic solvent was removed under reduced pressure. After extracting with ethyl acetate (2 × 20ml), it was washed with salt water (20ml), and the organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. No additional purification was required to carry out the next reaction.

[0390] 1 H-NMR (400 MHz, chloroform-D) δ 7.29-7.26 (m, 1H), 7.25 (d, J = 2.7 Hz, 1H), 7.16 (dd, J = 8.7, 1.8 Hz, 1H), 5.44 (s, 1H), 3.66-3.61 (m, 3H), 1.64-1.55 (m, 6H)

[0391] Preparation 19: Methyl 2-(6-aminopyridin-3-yl)-2-methylpropanoate

[0392]

[0393] Step 1: Methyl 2-(6-chloropyridin-3-yl)acetate

[0394] Acetyl chloride was added dropwise to 48.6 mL of methanol at 0° C., followed by stirring for 15 minutes. After adding 2-(6-chloropyridin-3-yl)acetic acid (2.50 g, 14.6 mmol), the mixture was stirred at 100° C. for 5 hours, and the organic solvent was removed under reduced pressure. It was diluted with ethyl acetate, washed with brine, and the organic solvent was dehydrated over magnesium sulfate and removed under reduced pressure to obtain the desired product (yield 96%).

[0395] 1 H-NMR (400 MHz, chloroform-D) δ 8.29 (d, J = 2.3 Hz, 1H), 7.62 (dd, J = 8.2, 2.7 Hz, 1H), 7.31 (d, J = 7.8 Hz, 1H), 3.72 (s, 3H), 3.62 (s, 2H)

[0396] Step 2: Methyl 2-(6-chloropyridin-3-yl)-2-methylpropanoate

[0397] The temperature of DMF in which sodium hydride (60%, 0.948 g, 23.7 mmol) was dissolved was lowered to 0° C., and methyl 2-(6-chloropyridin-3-yl)acetate synthesized in step 1 was added. After stirring at 0° C. for 15 minutes, iodomethane (2.70 ml, 43.1 mmol) was added dropwise. After stirring at 0° C. for another 5 minutes, the mixture was stirred at room temperature for 15 hours. After washing with ethyl acetate, it was washed with 1N hydrochloric acid solution, and the organic solvent was dehydrated over magnesium sulfate and removed under reduced pressure. The desired product was obtained by purification on a silica gel column (ethyl acetate: hexane) (yield 59%).

[0398] 1 H-NMR (400 MHz, chloroform-D) δ 8.38 (d, J = 2.7 Hz, 1H), 7.63 (dd, J = 8.2, 2.7 Hz, 1H), 7.29 (d, J = 8.2 Hz, 1H), 3.67 (s, 3H), 1.61 (s, 6H)

[0399] Step 3: Methyl 2-(6-((tert-Butoxycarbonyl)amino)pyridin-3-yl)-2-methylpropanoate

[0400] 2-(6-chloropyridin-3-yl)-2-methylpropionic acid methyl ester (0.47g, 2.2mmol), tert-butyl carbamate (0.77g, 6.6mmol), cesium carbonate (1.08g, 3.30mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthine (255mg, 0.440mmol) and tris(dibenzylideneacetone)dipalladium (0) (201mg, 0.220mmol) synthesized in step 2 were dissolved in 11.0ml 1,4-dioxane, and dissolved oxygen was removed by nitrogen bubbling under stirring, and the inflow of external air was blocked in a sealed container. The reaction was stirred at 140°C for 15 hours and then cooled to room temperature. After filtering through a diatomaceous earth pad and removing the organic solvent under reduced pressure, it was dissolved in ethyl acetate and washed with salt water. The organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product was obtained by purification on a silica gel column (ethyl acetate:hexane) (yield 26%).

[0401] 1 H-NMR (400 MHz, chloroform-D) δ 8.22 (d, J = 2.3 Hz, 1H), 7.95-7.79 (1H), 7.63 (dd, J = 8.9, 2.5 Hz, 1H), 7.47-7.36 (1H), 3.65 (s, 3H), 1.66-1.58 (6H), 1.52 (s, 9H)

[0402] Step 4: Methyl 2-(6-aminopyridin-3-yl)-2-methylpropanoate

[0403] After dissolving methyl 2-(6-((tert-butoxycarbonyl)amino)pyridin-3-yl)-2-methylpropanoate (169 mg, 0.574 mmol) synthesized in step 3 in 3.00 mL of DCM, a 4N solution of hydrochloric acid in dioxane was added dropwise. After stirring at room temperature overnight, the organic solvent was removed under reduced pressure, neutralized, extracted with ethyl acetate, and purified by silica gel column (DCM:methanol) to give the desired product (yield 71%).

[0404] 1 H-NMR (400 MHz, chloroform-D) δ 7.81-7.62 (m, 2H), 7.43 (s, 2H), 7.18 (d, J = 9.1 Hz, 1H), 3.68 (s, 3H), 1.55 (s, 6H)

[0405] Preparation Example 20: Ethyl 2-(2-aminopyrimidin-4-yl)-2-methylpropanoate

[0406]

[0407] Step 1: Diethyl 2-(2-chloropyrimidin-4-yl)malonate

[0408] Sodium hydride (60%, 7.89 g, 197 mmol) was added to 300 mL of THF in which diethyl malonate (15.8 g, 99.0 mmol) was dissolved at 0 ° C. After stirring at the same temperature for 30 minutes, 2,4-dichloropyrimidine (9.80 g, 65.8 mmol) was added, and then refluxed at 90 ° C for 3 hours. The reaction was terminated by adding a saturated aqueous ammonium chloride solution to the reaction mixture. It was then extracted with ethyl acetate. The organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 96%) was obtained by purification with a silica gel column (ethyl acetate: hexane).

[0409] 1 H-NMR (400MHz, chloroform-D) δ8.66(d,J=5.0Hz,1H),7.56(d,J=5.0Hz,1H),4.85(s,1H),4.37-4.17(m,4H),1.29(q,J=7.0Hz,6H)

[0410] Step 2: Ethyl 2-(2-chloropyrimidin-4-yl)acetate

[0411] The 2-(2-chloropyrimidin-4-yl)-malonic acid diethyl ester (17.3 g, 63.4 mmol) synthesized in step 1 and sodium ethoxide (20%, 6.48 g, 19.0 mmol) were dissolved in 150 ml of ethanol and refluxed for 3 hours. The pH was adjusted to pH 7 using a 1N aqueous hydrochloric acid solution, extracted with ethyl acetate, dehydrated over magnesium sulfate, and purified by a silica gel column (ethyl acetate: hexane) to obtain the desired product (yield 68%).

[0412] 1 H-NMR (400 MHz, chloroform-D) δ 8.59 (d, J = 5.0 Hz, 1H), 7.34 (d, J = 5.0 Hz, 1H), 4.31-4.12 (2H), 3.83 (s, 2H), 1.38-1.19 (m, 3H)

[0413] Step 3: Ethyl 2-(2-aminopyrimidin-4-yl)-2-methylpropanoate

[0414] The desired product was obtained in a similar manner to Preparation Example 19 (step 2, step 3, step 4) using ethyl 2-(2-chloropyrimidin-4-yl)acetate (5.70 g, 28.4 mmol) synthesized in step 2 (3-step yield 36%).

[0415] m / z(M+H) + C 10 H 16 The calculated value of N3O2 is 210, and the measured value is 210

[0416] Preparation Example 21: 3-(2-aminobenzo[d] Methyl 2,2-dimethyloxazol-5-yl)-2,2-dimethylpropanoate

[0417]

[0418] Step 1: Methyl 3-(4-hydroxyphenyl)-2,2-dimethylpropionate

[0419] Indium bromide (III) (0.41 g, 1.16 mmol) and dimethyl ketene trimethylsilylmethyl acetal (6.08 g, 34.9 mmol) were dissolved in dichloromethane, and 1-(benzyloxy)-4-(bromomethyl)benzene (6.44 g, 23.2 mmol) was slowly added. After stirring at room temperature for 2 hours, the reaction solution was poured into a saturated aqueous sodium bicarbonate solution. After the mixture was extracted with ethyl acetate, the organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 60%) was obtained by purification with a silica gel column (ethyl acetate: hexane = 1: 3).

[0420] 1H-NMR (400 MHz, chloroform-D) δ 6.96 (d, J = 8.7 Hz, 2H), 6.75-6.68 (2H), 4.86-4.71 (1H), 3.65 (s, 3H), 2.78 (s, 2H), 1.20-1.13 (m, 6H)

[0421] Step 2: Methyl 3-(4-hydroxy-3-nitrophenyl)-2,2-dimethylpropionate

[0422] The 3-(4-hydroxyphenyl)-2,2-dimethylpropionic acid methyl ester (2.9 g, 13.9 mmol) synthesized in step 1 was dissolved in acetic acid, cooled to 0 ° C, and nitric acid (70%, 1.02 ml, 16.01 mmol) was slowly added. The reaction temperature was gradually raised to room temperature for 1 hour and then stirred. After the reaction was completed, it was extracted with ethyl acetate, the organic solvent was dehydrated on magnesium sulfate, and the organic solvent was removed under reduced pressure. The desired product was obtained by purification with a silica gel column (ethyl acetate: hexane = 1: 3) (yield 56%).

[0423] 1 H-NMR (400 MHz, chloroform-D) δ 10.47 (s, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.34 (dd, J = 8.5, 2.1 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 3.68 (t, J = 15.1 Hz, 3H), 2.82 (d, J = 15.1 Hz, 2H), 1.20 (s, 6H)

[0424] Step 3: Methyl 3-(3-amino-4-hydroxyphenyl)-2,2-dimethylpropanoate

[0425] Methyl 3-(4-hydroxy-3-nitrophenyl)-2,2-dimethylpropanoate (1.97 g, 7.78 mmol) prepared in step 2 was dissolved in methanol, and Pd / C (207 mg, 0.19 mmol) was added. A hydrogen balloon was then connected and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the desired compound was obtained by filtration through celite (yield 98%).

[0426] 1 H-NMR (400 MHz, chloroform-D) δ 6.84 (s, 1H), 6.72 (d, J = 8.2 Hz, 1H), 6.62-6.54 (1H), 5.44 (s, 2H), 3.62 (s, 3H), 2.65 (s, 2H), 1.12 (d, J = 7.8 Hz, 6H)

[0427] Step 4: 3-(2-aminobenzo[d] Methyl 2,2-dimethyloxazol-5-yl)-2,2-dimethylpropanoate

[0428] The 3-(3-amino-4-hydroxyphenyl)-2,2-dimethylpropionic acid methyl ester (1.7 g, 7.61 mmol) synthesized in step 3 was dissolved in methanol, cooled to 5 ° C, and cyanogen bromide (3.1 ml, 9.14 mmol) dissolved in 10 mL of water was slowly added while stirring vigorously. After stirring at room temperature for 2 hours, sodium bicarbonate (640 mg, 7.61 mmol) was added within 1 hour to adjust the pH of the reaction solution from 6.5 to 7.0, and then stirring was continued at room temperature for 1 hour. The obtained solid was filtered, washed with cold water and recrystallized in ethanol to obtain the desired compound (yield 65%).

[0429] 1 H-NMR (400 MHz, chloroform-d) δ 7.15 (d, J = 8.2 Hz, 1H), 7.09 (d, J = 0.9 Hz, 1H), 6.81 (s, 1H), 5.39 (s, 2H), 3.66 (s, 3H), 2.90 (s, 2H), 1.17 (d, J = 13.3 Hz, 6H)

[0430] Preparation 22: (E)-3-(2-aminobenzo[d] Methyl 2-oxazol-5-yl)acrylate

[0431]

[0432] Step 1: Methyl (E)-3-(4-hydroxy-3-nitrophenyl)acrylate

[0433] Under nitrogen, sodium hydride (2.154 g, 90 mmol) was dissolved in 6 mL of DMF. Methyl 2-(diethoxyphosphoryl)acetate (11.32 g, 53.9 mmol) was dissolved in THF and slowly added dropwise, followed by stirring at 0°C for 15 minutes. 4-Hydroxy-3-nitrobenzaldehyde (3 g, 17.95 mmol) was then added, and the mixture was stirred at room temperature for 4 hours. After TLC confirmed the completion of the reaction, the organic solvent was removed under reduced pressure. After extraction with ethyl acetate (2 x 20 ml), it was washed with brine (20 ml), and the organic solvent was dried over magnesium sulfate and removed under reduced pressure. The next reaction was carried out without further purification.

[0434] Step 2: Methyl (E)-3-(3-amino-4-hydroxyphenyl)acrylate

[0435] The (E)-3-(4-hydroxy-3-nitrophenyl) methyl acrylate (4 g, 17.92 mmol), iron (3.5 g, 62.7 mmol) and 3.08 mL of acetic acid synthesized in step 1 were dissolved in 60 mL of ethanol and stirred at 75° C. for 4 hours. After confirming completion of the reaction by TLC, the organic solvent was removed under reduced pressure. After extraction with ethyl acetate (2×30 mL), it was washed with brine (20 mL), and the organic solvent was dehydrated over magnesium sulfate and removed under reduced pressure. The desired product (yield 20%) was obtained by purification on a silica gel column (ethyl acetate: hexane = 1:9).

[0436] 1 H-NMR (400 MHz, methanol-D4) δ 7.59-7.42 (m, 1H), 7.07-6.88 (m, 1H), 6.88-6.74 (m, 1H), 6.73-6.58 (m, 1H), 6.29-6.10 (m, 1H), 3.82-3.63 (m, 3H), 3.35-3.21 (m, 2H)

[0437] Step 3: (E)-3-(2-aminobenzo[d] Methyl 2-oxazol-5-yl)acrylate

[0438] The desired product was obtained in a similar manner to Step 6 of Preparation Example 18 using methyl (E)-3-(3-amino-4-hydroxyphenyl)acrylate (0.7 g, 3.62 mmol) synthesized in Step 2 (yield 67%).

[0439] 1 H-NMR (400 MHz, methanol-D4) δ 7.82-7.58 (m, 1H), 7.55-7.38 (m, 1H), 7.36-7.19 (m, 2H), 6.53-6.35 (m, 1H), 3.86-3.62 (3H)

[0440] Preparation Example 23: 3-(2-aminobenzo[d] Methyl oxazol-5-yl)propionate

[0441]

[0442] Step 1: Methyl 3-(3-amino-4-hydroxyphenyl)propionate

[0443] The desired product was obtained in a similar manner to Step 3 of Preparation 94 using methyl (E)-3-(4-hydroxy-3-nitrophenyl)acrylate (5.34 g, 23.93 mmol) obtained in Step 1 of Preparation 22. The product was carried on to the next reaction without further purification.

[0444] Step 2: 3-(2-aminobenzo[d] Methyl oxazol-5-yl)propionate

[0445] The desired product was obtained in a similar manner to Step 6 of Preparation 18 using methyl 3-(3-amino-4-hydroxyphenyl)propanoate (4.67 g, 23.92 mmol) synthesized in Step 1 (yield 40%).

[0446] m / z(M+H) + C 11 H 13 The calculated value of N2O3 is 221, and the measured value is 221

[0447] Preparation Example 24: 3-(2-aminobenzo[d] Methyl oxazol-6-yl)propionate

[0448]

[0449] Step 1: Methyl 3-(4-amino-3-hydroxyphenyl)propionate

[0450] The desired product was obtained in a similar manner to Preparation 22 (Step 1) and Preparation 94 (Step 3) using 3-hydroxy-4-nitrobenzaldehyde (1.8 g, 10.77 mmol) (36% yield over 2 steps).

[0451] 1 H-NMR (400 MHz, methanol-D4) δ 6.74-6.57 (m, 1H), 6.57-6.50 (m, 1H), 6.50-6.35 (m, 1H), 3.65-3.49 (m, 3H), 2.82-2.59 (m, 2H), 2.59-2.39 (2H)

[0452] Step 2: 3-(2-aminobenzo[d] Methyl oxazol-6-yl)propionate

[0453] The desired product was obtained in a similar manner to Preparation 18 (Step 6) using methyl 3-(4-amino-3-hydroxyphenyl)propanoate (0.75 g, 3.87 mmol) synthesized in Step 1 (yield 51.7%).

[0454] m / z(M+H) + C 11 H 13 The calculated value of N2O3 is 221, and the measured value is 221

[0455] Preparation Example 25: 4-phenyl Azol-2-amine

[0456]

[0457] 2-Bromo-1-phenylethan-1-one (0.100 g, 0.502 mmol) was dissolved in acetonitrile (5.02 ml), stirred at room temperature, and urea (0.302 g, 5.02 mmol) was added. After stirring at 80° C. for 16 hours, the solvent was removed under reduced pressure. The desired product was obtained by purification on a silica gel column (yield 19.8%).

[0458] 1 H-NMR (500 MHz, chloroform-D) δ 7.74-7.55 (m, 2H), 7.55-7.44 (m, 1H), 7.44-7.34 (m, 2H), 7.30 (t, J = 7.5 Hz, 1H), 5.15 (d, J = 42.1 Hz, 2H)

[0459] Preparation 26: Methyl 2-(4-(2-aminopyridin-4-yl)phenyl)-2-methylpropanoate

[0460] Step 1: Methyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoflorin-2-yl)phenyl)propanoate ester

[0461] Methyl 2-(4-bromophenyl)-2-methylpropanoate (1 g, 3.89 mmol) and bis(pinacolato)diboron (1.481 g, 5.83 mmol) were dissolved in toluene (19.45 ml), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (0.159 g, 0.194 mmol) and potassium acetate (1.527 g, 15.56 mmol) were added. The mixture was refluxed at 110°C for 16 hours. It was filtered through a pad of celite, and the organic solvent was removed under reduced pressure. The desired product was obtained by purification on a silica gel column (yield 72%).

[0462] 1 H-NMR (400 MHz, chloroform-D) δ 7.76 (d, J = 8.2 Hz, 2H), 7.32 (d, J = 8.2 Hz, 2H), 3.62 (s, 3H), 1.55 (d, J = 13.7 Hz, 7H), 1.32 (s, 12H)

[0463] Step 2: Methyl 2-(4-(2-aminopyridin-4-yl)phenyl)-2-methylpropanoate

[0464] The desired product was obtained in a similar manner to Preparation Example 11 using methyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoflorin-2-yl)phenyl)propanoate (0.851 g, 2.80 mmol) and 4-bromopyridin-2-amine (0.484 g, 2.80 mmol) obtained in step 1 (yield 100%).

[0465] 1 H-NMR (400 MHz, chloroform-D) δ 8.10 (d, J = 5.5 Hz, 1H), 7.54 (d, J = 8.2 Hz, 2H), 7.44-7.38 (m, 2H), 6.86 (dd, J = 5.5, 1.4 Hz, 1H), 6.68 (s, 2H), 4.46 (s, 1H), 3.67 (s, 3H), 1.60 (s, 6H)

[0466] Preparation 27: Methyl 2-(3-(2-aminopyridin-4-yl)phenyl)-2-methylpropanoate

[0467]

[0468] The desired product was obtained in a similar manner to Preparation 26 using methyl 2-(3-bromophenyl)-2-methylpropanoate (1 g, 3.89 mmol) (90% yield over 2 steps).

[0469] 1 H-NMR (400 MHz, chloroform-D) δ 8.15 (d, J = 5.5 Hz, 1H), 7.55 (s, 1H), 7.50-7.39 (m, 3H), 6.89 (dd, J = 5.2, 1.5 Hz, 1H), 6.71 (s, 1H), 4.51 (s, 2H), 3.70 (s, 3H), 1.65 (s, 6H)

[0470] Preparation Example 28: Ethyl 1-(2-aminopyrimidin-4-yl)piperidine-4-carboxylate

[0471]

[0472] Step 1: Ethyl 1-(2-chloropyrimidin-4-yl)piperidine-4-carboxylate

[0473] 2,4-Dichloropyrimidine (0.1 g, 0.671 mmol) was dissolved in ethanol (6.71 ml), and ethyl piperidine-4-carboxylate (0.124 ml, 0.806 mmol) and TEA (0.187 ml, 1.343 mmol) were added. The mixture was stirred at 85°C for 3 hours. After the solvent was removed under reduced pressure, the mixture was dissolved in ethyl acetate and washed with water. The desired product was obtained by purification on a silica gel column (yield 80%).

[0474] 1H-NMR (chloroform-D) δ8.05 (d, J=6.4 Hz, 1H), 6.42 (d, J=6.1 Hz, 1H), 4.27 (s, 2H), 4.22-4.16 (2H), 3.22-3.06 (2H), 2.63 (tt, J=10.6, 4.1 Hz, 1H), 2.06-1.96 (m, 2H), 1.86-1.67 (2H), 1.29 (td, J=7.2, 4.5 Hz, 3H)

[0475] Step 2: Ethyl 1-(2-((tert-Butoxycarbonyl)amino)pyrimidin-4-yl)piperidine-4-carboxylate

[0476] The desired product was obtained in a similar manner to Step 1 of Preparation 2 using ethyl 1-(2-chloropyrimidin-4-yl)piperidine-4-carboxylate (1.43 g, 5.30 mmol) obtained in Step 1 and tert-butyl carbamate (0.683 g, 5.83 mmol) (yield 37%).

[0477] 1 H-NMR (500 MHz, chloroform-D) δ 7.88 (d, J = 6.1 Hz, 1H), 6.04-5.92 (1H), 4.76-4.70 (1H), 4.26 (d, J = 13.1 Hz, 2H), 4.22-4.09 (m, 2H), 3.09-2.93 (m, 2H), 2.66-2.50 (m, 1H), 1.98 (dd, J = 13.6, 3.8 Hz, 2H), 1.82-1.68 (2H), 1.64 (s, 9H), 1.31-1.22 (m, 3H)

[0478] Step 3: Ethyl 1-(2-aminopyrimidin-4-yl)piperidine-4-carboxylate

[0479] Ethyl 1-(2-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)piperidine-4-carboxylate (0.480 g, 1.370 mmol) obtained in step 2 was dissolved in DCM (12.3 ml), and trifluoroacetic acid (1.37 ml) dissolved in DCM was added, followed by stirring at room temperature for 2 hours. After the solvent was removed under reduced pressure, it was dissolved in DCM and washed with water. The desired product was obtained by purification on a silica gel column (yield 100%).

[0480] 1H-NMR (chloroform-D) δ10.02-9.49(1H),7.56(d,J=7.3Hz,1H),6.10(d,J=7.6Hz,1H),4.90-4.54(1H),4.20(q,J=7.1Hz,2H),4. 00-3.77(1H),3.28(d,J=16.5Hz,2H),2.74-2.62(m,1H),2.07(d,J=12.5Hz,2H),1.91-1.69(2H),1.30(t,J=7.2Hz,3H)

[0481] Preparation Example 29: Ethyl 1-(6-aminopyridin-2-yl)piperidine-4-carboxylate

[0482]

[0483] Step 1: Ethyl 1-(6-chloropyridin-2-yl)piperidine-4-carboxylate

[0484] 2,6-Dichloropyridine (0.565 g, 3.82 mmol) was dissolved in ethanol (6.71 ml), and ethyl piperidine-4-carboxylate (0.500 g, 3.18 mmol) and DIPEA (1.11 ml, 6.36 mmol) were added. It was stirred at 100 ° C for 16 hours. After the reaction was terminated by adding water, it was dissolved in diethyl ether and washed with water. The desired product was obtained by purification on a silica gel column (yield 53%).

[0485] 1 H-NMR (chloroform-D) δ7.40(t,J=7.8Hz,1H),6.59(d,J=7.6Hz,1H),6.52(d,J=8.2Hz,1H),4.38-4.04(m,4H),3.13-2. 91(m,2H),2.55(tt,J=11.0,3.9Hz,1H),2.01(dd,J=13.4,3.4Hz,2H),1.88-1.68(m,2H),1.29(t,J=7.2Hz,3H)

[0486] Step 2: Ethyl 1-(6-aminopyridin-2-yl)piperidine-4-carboxylate

[0487] The desired product was obtained in a similar manner to Preparation 28 (step 2, step 3) using ethyl 1-(6-chloropyridin-2-yl)piperidine-4-carboxylate obtained in step 1 (yield 36% over 2 steps).

[0488] 1H-NMR (500MHz, chloroform-D) δ7.49(t,J=8.2Hz,1H),5.95(dd,J=8.4,5.0Hz,2H),4.19(q,J=7.0Hz,2H),3.94(d,J=13.7Hz,2 H),3.22(t,J=10.8Hz,2H),2.69-2.54(m,1H),2.08(dd,J=13.9,3.5Hz,2H),1.98-1.79(m,2H),1.29(t,J=7.0Hz,3H)

[0489] Preparation Example 30: (R)-1-(2-aminopyrimidin-4-yl)piperidine-3-carboxylic acid ethyl ester

[0490]

[0491] The desired product was obtained in a similar manner to Preparation 28 using (R)-piperidine-3-carboxylic acid ethyl ester (0.621 ml, 4.03 mmol) (6% yield over 3 steps).

[0492] 1 H-NMR (500MHz, chloroform-D) δ7.68(d,J=6.7Hz,1H),6.49-6.21(1H),6.07(d,J=6.7Hz,1H),4.31(d,J=13.1Hz,1H),4.16(q,J=7.1Hz,2H),4.01(d,J=1 3.1Hz,1H),3.43-3.30(1H),3.30-3.16(1H),2.63-2.47(m,1H),2.19-2 .03(m,1H),1.91-1.76(m,2H),1.65-1.46(m,1H),1.26(t,J=7.0Hz,3H)

[0493] Preparation Example 31: (R)-1-(6-aminopyridin-2-yl)piperidine-3-carboxylic acid ethyl ester

[0494]

[0495] The desired product was obtained in a similar manner to Preparation 29 using (R)-piperidine-3-carboxylic acid ethyl ester (0.500 g, 3.18 mmol) (37% yield over 3 steps).

[0496] 1H-NMR (500MHz, chloroform-D) δ7.49(t,J=8.2Hz,1H),5.95(dd,J=8.4,5.0Hz,2H),4.19(q,J=7.0Hz,2H),3.94(d,J=13.7Hz,2 H),3.22(t,J=10.8Hz,2H),2.69-2.54(m,1H),2.08(dd,J=13.9,3.5Hz,2H),1.98-1.79(m,2H),1.29(t,J=7.0Hz,3H)

[0497] Preparation Example 32: Ethyl 2-(1-(2-aminopyrimidin-4-yl)piperidin-4-yl)acetate

[0498]

[0499] Step 1: Ethyl 2-(1-(2-chloropyrimidin-4-yl)piperidin-4-yl)acetate

[0500] The desired product was obtained in a similar manner to Step 4 of Preparation 36 using ethyl 2-(piperidin-4-yl)acetate (0.315 g, 1.84 mmol) obtained in Step 3, 2,6-dichloropyrimidine (2.023 mmol) and 0.77 mL of triethylamine (yield 86%).

[0501] 1 H-NMR (400 MHz, chloroform-D) δ 7.90-7.72 (m, 1H), 6.34-6.17 (m, 1H), 4.65-4.02 (m, 2H), 3.98 (q, J = 7.2 Hz, 2H), 2.94-2.62 (m, 2H), 2.21-2.04 (m, 2H), 2.04-1.81 (m, 1H), 1.81-1.55 (m, 2H), 1.23-0.93 (m, 5H)

[0502] Step 2: Ethyl 2-(1-(2-aminopyrimidin-4-yl)piperidin-4-yl)acetate

[0503] The desired product was obtained in a manner similar to Preparation Example 19 (step 3, step 4) using ethyl 2-(1-(2-chloropyrimidin-4-yl)piperidin-4-yl)acetate (0.45 g, 1.586 mmol) synthesized in step 1 (yield 61% over 2 steps).

[0504] 1H-NMR (400MHz, chloroform-D) δ7.92-7.74(m,1H),5.93(d,J=6.4Hz,1H),4.88-4.57(2H),4.32(d,J=13.3Hz,2H),4.13(q,J= 7.2Hz,2H),3.00-2.71(m,2H),2.41-2.11(m,2H),2.06(qt,J=11.2,3.8Hz,1H),1.87-1.63(m,2H),1.37-1.04(m,5H)

[0505] Preparation Example 33: Methyl 2-(1-(2-aminopyrimidin-4-yl)piperidin-4-yl)-2-methylpropanoate

[0506]

[0507] Step 1: Methyl 2-(1-(2-chloropyrimidin-4-yl)piperidin-4-yl)-2-methylpropanoate

[0508] The desired product was obtained in a similar manner to Step 4 of Preparation Example 36 using methyl 2-methyl-2-(piperidin-4-yl)propanoate (0.26 g, 1.403 mmol) obtained in Step 4 of Preparation Example 34 and 2,4-dichloropyrimidine (0.23 g, 1.544 mmol) (yield 81%).

[0509] 1 H-NMR (400 MHz, chloroform-D) δ 8.13-7.81 (m, 1H), 6.44-6.26 (m, 1H), 4.41 (s, 1H), 3.72-3.52 (m, 3H), 2.82 (d, J = 9.1 Hz, 2H), 2.32-1.74 (m, 2H), 1.63 (d, J = 8.7 Hz, 2H), 1.43-1.16 (m, 2H), 1.16-0.91 (m, 6H)

[0510] Step 2: Methyl 2-(1-(2-aminopyrimidin-4-yl)piperidin-4-yl)-2-methylpropanoate

[0511] The desired product was obtained in a similar manner to Preparation 19 (steps 3 and 4) using methyl 2-(1-(2-chloropyrimidin-4-yl)piperidin-4-yl)-2-methylpropanoate (0.344 g, 1.155 mmol) obtained in step 1 (yield 59% over 2 steps).

[0512] 1H-NMR (400 MHz, chloroform-D) δ 7.92-7.67 (m, 1H), 5.96-5.77 (m, 1H), 4.83 (d, J = 43.0 Hz, 2H), 4.50-4.27 (m, 2H), 3.72-3.58 (m, 3H), 2.81-2.59 (m, 2H), 1.93-1.70 (m, 1H), 1.68-1.42 (m, 2H), 1.31-1.15 (m, 2H), 1.15-0.96 (m, 6H)

[0513] Preparation Example 34: Methyl 2-(1-(6-aminopyridin-2-yl)piperidin-4-yl)-2-methylpropanoate

[0514]

[0515] Step 1: tert-Butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate

[0516] 2-(triphenyl-λ 5 -phosphinyl) methyl acetate (15.6 g, 46.7 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol) were dissolved in 50 ml of toluene and stirred at room temperature for 4 hours. After confirming the disappearance of the starting material by TLC, the organic solvent was removed under reduced pressure. After extraction with ethyl acetate (2×30 ml), the mixture was washed with brine (20 ml), the organic solvent was dehydrated over magnesium sulfate, and then the organic solvent was removed under reduced pressure. The desired product was obtained by purification on a silica gel column (ethyl acetate: hexane = 1:9) (yield 94%).

[0517] 1 H-NMR (400 MHz, chloroform-D) δ 5.70 (s, 1H), 3.74-3.63 (3H), 3.56-3.38 (m, 4H), 2.92 (t, J = 5.7 Hz, 2H), 2.36-2.20 (m, 2H), 1.51-1.37 (m, 9H)

[0518] Step 2: tert-Butyl 4-(2-methoxy-2-oxoethyl)piperidine-1-carboxylate

[0519] The desired product was obtained in a similar manner to Step 3 of Preparation 94 using tert-butyl 4-(2-methoxy-2-oxoethylidene)piperidine-1-carboxylate (1 g, 3.92 mmol) obtained in Step 1 (yield 99%).

[0520] 1H-NMR (chloroform-D) δ 4.20-3.96 (m, 2H), 3.75-3.64 (m, 3H), 2.73 (t, J = 11.1 Hz, 2H), 2.30-2.21 (2H), 2.00-1.89 (m, 1H), 1.70 (d, J = 13.1 Hz, 2H), 1.51-1.41 (m, 9H), 1.17 (qd, J = 12.3, 4.2 Hz, 2H)

[0521] Step 3: tert-Butyl 4-(1-methoxy-2-methyl-1-oxopropan-2-yl)piperidine-1-carboxylate

[0522] Under nitrogen, 1.67mL diisopropylamine is dissolved in 7.5mL THF, and 4.66mL n-butyl lithium is slowly added dropwise at 0 ℃, then stirred for 30 minutes.Then under nitrogen, 4-(2-methoxy-2-oxoethyl) piperidine-1-tert-butyl formate (1g, 3.89mmol) synthesized in step 2 is dissolved in 5mL THF, slowly added dropwise and stirred for 30 minutes.Then 1.22mL iodomethane is added, and stirred for 1 hour at-78 ℃. This is repeated once more, and after stirring at room temperature for 4 hours, the reaction is confirmed to be complete by TLC. The reaction is terminated with ammonium chloride, extracted with ethyl acetate (2 × 20ml), washed with salt solution (10ml), dehydrated on magnesium sulfate, and removed under reduced pressure with organic solvent. By using silica gel column purification (ethyl acetate: hexane=1:9), desired product (yield 68%) is obtained.

[0523] 1 H-NMR (chloroform-D) δ 4.14 (q, J = 7.1 Hz, 2H), 3.70 (q, J = 4.1 Hz, 3H), 2.66 (d, J = 12.5 Hz, 2H), 1.77-1.67 (m, 1H), 1.66-1.59 (m, 2H), 1.47 (s, 9H), 1.31-1.18 (m, 2H), 1.18-1.08 (m, 6H)

[0524] Step 4: Methyl 2-methyl-2-(piperidin-4-yl)propanoate

[0525] The desired product was obtained in a similar manner to Step 3 of Preparation 36 using tert-butyl 4-(1-methoxy-2-methyl-1-oxopropan-2-yl)piperidine-1-carboxylate (0.35 g, 1.226 mmol) synthesized in Step 3 (yield 99%).

[0526] m / z(M+H) + C 10 H 20 The calculated value of NO2 is 186, and the measured value is 186

[0527] Step 5: Methyl 2-(1-(6-chloropyridin-2-yl)piperidin-4-yl)-2-methylpropanoate

[0528] The desired product was obtained in a similar manner to Step 4 of Preparation 36 using methyl 2-methyl-2-(piperidin-4-yl)propanoate (0.227 g, 1.225 mmol) synthesized in Step 4 (yield 42%).

[0529] 1 H-NMR (400 MHz, chloroform-D) δ7.48-7.29 (m, 1H), 6.60-6.48 (1H), 6.48-6.37 (1H), 4.44-4.23 (m, 2H), 3.73-3.54 (m, 3H), 2.83-2.62 (m, 2H), 1.90-1.71 (m, 1H), 1.71-1.47 (m, 2H), 1.47-1.19 (m, 2H), 1.19-1.05 (m, 6H)

[0530] Step 6: Methyl 2-(1-(6-aminopyridin-2-yl)piperidin-4-yl)-2-methylpropanoate

[0531] The desired product was obtained in a similar manner to Preparation 19 (steps 3 and 4) using methyl 2-(1-(6-chloropyridin-2-yl)piperidin-4-yl)-2-methylpropanoate (0.16 g, 0.539 mmol) synthesized in step 5 (yield 43% over 2 steps).

[0532] 1 H-NMR (400MHz, chloroform-D) δ7.30-7.17(m,1H),6.07-5.91(m,1H),5.91-5.73(m,1H),4.29(d,J=12.8Hz,2H),4.12(d,J=18.8Hz,2H ),3.66(dd,J=15.8,14.9Hz,3H),2.75-2.50(2H),1.85-1.70(m,1H),1.61-1.43(m,2H),1.43-1.26(m,2H),1.18-1.04(m,6H)

[0533] Preparation Example 35: Ethyl 2-(4-(2-aminopyrimidin-4-yl)piperazin-1-yl)acetate

[0534]

[0535] Step 1: tert-Butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate

[0536] 2,4-Dichloropyrimidine (0.200 g, 1.343 mmol) was dissolved in DCM (6.71 ml), followed by the addition of tert-butyl piperazine-1-carboxylate (0.300 g, 1.611 mmol) and DIPEA (0.586 ml, 3.36 mmol). The mixture was stirred at room temperature for 16 hours. After the solvent was removed under reduced pressure, it was dissolved in ethyl acetate and washed with water. The desired product was obtained by purification on a silica gel column (yield 83%).

[0537] 1 H-NMR (400MHz, chloroform-D) δ8.06(d,J=5.9Hz,1H),6.38(d,J=5.9Hz,1H),3.71-3.59(3H),3.57-3.45(m,4H),1.52-1.43(9H)

[0538] Step 2: 2-Chloro-4-(piperazin-1-yl)pyrimidine hydrochloride

[0539] The desired product was obtained in a similar manner to Step 3 of Preparation 28 using tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate (0.332 g, 1.11 mmol) obtained in Step 1 (yield 100%).

[0540] 1 H-NMR (400MHz, methanol-D4) δ8.25(d,J=6.9Hz,1H),7.13(dd,J=7.1,1.1Hz,1H),4.15(t,J=4.8Hz,4H),3.40(t,J=5.3Hz,4H)

[0541] Step 3: Ethyl 2-(4-(2-chloropyrimidin-4-yl)piperazin-1-yl)acetate

[0542] The 2-chloro-4-(piperazin-1-yl)pyrimidine hydrochloride (0.095 g, 0.404 mmol) obtained in step 2 was dissolved in acetonitrile (4 ml), and then ethyl 2-bromoacetate (0.067 ml, 0.606 mmol) and potassium carbonate (0.168 g, 1.212 mmol) were added. It was stirred at 60° C. for 16 hours. After removing the solvent under reduced pressure, it was dissolved in ethyl acetate and washed with water. The organic solvent was dehydrated over magnesium sulfate and removed under reduced pressure. The desired product was obtained by purification on a silica gel column (yield 33%).

[0543] 1H-NMR (500 MHz, chloroform-d) δ 8.04 (d, J = 6.1 Hz, 1H), 6.39 (d, J = 6.1 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.72 (s, 4H), 3.27 (s, 2H), 2.67 (t, J = 5.0 Hz, 4H), 1.28 (t, J = 7.0 Hz, 3H)

[0544] Step 4: Ethyl 2-(4-(2-aminopyrimidin-4-yl)piperazin-1-yl)acetate

[0545] The desired product was obtained in a similar manner to Preparation 2 using ethyl 2-(4-(2-chloropyrimidin-4-yl)piperazin-1-yl)acetate (0.038 g, 133 mmol) obtained in Step 3 (33% yield over 2 steps).

[0546] 1 H-NMR (400MHz, chloroform-D) δ7.84 (d, J = 5.9 Hz, 1H), 5.91 (d, J = 5.9 Hz, 1H), 4.73 (s, 2H), 4.18 (q, J = 7. 2Hz,2H),3.62(t,J=4.8Hz,4H),3.24(d,J=7.8Hz,2H),2.60(t,J=5.0Hz,4H),1.31-1.23(m,3H)

[0547] Preparation Example 36: Ethyl 2-(1-(6-aminopyridin-2-yl)piperidin-4-yl)acetate

[0548]

[0549] Step 1: tert-Butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate

[0550] Under nitrogen, ethyl 2-(diethoxyphosphoryl)acetate (6.75g, 30.1mmol) was dissolved in 40mLTHF, sodium hydride (1.204g, 50.2mmol) was added at 0°C, tert-butyl 4-oxopiperidine-1-formate (5g, 25.09mmol) was dissolved in 10mLTHF and slowly added dropwise. After stirring at room temperature for 15 hours, the disappearance of the starting material was confirmed by TLC. The reaction was terminated with ammonium chloride, extracted with ethyl acetate (2×30ml) and washed with brine (20ml), and the organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 25%) was obtained by purification with a silica gel column (ethyl acetate: hexane=1:9).

[0551] 1H-NMR (400 MHz, chloroform-D) δ 5.51 (s, 1H), 4.19-4.01 (m, 2H), 3.95-3.78 (m, 2H), 3.56-3.43 (m, 2H), 3.08-2.91 (2H), 2.07 (d, J = 38.4 Hz, 2H), 1.55-1.36 (9H), 1.31-1.18 (m, 3H)

[0552] Step 2: tert-Butyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate

[0553] The desired product was obtained in a similar manner to Step 3 of Preparation 94 using tert-butyl 4-(2-ethoxy-2-oxoethylidene)piperidine-1-carboxylate (0.6 g, 2.228 mmol) obtained in Step 1 (yield 99%).

[0554] 1 H-NMR (400 MHz, chloroform-D) δ 4.26-3.90 (m, 4H), 2.84-2.58 (m, 2H), 2.21 (d, J = 7.3 Hz, 2H), 2.01-1.78 (m, 1H), 1.73-1.59 (2H), 1.48-1.39 (m, 9H), 1.32-1.19 (m, 3H), 1.19-1.02 (m, 2H)

[0555] Step 3: Ethyl 2-(piperidin-4-yl)acetate

[0556] The tert-butyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (0.6 g, 2.248 mmol) obtained in step 2 was dissolved in 10 mL of dichloromethane, 2.76 mL of 4.0 M hydrochloric acid solution (1,4-dioxane) was added dropwise and stirred at room temperature for 15 hours. The reaction was terminated with 1N aqueous sodium hydroxide solution, extracted with ethyl acetate (2 x 15 ml), washed with brine (10 ml), and the organic solvent was dehydrated over magnesium sulfate and removed under reduced pressure. The desired product (yield 99%) was obtained by purification on a silica gel column (ethyl acetate: hexane = 1:9).

[0557] m / z(M+H) + C9H 18 The calculated value of NO2 is 172, and the measured value is 172

[0558] Step 4: Ethyl 2-(1-(6-chloropyridin-2-yl)piperidin-4-yl)acetate

[0559] The ethyl 2-(piperidin-4-yl)acetate (0.385g, 2.247mmol), 2,6-dichloropyridine (0.399g, 2.7mmol) and 0.982mL DIPEA obtained in step 3 were dissolved in 8mL DMF and stirred at 100°C for 15 hours. After confirming that the reaction was complete by TLC, the organic solvent was removed under reduced pressure. After extraction with ethyl acetate (2×15ml), it was washed with brine (20ml), and the organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 35%) was obtained by purification with a silica gel column (ethyl acetate: hexane = 1:9).

[0560] 1 H-NMR (chloroform-D) δ7.38(t,J=7.9Hz,1H),6.57(d,J=7.3Hz,1H),6.51(d,J=8.5Hz,1H),4.38-4.23(2H),4.17(q,J=7. 1Hz,2H),2.88(td,J=12.7,2.3Hz,2H),2.36-2.19(m,2H),2.17-1.98(m,1H),1.88-1.75(2H),1.37-1.19(m,5H)

[0561] Step 5: Ethyl 2-(1-(6-aminopyridin-2-yl)piperidin-4-yl)acetate

[0562] The desired product was obtained in a similar manner to Preparation 19 (step 3, step 4) using ethyl 2-(1-(6-chloropyridin-2-yl)piperidin-4-yl)acetate (0.22 g, 0.778 mmol) obtained in step 4 (yield 69% over 2 steps).

[0563] 1 H-NMR (chloroform-D) δ7.30 (s, 1H), 6.03 (d, J = 8.2Hz, 1H), 5.86 (d, J = 7.9Hz, 1H), 4.33-4.22 (2H), 4.17 (q, J = 7.2Hz, 2H), 2. 80(t,J=12.2Hz,2H),2.28(t,J=7.6Hz,2H),2.02(tt,J=11.3,3.8Hz,1H),1.80(d,J=12.8Hz,2H),1.41-1.21(m,5H)

[0564] Preparation 37: (2-aminopyrimidin-4-yl)-L-proline methyl ester

[0565]

[0566] The desired product was obtained in a similar manner to Preparation 28 using L-proline methyl ester hydrochloride (0.267 g, 1.611 mmol) (yield 40% over 3 steps).

[0567] 1 H-NMR (400 MHz, chloroform-D) δ 7.88 (d, J = 6.1 Hz, 1H), 6.03-5.72 (1H), 4.70 (s, 2H), 4.65-4.41 (1H), 3.88-3.70 (3H), 3.70-3.55 (1H), 3.55-3.30 (1H), 2.52-2.22 (1H), 2.22-2.00 (m, 3H)

[0568] Preparation Example 38: Methyl 1-(6-aminopyridin-2-yl)pyrrolidine-3-carboxylate

[0569]

[0570] The desired product was obtained in a similar manner to Preparation 29 using methyl pyrrolidine-3-carboxylate hydrochloride (0.500 g, 3.02 mmol) (10% yield over 3 steps).

[0571] 1 H-NMR (400MHz, chloroform-D) δ7.26(m,1H),5.83(d,J=7.6Hz,1H),5.77(d,J=7.9Hz,1H),4.26-4.07(m,2H) ,3.85-3.70(m,4H),3.70-3.53(m,2H),3.53-3.37(m,1H),3.18(t,J=7.6Hz,1H),2.37-2.20(m,2H)

[0572] Preparation Example 39: Methyl 1-(2-aminopyrimidin-4-yl)pyrrolidine-3-carboxylate

[0573]

[0574] The desired product was obtained in a similar manner to Preparation 28 using methyl pyrrolidine-3-carboxylate hydrochloride (0.667 g, 4.03 mmol) (14% yield over 3 steps).

[0575] 1H-NMR (500 MHz, chloroform-D) δ 7.77 (d, J = 6.1 Hz, 1H), 5.69 (d, J = 6.1 Hz, 1H), 5.22 (s, 2H), 3.79-3.65 (m, 4H), 3.65-3.46 (m, 2H), 3.40 (s, 1H), 3.13 (t, J = 7.0 Hz, 1H), 2.21 (d, J = 7.0 Hz, 2H)

[0576] Preparation Example 40: Ethyl 1-(2-aminopyrimidin-4-yl)-3-methylpiperidine-3-carboxylate

[0577]

[0578] Step 1: 1-(tert-Butyl)3-ethylpiperidine-1,3-dicarboxylate

[0579] Piperidine-3-ethyl formate (1.0g, 6.36mmol) is dissolved in DCM (50ml), then tert-Butyl dicarbonate (1.754ml, 7.63mmol) and TEA (1.733ml, 12.72mmol) are added. It was stirred at room temperature for 4 hours. After the reaction was terminated by adding water, it was dissolved in DCM and washed with water. The organic solvent is dehydrated on magnesium sulfate, and the organic solvent is removed under reduced pressure. Obtain required product (yield 70%) by using silica gel column purification.

[0580] 1 H-NMR (500 MHz, chloroform-D) δ 4.16 (q, J = 7.1 Hz, 3H), 3.94 (d, J = 12.8 Hz, 1H), 2.93 (s, 1H), 2.87-2.75 (m, 1H), 2.45 (t, J = 10.5 Hz, 1H), 2.06 (dd, J = 13.1, 4.0 Hz, 1H), 1.72 (dt, J = 13.1, 3.7 Hz, 1H), 1.68-1.59 (m, 1H), 1.51-1.45 (m, 10H), 1.32-1.17 (m, 3H)

[0581] Step 2: 1-(tert-Butyl)3-ethyl 3-methylpiperidine-1,3-dicarboxylate

[0582] Diisopropylamine (1.277ml, 8.96mmol) was dissolved in THF (22.4ml), and n-butyllithium (3.58ml, 8.96mmol) was then added at -78°C. The mixture was stirred at -78°C for 10 minutes and at room temperature for 10 minutes, and then the temperature was lowered to -78°C. Piperidine-1,3-dicarboxylic acid 1-(tert-butyl) 3-ethyl ester (1.153g, 4.48mmol) obtained in step 1 was dissolved in THF (22.40ml) and added to the reaction mixture. After stirring at -78°C for 1 hour, iodomethane (0.336ml, 5.37mmol) was added and stirred at room temperature for 1 hour. After terminating the reaction with aqueous ammonium chloride solution, it was dissolved in ethyl acetate and washed with water. The organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 21%) was obtained by purification with a silica gel column.

[0583] 1 H-NMR (400 MHz, chloroform-D) δ 4.21-4.03 (m, 2H), 3.82 (d, J = 13.3 Hz, 1H), 3.48-3.36 (m, 1H), 3.32-3.18 (m, 1H), 3.17-3.07 (1H), 2.07-1.95 (m, 1H), 1.58 (d, J = 7.3 Hz, 1H), 1.56 (s, 1H), 1.52 (dd, J = 9.6, 4.1 Hz, 0H), 1.48-1.38 (m, 11H), 1.29-1.20 (m, 3H), 1.14 (s, 3H)

[0584] Step 3: Ethyl 3-methylpiperidine-3-carboxylate hydrochloride

[0585] The desired product was obtained in a similar manner to Step 2 of Preparation 1 using 1-(tert-butyl)3-ethyl 3-methylpiperidine-1,3-dicarboxylate (0.250 g, 0.921 mmol) obtained in Step 2 and used in the next step without further purification.

[0586] m / z(M+H) + C9H 18 The calculated value of NO2 is 172, and the measured value is 172

[0587] Step 4: Ethyl 1-(2-aminopyrimidin-4-yl)-3-methylpiperidine-3-carboxylate

[0588] The desired product was obtained in a similar manner to Preparation 28 using ethyl 3-methylpiperidine-3-carboxylate hydrochloride (0.191 g, 0.921 mmol) obtained in Step 3 (yield over 3 steps, 45%).

[0589] 1H-NMR (500 MHz, chloroform-D) δ 7.83 (q, J = 6.2 Hz, 1H), 6.01 (d, J = 6.4 Hz, 1H), 4.84 (d, J = 17.1 Hz, 2H), 4.31-4.02 (m, 3H), 3.98 (d, J = 12.2 Hz, 1H), 3.24-2.93 (m, 2H), 2.18 (dt, J = 13.2, 5.0 Hz, 1H), 1.69-1.53 ​​(m, 2H), 1.53-1.41 (m, 1H), 1.20-0.94 (m, 6H)

[0590] Preparation Example 41: (S)-2-(1-(2-aminopyrimidin-4-yl)piperidin-3-yl)acetic acid benzyl ester

[0591]

[0592] Step 1: (R)-1-(2-chloropyrimidin-4-yl)piperidine-3-carboxylic acid

[0593] To THF (17.6 ml) and ethanol (17.6 ml) was added the intermediate (R)-1-(2-chloropyrimidin-4-yl)piperidine-3-carboxylic acid ethyl ester (0.950 g, 3.52 mmol) obtained in Preparation Example 30, followed by addition of 6N aqueous sodium hydroxide solution (2.94 ml, 17.61 mmol) and stirring at room temperature for 4 hours. After removing the solvent under reduced pressure, the mixture was dissolved in ethyl acetate and washed with water. The desired product was obtained by purification on a silica gel column (yield 66%).

[0594] 1 H-NMR (400MHz, chloroform-D) δ8.02(d,J=6.4Hz,1H),6.43(d,J=5.9Hz,1H),4.40-4.18(1H),4.18-4.11(2H),4.02(s,1H),3.39(dd,J=13.5,9.4 Hz,1H),3.25(t,J=10.5Hz,1H),2.61-2.44(m,1H),2.16-2.04(m,1H),1.93-1.70(m,2H),1.63-1.54(m,1H),1.25(td,J=7.1,2.7Hz,3H)

[0595] Step 2: (S)-Benzyl 2-(1-(2-chloropyrimidin-4-yl)piperidin-3-yl)acetate

[0596] The (R)-1-(2-chloropyrimidin-4-yl)piperidine-3-carboxylic acid (0.300 g, 1.241 mmol) obtained in step 1 was dissolved in DCM (12.4 ml), and oxalyl chloride (0.543 ml, 6.21 mmol) and DMF (0.481 μl, 6.21 μmol) were added dropwise sequentially. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure. The reaction was dissolved in acetonitrile (10.3 ml) and THF (10.3 ml), and 2M trimethylsilyldiazomethane (1.86 ml, 3.72 mmol) dissolved in diethyl ether was added at 0°C. After stirring at room temperature for 16 hours, the solvent was removed under reduced pressure. The reaction was dissolved in 2,4,6-trimethylpyridine (8.26 ml), benzyl alcohol (0.271 ml, 2.61 mmol) was added, and then stirred at 180°C for 7 minutes. After the reaction was terminated by adding water, it was dissolved in diethyl ether, washed with water, and dehydrated over magnesium sulfate. The desired product was obtained by purification using a silica gel column (yield 52%).

[0597] 1 H-NMR (500MHz, chloroform-D) δ8.07(t,J=5.6Hz,1H),6.49(d,J=6.4Hz,1H),4.49-4.17(1H),4.06(t,J=6.1Hz,1H),3.45(dd,J=1 3.3,9.3Hz,1H),3.40-3.26(m,1H),2.73-2.59(m,1H),2.17(dd,J=17.7,4.6Hz,1H),2.01-1.79(m,2H),1.73-1.54(m,1H)

[0598] Step 3: (S)-Benzyl 2-(1-(2-aminopyrimidin-4-yl)piperidin-3-yl)acetate

[0599] The desired product was obtained in a similar manner to Preparation 2 using (S)-benzyl 2-(1-(2-chloropyrimidin-4-yl)piperidin-3-yl)acetate (0.224 g, 0.648 mmol) obtained in Step 2 (yield 40% over 2 steps).

[0600] 1H-NMR (500 MHz, chloroform-D) δ 7.82 (d, J = 6.4 Hz, 1H), 7.43-7.35 (m, 5H), 5.89 (d, J = 6.1 Hz, 1H), 5.17 (t, J = 12.8 Hz, 2H), 4.66 (s, 2H), 4.18 (d, J = 11.6 Hz, 2H), 3.03-2.92 (m, 1H) ,2.77(dd,J=13.1,10.1Hz,1H),2.44-2.25(m,2H),2.07(dd,J=10.7,7.3Hz,1H),1. 96-1.86(m,1H),1.72(dt,J=13.4,4.0Hz,1H),1.60-1.47(m,1H),1.39-1.22(m,1H)

[0601] Preparation Example 42: Ethyl (S,E)-3-(1-(2-aminopyrimidin-4-yl)piperidin-3-yl)acrylate

[0602]

[0603] Step 1: (R)-tert-Butyl 3-Formylpiperidine-1-carboxylate

[0604] The piperidine-1,3-dicarboxylic acid 1-(tert-butyl) 3-ethyl ester (1.73 g, 6.72 mmol) obtained in step 1 of Preparation Example 40 was dissolved in toluene (67.2 ml), and then 1 M diisobutylaluminum hydride (16.81 ml, 16.81 mmol) was added dropwise at -78 ° C and stirred for 3 hours and 30 minutes. The reaction was terminated by slowly adding ethyl acetate (10 ml) and methanol (5 ml) at -78 ° C. After 15 minutes, 1 M potassium sodium tartrate aqueous solution was added and stirred for 1 hour, then diluted with ethyl acetate and filtered to remove the precipitate. The organic solvent was removed under reduced pressure and then purified by silica gel column to obtain the desired product (yield 20%).

[0605] 1 H-NMR (400 MHz, chloroform-D) δ 9.69 (s, 1H), 3.91 (d, J = 13.3 Hz, 1H), 3.64 (d, J = 12.3 Hz, 1H), 3.31 (dd, J = 13.5, 8.5 Hz, 1H), 3.14-2.99 (m, 1H), 2.41 (s, 1H), 1.93 (d, J = 3.7 Hz, 1H), 1.76-1.59 (m, 2H), 1.52-1.46 (m, 1H), 1.46-1.36 (9H)

[0606] Step 2: (S,E)-tert-Butyl 3-(3-ethoxy-3-oxopropan-1-phenyl-1-yl)piperidine-1-carboxylate

[0607] (R)-tert-Butyl 3-formylpiperidine-1-carboxylate (0.283 g, 1.327 mmol) obtained in step 1 was dissolved in DCM (6.63 ml), ethyl 2-(triphenyl-15-phosphinoyl)acetate (0.601 g, 1.725 mmol) was added, and stirred at room temperature for 16 hours. The organic solvent was removed under reduced pressure, and then purified by silica gel column to obtain the desired product (yield 96%).

[0608] 1 H-NMR (400MHz, chloroform-D) δ6.83 (dd, J=15.8, 6.6Hz, 1H), 5.85 (dd, J=16.0, 1.4Hz, 1H ),4.18(q,J=7.0Hz,2H),3.89(td,J=8.6,4.3Hz,2H),2.81(t,J=11.2Hz,2H),2. 43-2.22(m,1H),1.87(dd,J=13.0,3.9Hz,1H),1.67(dt,J=13.0,3.9Hz,1H),1.4 8(s,1H),1.43(d,J=14.6Hz,9H),1.41-1.31(m,1H),1.27(dd,J=13.5,6.2Hz,3H)

[0609] Step 3: Ethyl (S,E)-3-(1-(2-chloropyrimidin-4-yl)piperidin-3-yl)acrylate

[0610] Ethyl (S,E)-3-(piperidin-3-yl)acrylate hydrochloride was obtained in a manner similar to that in Step 2 of Preparation 1 using tert-butyl (S,E)-3-(3-ethoxy-3-oxopropan-1-phenyl-1-yl)piperidine-1-carboxylate obtained in Step 2 and then used without further purification in a manner similar to that in Step 1 of Preparation 28 to obtain the desired product (yield 91%).

[0611] 1 H-NMR (400MHz, chloroform-D) δ8.02 (d, J=6.4Hz, 1H), 6.86 (dd, J=15.8, 7.1Hz, 1H), 6.39 (d,J=5.9Hz,1H),5.89(dd,J=16.0,1.4Hz,1H),4.51-4.15(m,3H),3.06-2.92(m, 1H),2.86(dd,J=13.0,10.7Hz,1H),2.51-2.31(m,1H),2.01-1.92(1H),1.90-1. 78(1H),1.65-1.55(m,1H),1.54(s,3H),1.52-1.41(m,1H),1.29(t,J=7.1Hz,3H)

[0612] Step 4: Ethyl (S,E)-3-(1-(2-aminopyrimidin-4-yl)piperidin-3-yl)acrylate

[0613] The desired product was prepared in a similar manner to Preparation 2 using ethyl (S,E)-3-(1-(2-chloropyrimidin-4-yl)piperidin-3-yl)acrylate obtained in Step 3 (yield 49% over 2 steps).

[0614] 1 H-NMR (500 MHz, chloroform-D) δ 7.94-7.81 (m, 1H), 6.91 (dd, J = 15.9, 7.0 Hz, 1H), 5.97 (t, J = 6.0 Hz, 1H), 5.95-5.84 (1H), 4.73 (d, J = 18.0 Hz, 2H), 4.41 (s, 1H), 4.23 (q, J = 7.1 Hz, 2H), 4.20-4. 06(m,1H),3.00-2.85(m,1H),2.78(dd,J=13.1,10.4Hz,1H),2.48-2.31(1H),1.98(d,J=1 2.5Hz,1H),1.87-1.77(m,1H),1.62-1.53(m,1H),1.53-1.42(m,1H),1.32(t,J=7.2Hz,3H)

[0615] Preparation Example 43: Ethyl 1-(2-aminopyrimidin-4-yl)piperidine-3-carboxylate

[0616]

[0617] The desired product was obtained in a similar manner to Preparation 28 using ethyl piperidine-3-carboxylate (0.626 ml, 4.03 mmol) (14% yield over 3 steps).

[0618] 1 H-NMR (500 MHz, chloroform-D) δ7.86 (d, J = 6.1 Hz, 1H), 6.01 (d, J = 6.4 Hz, 1H), 4.93 (s, 2H), 4.58-4.29 (1H), 4.29-4.14 (2H), 4.14-4.01 (1H), 3.33-3.12 (1H), 3.12-2.98 (1H), 2.67-2.43 (m, 1H), 2.23-1.96 (1H), 1.82 (d, J = 4.0 Hz, 1H), 1.74-1.61 (1H), 1.56 (s, 1H), 1.39-1.23 (3H)

[0619] Preparation 44: (S)-tert-Butyl 2-((1-(2-aminopyrimidin-4-yl)piperidin-3-yl)oxy)acetate

[0620]

[0621] Step 1: (S)-3-Hydroxypiperidine-1-carboxylic acid benzyl ester

[0622] (S)-Piperidin-3-ol hydrochloride (1.0 g, 7.27 mmol) was dissolved in DCM (14.5 ml), TEA (2.026 ml, 14.53 mmol) was added, and benzyl chloroformate (1.025 ml, 7.27 mmol) was added dropwise at 0°C for 2 hours and 30 minutes. The mixture was stirred at 0°C for another 30 minutes, diluted with DCM and washed with 1N aqueous HCl. The organic solvent was dried over magnesium sulfate and then removed under reduced pressure. It was used immediately in the next reaction without further purification.

[0623] 1 H-NMR (500 MHz, chloroform-D) δ7.57-7.31 (m, 5H), 5.27-5.09 (2H), 3.90-3.70 (m, 2H), 3.61 (s, 1H), 3.38-3.15 (m, 2H), 2.00-1.87 (m, 1H), 1.87-1.73 (1H), 1.73-1.46 (m, 3H)

[0624] Step 2: (S)-benzyl 3-(2-(tert-butoxy)-2-oxoethoxy)piperidine-1-carboxylate

[0625] After the (S)-3-hydroxypiperidine-1-benzyl carboxylate (7.27mmol) obtained in step 1 was dissolved in toluene (14.5ml), 2-bromoacetic acid tert-butyl ester (1.611ml, 10.91mmol) and tetra-n-butylammonium hydrogen sulfate (0.074g, 0.218mmol) dissolved in 5mL water were added. Sodium hydroxide (7.27g, 182mmol) dissolved in 7.27mL water was added dropwise to the reaction. After stirring at room temperature for 16 hours, it was dissolved in ethyl acetate and washed with salt water. The organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 59%) was obtained by purification with a silica gel column.

[0626] 1 H-NMR (400MHz, chloroform-D) δ7.46-7.26(5H),5.11(s,2H),3.96(s,2H),3.88(d,J=11.4Hz,1H),3.66(d,J=12.8H z,1H),3.41(s,1H),3.21-3.07(2H),1.96(s,1H),1.77(d,J=3.7Hz,1H),1.59(d,J=9.6Hz,1H),1.45(s,9H)

[0627] Step 3: (S)-tert-Butyl 2-(piperidin-3-yloxy)acetate

[0628] The (S)-3-(2-(tert-butoxy)-2-oxoethoxy)piperidine-1-carboxylic acid benzyl ester obtained in step 2 was dissolved in ethanol (21.2 ml), and then Pd / C (0.1485 g, 1.395 mmol) was added and deprotection reaction was carried out using a hydrogen balloon. After filtration through a celite pad, the solvent was removed under reduced pressure, and purification was performed on a silica gel column to obtain the desired product (yield 100%).

[0629] 1 H-NMR (500 MHz, chloroform-D) δ 4.03 (dd, J = 25.9, 16.5 Hz, 2H), 3.45-3.31 (m, 1H), 3.09 (dd, J = 12.4, 2.6 Hz, 1H), 2.90-2.78 (m, 1H), 2.78-2.62 (2H), 2.04-1.91 (m, 1H), 1.79-1.70 (1H), 1.61 (tt, J = 12.8, 4.4 Hz, 1H), 1.56-1.39 (m, 11H)

[0630] Step 4: (S)-tert-Butyl 2-((1-(2-aminopyrimidin-4-yl)piperidin-3-yl)oxy)acetate

[0631] The desired product was obtained in a similar manner to Preparation 28 using (S)-tert-butyl 2-(piperidin-3-yloxy)acetate (0.517 g, 1.577 mmol) obtained in Step 3 (yield 50% over 3 steps).

[0632] 1 H-NMR (400 MHz, chloroform-D) δ 7.83 (t, J = 3.2 Hz, 1H), 5.96 (d, J = 6.4 Hz, 1H), 4.64 (s, 2H), 4.15 (d, J = 11.9 Hz, 1H), 4.06-4.00 (2H), 3.87 (s, 1H), 3.41 (t, J = 4.1 Hz, 1H), 3.21-3.04 (m, 2H), 2.05 (s, 1H), 1.83 (s, 1H), 1.53-1.38 (m, 11H)

[0633] Preparation 45: (S)-tert-Butyl 2-((1-(6-aminopyridin-2-yl)piperidin-3-yl)oxy)acetate

[0634]

[0635] The desired product was obtained in a manner similar to Step 1 and Preparation 2 of Preparation 29 using tert-butyl (S)-2-(piperidin-3-yloxy)acetate (0.503 g, 2.336 ml) prepared in Step 3 of Preparation 44 (6% yield over 3 steps).

[0636] 1 H-NMR (400MHz, chloroform-D) δ7.22(d,J=7.8Hz,1H),6.01(d,J=8.2Hz,1H),5.82(d,J=7.8Hz,1H),4.25(dd,J=12.3,4.1Hz,1H),4.22-4.09(m,2H),4.05( s,2H),3.94-3.85(m,1H),3.45(td,J=9.1,4.4Hz,1H),2.92-2.80(m,2H) ,2.09(d,J=3.7Hz,1H),1.89-1.74(m,1H),1.55-1.49(m,2H),1.47(s,9H)

[0637] Preparation 46: (R)-tert-Butyl 2-((1-(2-aminopyrimidin-4-yl)piperidin-3-yl)oxy)acetate

[0638]

[0639] The desired product was obtained in a similar manner to Preparation 44 using (R)-piperidin-3-ol hydrochloride (1.0 g, 7.27 mmol) (23% yield over 5 steps).

[0640] 1 H-NMR (400 MHz, chloroform-D) δ7.80 (d, J=6.4 Hz, 1H), 5.96 (d, J=6.4 Hz, 1H), 4.91 (s, 1H), 4.21-4.08 (1H), 4.08-3.96 (2H), 3.84 (d, J=12.8 Hz, 1H), 3.55-3.37 (m, 1H), 3.27-3.08 (2H), 2.29-1.89 (m, 1H), 1.90-1.75 (m, 1H), 1.69-1.57 (m, 1H), 1.57-1.48 (m, 1H), 1.47 (s, 9H)

[0641] Preparation 47: (R)-tert-Butyl 2-((1-(2-aminopyrimidin-4-yl)piperidin-3-yl)oxy)-2-methylpropanoate

[0642]

[0643] Step 1: (R)-1-Benzylpiperidin-3-ol

[0644] (R)-piperidin-3-ol hydrochloride (1.0 g, 7.27 mmol) was dissolved in DMF (14.5 ml) and potassium carbonate (2.210 g, 15.99 mmol) and benzyl bromide (0.951 ml, 7.99 mmol) were added. The reaction was stirred at 60° C. for 3 days. After filtering the potassium carbonate, the DMF solvent was removed under reduced pressure. The desired product was obtained by purification on a silica gel column (yield 57%).

[0645] 1 H-NMR (500 MHz, chloroform-D) δ 7.33 (td, J = 8.0, 6.1 Hz, 4H), 7.28-7.23 (m, 1H), 3.84 (t, J = 3.8 Hz, 1H), 3.53 (s, 2H), 2.50 (d, J = 14.0 Hz, 3H), 2.27 (s, 1H), 1.95-1.74 (1H), 1.75-1.46 (m, 3H)

[0646] Step 2: (R)-tert-Butyl 2-((1-phenylmethylpiperidin-3-yl)oxy)acetate

[0647] The desired product was obtained in a similar manner to Step 2 of Preparation 44 using (R)-1-benzylpiperidin-3-ol (0.785 g, 4.10 mmol) prepared in Step 1 (yield 40%).

[0648] 1 H-NMR (400 MHz, chloroform-D) δ 7.39-7.26 (m, 4H), 7.24-7.20 (m, 1H), 3.96 (s, 2H), 3.52 (s, 2H), 3.49-3.39 (m, 1H), 3.06-2.91 (m, 1H), 2.65 (d, J = 11.0 Hz, 1H), 2.07-1.90 (3H), 1.71 (dt, J = 13.7, 3.7 Hz, 1H), 1.55-1.46 (1H), 1.46-1.40 (m, 9H), 1.28 (ddd, J = 22.1, 12.2, 4.5 Hz, 1H)

[0649] Step 3: (R)-tert-Butyl 2-((1-phenylmethylpiperidin-3-yl)oxy)-2-methylpropanoate

[0650] After dissolving tert-butyl (R)-2-((1-benzylpiperidin-3-yl)oxy)acetate (0.507 g, 1.660 mmol) prepared in Step 2 in THF (10 ml), lithium bis(trimethylsilyl)amide (1.938 ml, 2.52 mmol) was added at -78°C. After stirring at room temperature for 1 hour, the mixture was cooled to -78°C, and then iodomethane (0.068 ml, 1.109 mmol) dissolved in THF (0.7 ml) was added. The mixture was stirred at room temperature for another 1 hour. Purification on a silica gel column gave tert-butyl 2-(((R)-1-benzylpiperidin-3-yl)oxy)propanoate to which a methyl group had been added. The same procedure was repeated to obtain the desired product (yield 38%).

[0651] 1 H-NMR (400MHz, chloroform-D) δ7.28(d,J=4.6Hz,4H),7.24-7.15(m,1H),3.48(d,J =3.7Hz,2H),3.46-3.37(m,1H),3.01(dt,J=10.5,2.1Hz,1H),2.76-2.64( m,1H),2.04-1.81(m,4H),1.64(tt,J=10.2,3.4Hz,1H),1.58-1.45(m,1H) ,1.37(d,J=6.9Hz,9H),1.34(s,3H),1.33-1.29(m,3H),1.29-1.14(m,1H)

[0652] Step 4: (R)-tert-Butyl 2-((1-(2-aminopyrimidin-4-yl)piperidin-3-yl)oxy)-2-methylpropanoate

[0653] The desired product was obtained in a similar manner to Preparation 44 (Step 3, Step 4) using (R)-tert-butyl 2-((1-benzylpiperidin-3-yl)oxy)-2-methylpropanoate prepared in Step 3 (43% yield over 4 steps).

[0654] 1 H-NMR (400 MHz, chloroform-D) δ 8.14 (d, J = 95.6 Hz, 1H), 6.29 (s, 1H), 4.45 (s, 2H), 3.54 (s, 1H), 3.13 (s, 2H), 2.33-2.01 (m, 3H), 1.46 (s, 9H), 1.38 (d, J = 14.2 Hz, 6H)

[0655] Preparation Example 48: Methyl 1-(2-aminopyrimidin-4-yl)-3-methylpyrrolidine-3-carboxylate

[0656]

[0657] The desired product was obtained in a similar manner to Preparation 40 using methyl pyrrolidine-3-carboxylate hydrochloride (1.0 g, 6.04 mmol) (30% yield over 6 steps).

[0658] 1 H-NMR (400 MHz, chloroform-D) δ7.82 (d, J=5.9 Hz, 1H), 5.72 (d, J=5.9 Hz, 1H), 4.68 (s, 2H), 3.99-3.76 (1H), 3.71 (s, 3H), 3.52 (s, 1H), 2.54-2.36 (1H), 1.95-1.81 (m, 1H), 1.63 (m, 2H), 1.38 (s, 3H)

[0659] Preparation Example 49: Methyl 1-(6-aminopyridin-2-yl)-3-methylpyrrolidine-3-carboxylate

[0660]

[0661] The desired product was obtained in a similar manner to Preparation 29 using methyl 3-methylpyrrolidine-3-carboxylate hydrochloride (0.390 g, 2.171 mmol) prepared in Preparation 48 (10% yield over 3 steps).

[0662] 1 H-NMR (400 MHz, chloroform-D) δ 7.22 (t, J = 8.0 Hz, 1H), 5.78 (d, J = 7.3 Hz, 1H), 5.71 (d, J = 8.2 Hz, 1H), 4.13 (s, 2H), 3.83 (d, J = 10.5 Hz, 1H), 3.69 (s, 3H), 3.57-3.41 (m, 2H), 3.32 (d, J = 10.5 Hz, 1H), 2.51-2.36 (m, 1H), 1.92-1.80 (m, 1H), 1.37 (s, 3H)

[0663] Preparation Example 50: Methyl (1r,4r)-4-((2-aminopyrimidin-4-yl)oxy)cyclohexane-1-carboxylate

[0664]

[0665] Step 1: Methyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate

[0666] (1r,4r)-4-Hydroxycyclohexane-1-carboxylic acid (0.300 g, 2.081 mmol) was dissolved in methanol (10 ml) and sulfuric acid (0.017 ml, 0.312 mmol) was added. After stirring at 60°C for 16 hours, the organic solvent was removed under reduced pressure and the product was purified by silica gel column to obtain the desired product (yield 100%).

[0667] 1 H-NMR (400 MHz, chloroform-d) δ 8.25 (d, J = 5.9 Hz, 1H), 6.64-6.50 (m, 1H), 5.16-5.05 (1H), 3.73-3.62 (m, 3H), 2.35 (tt, J = 11.4, 3.7 Hz, 1H), 2.18 (dt, J = 12.8, 3.5 Hz, 2H), 2.07 (dd, J = 14.2, 3.7 Hz, 2H), 1.74-1.56 (m, 2H), 1.49 (ddd, J = 23.0, 12.7, 3.5 Hz, 2H)

[0668] Step 2: Methyl (1r,4r)-4-((2-aminopyrimidin-4-yl)oxy)cyclohexane-1-carboxylate

[0669] The desired product was obtained in a similar manner to Preparation 117 using methyl (1r,4r)-4-hydroxycyclohexane-1-carboxylate (0.333 g, 2.105 mmol) (yield 28% over 2 steps).

[0670] 1 H-NMR (400MHz, chloroform-D) δ7.98(d,J=5.9Hz,1H),6.01(d,J=5.5Hz,1H),5.02-4.89(m,1H),4.82(s,2H),3.68(dd,J=7 .3,2.7Hz,5H),2.44-2.26(m,1H),2.20-1.99(m,4H),1.71-1.57(m,2H),1.52(s,1H),1.41(dd,J=12.6,3.4Hz,1H)

[0671] Preparation Example 51: Methyl (1s,4s)-4-((2-aminopyrimidin-4-yl)oxy)cyclohexane-1-carboxylate

[0672]

[0673] The desired product was obtained in a similar manner to Preparation 50 using (1s,4s)-4-hydroxycyclohexane-1-carboxylic acid (1.000 g, 6.94 mmol) (yield 20% over 3 steps).

[0674] 1H-NMR (400MHz, chloroform-D) δ7.93 (t, J=5.7Hz, 1H), 6.00 (t, J=5.7Hz, 1H), 5.20-4.9 7(m,3H),3.64(s,3H),2.45-2.31(m,1H),2.04-1.81(m,4H),1.79-1.52(m,4H)

[0675] Preparation Example 52: Methyl 2-(3-(6-aminopyridin-2-yl)phenyl)-2-methylpropanoate

[0676]

[0677] Step 1: Methyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate ester

[0678] After dissolving methyl 2-(3-bromophenyl)-2-methylpropanoate (250 mg, 0.972 mmol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bi(1,3,2-dioxaborolane) (296 mg, 1.17 mmol), potassium acetate (286 mg, 2.92 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (39.7 mg, 0.0490 mmol) in 9.72 mL of 1,4-dioxane, dissolved oxygen was removed by bubbling nitrogen with stirring, and the inflow of external air was blocked in a sealed container. The reaction was stirred at 110° C. for 15 hours and then cooled to room temperature. After filtering through a celite pad and removing the organic solvent under reduced pressure, the desired product was obtained by purification on a silica gel column (ethyl acetate: hexane) (yield 94%).

[0679] 1 H-NMR (400 MHz, chloroform-D) δ 7.77 (s, 1H), 7.69 (d, J = 7.3 Hz, 1H), 7.46-7.37 (1H), 7.33 (t, J = 7.5 Hz, 1H), 3.65 (s, 3H), 1.60 (s, 6H), 1.34 (s, 12H)

[0680] Step 2: Methyl 2-(3-(6-((tert-Butoxycarbonyl)amino)pyridin-2-yl)phenyl)2-methylpropanoate

[0681] By 2- methyl -2- (3- (4,4,5,5- tetramethyl -1,3,2- dioxaborolan alkane -2- bases) phenyl) methyl propionate (279mg, 0.917mmol) and (6- bromopyridin -2- bases) tert-butyl carbamate (251mg, 0.917mmol) obtained in step 1 and in preparation example 73, 2M sodium carbonate aqueous solution (1.38ml, 2.75mmol) and bis (triphenylphosphine) dichloropalladium (64mg, 0.092mmol) are dissolved in 7.64mL dimethoxyethane, under stirring, dissolved oxygen is removed by nitrogen bubbling, and the inflow of external air is blocked in a sealed container. The reaction is stirred at 100 DEG C for 15 hours, then cooled to room temperature. After filtering through a diatomaceous earth pad and removing the organic solvent under reduced pressure, it is dissolved in ethyl acetate and washed with salt water. The organic solvent is dehydrated on magnesium sulfate, and the organic solvent is removed under reduced pressure. The desired product was obtained by purification on a silica gel column (ethyl acetate:hexane) (yield 72%).

[0682] 1 H-NMR (400 MHz, chloroform-D) δ 7.95 (d, J = 1.8 Hz, 1H), 7.86 (d, J = 8.2 Hz, 1H), 7.80 (dt, J = 7.3, 1.6 Hz, 1H), 7.76-7.66 (1H), 7.42-7.33 (m, 3H), 7.31 (s, 1H), 3.66 (s, 3H), 1.64 (s, 6H), 1.55 (s, 9H)

[0683] Step 3: Methyl 2-(3-(6-aminopyridin-2-yl)phenyl)-2-methylpropanoate

[0684] The desired product was obtained in a similar manner to Step 4 of Preparation 19 using methyl 2-(3-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)phenyl)2-methylpropanoate (244 mg, 0.659 mmol) synthesized in Step 2 (yield 81%).

[0685] 1 H-NMR (400MHz, chloroform-D) δ7.92(t,J=1.8Hz,1H),7.84-7.70(m,1H),7.50(t,J=8.0Hz,1H),7.39(t,J=7.5Hz,1H ),7.34(dt,J=7.9,1.6Hz,1H),7.07(d,J=7.3Hz,1H),6.54-6.39(1H),4.49(s,2H),3.66(s,3H),1.64(s,6H)

[0686] Preparation Example 53: Methyl 2-(3-(2-aminopyrimidin-4-yl)phenyl)-2-methylpropanoate

[0687]

[0688] Step 1: Methyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate ester

[0689] Methyl 2-(3-bromophenyl)-2-methylpropanoate (0.5 g, 1.944 mmol), 4,4,4,4,5,5,5,5-octamethyl-2,2-bis(1,3,2-dioxaborolane) (0.494 g, 1.944 mmol), potassium acetate (0.478 g, 4.862 mmol), and 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) dichloromethane complex (0.08 g, 0.098 mmol) were dissolved in 8 mL of 1,4-dioxane and stirred at 110°C for 4 hours. After TLC confirmed the completion of the reaction, the organic solvent was removed under reduced pressure. After extraction with ethyl acetate (2 x 15 ml), it was washed with brine (20 ml), and the organic solvent was dehydrated over magnesium sulfate and removed under reduced pressure. The desired product (yield 85%) was obtained by purification on a silica gel column (ethyl acetate: hexane = 1:9).

[0690] 1 H-NMR (400 MHz, chloroform-D) δ 7.76 (d, J = 0.9 Hz, 1H), 7.72-7.65 (m, 1H), 7.43-7.37 (m, 1H), 7.31 (t, J = 7.5 Hz, 1H), 3.71-3.53 (m, 3H), 1.59 (s, 6H), 1.33 (s, 12H)

[0691] Step 2: Methyl 2-(3-(2-chloropyrimidin-4-yl)phenyl)-2-methylpropanoate

[0692] The 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoic acid methyl ester (0.25 g, 0.822 mmol), 2,4-dichloropyrimidine (0.147 g, 0.986 mmol), 1 ml of sodium carbonate and bis(triphenylphosphine)palladium(II) dichloride (0.058 g, 0.082 mmol) obtained in step 1 were dissolved in 4 mL of DME and stirred at 100 ° C for 4 hours. After confirming the completion of the reaction by TLC, the organic solvent was removed under reduced pressure. After extraction with ethyl acetate (2×15 ml), it was washed with brine (20 ml), and the organic solvent was dehydrated over magnesium sulfate and removed under reduced pressure. The desired product (yield 80%) was obtained by purification with a silica gel column (ethyl acetate: hexane = 1:9).

[0693] 1H-NMR (400 MHz, chloroform-D) δ 8.66-8.55 (m, 1H), 8.05 (dd, J = 15.1, 1.8 Hz, 1H), 7.98-7.85 (m, 1H), 7.66-7.56 (m, 1H), 7.56-7.38 (m, 2H), 3.70-3.59 (3H), 1.67-1.58 (m, 6H)

[0694] Step 3: Methyl 2-(3-(2-aminopyrimidin-4-yl)phenyl)-2-methylpropanoate

[0695] The desired product was obtained in a similar manner to Preparation 19 (step 3, step 4) using methyl 2-(3-(2-chloropyrimidin-4-yl)phenyl)-2-methylpropanoate (0.19 g, 0.653 mmol) obtained in step 2 (yield 64% over 2 steps).

[0696] 1 H-NMR (400MHz, chloroform-D) δ8.31(d,J=5.5Hz,1H),8.00(t,J=1.6Hz,1H),7.84(dt,J=7.3,1.6Hz, 1H),7.50-7.38(2H),7.06(t,J=5.3Hz,1H),5.43(s,2H),3.65(t,J=15.3Hz,3H),1.63(s,6H)

[0697] Preparation Example 54: Methyl 2-(4-(6-aminopyridin-2-yl)phenyl)-2-methylpropanoate

[0698]

[0699] Step 1: Methyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate ester

[0700] The desired product was obtained in a similar manner to Step 1 of Preparation 53 using methyl 2-(4-bromophenyl)-2-methylpropanoate (1 g, 3.89 mmol) (yield 95%).

[0701] 1 H-NMR (chloroform-D) δ7.80 (d, J=8.2 Hz, 2H), 7.39-7.31 (m, 2H), 3.74-3.59 (m, 3H), 1.60 (s, 6H), 1.37-1.32 (m, 12H)

[0702] Step 2: Methyl 2-(4-(6-((tert-Butoxycarbonyl)amino)pyridin-2-yl)phenyl)-2-methylpropanoate

[0703] The desired product was obtained in a similar manner to Step 2 of Preparation Example 53 using methyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (0.62 g, 2.038 mmol) and tert-butyl (6-chloropyridin-2-yl)carbamate (0.559 g, 2.446 mmol) obtained in Step 1 (yield 62%).

[0704] 1 H-NMR (400 MHz, chloroform-d) δ 7.88 (dt, J = 8.5, 2.1 Hz, 2H), 7.84 (d, J = 8.2 Hz, 1H), 7.70 (t, J = 8.0 Hz, 1H), 7.44-7.38 (m, 2H), 7.36 (d, J = 7.3 Hz, 1H), 7.31 (d, J = 11.4 Hz, 1H), 3.65 (s, 3H), 1.60 (s, 6H), 1.52 (s, 9H)

[0705] Step 3: Methyl 2-(4-(6-aminopyridin-2-yl)phenyl)-2-methylpropanoate

[0706] The desired product was obtained in a similar manner to Step 4 of Preparation 19 using 2-(4-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)phenyl)-2-methylpropanoate (0.467 g, 1.263 mmol) obtained in Step 2 (yield 78%).

[0707] 1 H-NMR (400 MHz, chloroform-D) δ7.99-7.75 (m, 2H), 7.57-7.44 (m, 1H), 7.44-7.33 (m, 2H), 7.16-6.94 (m, 1H), 6.51-6.35 (m, 1H), 4.61 (s, 2H), 3.72-3.51 (m, 3H), 1.73-1.51 (m, 6H)

[0708] Preparation Example 55: Methyl 2-(4-(2-aminopyrimidin-4-yl)phenyl)-2-methylpropanoate

[0709]

[0710] Step 1: Methyl 2-(4-(2-chloropyrimidin-4-yl)phenyl)-2-methylpropanoate

[0711] The desired product was obtained in a similar manner to Step 2 of Preparation Example 53 using methyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (0.7 g, 2.301 mmol) and 2,4-dichloropyrimidine (0.411 g, 2.76 mmol) obtained in Step 1 of Preparation Example 54 (yield 99%).

[0712] 1 H-NMR (400 MHz, chloroform-D) δ 8.65-8.56 (m, 1H), 8.09-8.01 (m, 2H), 7.61 (d, J = 5.5 Hz, 1H), 7.53-7.43 (m, 2H), 3.66 (d, J = 5.5 Hz, 3H), 1.62 (d, J = 9.6 Hz, 6H)

[0713] Step 2: Methyl 2-(4-(2-aminopyrimidin-4-yl)phenyl)-2-methylpropanoate

[0714] The desired product was obtained in a similar manner to Preparation 19 (step 3, step 4) using methyl 2-(4-(2-chloropyrimidin-4-yl)phenyl)-2-methylpropanoate (0.59 g, 2.029 mmol) obtained in step 1 (yield 44% over 2 steps).

[0715] 1 H-NMR (400 MHz, chloroform-D) δ 8.43-8.20 (m, 1H), 8.05-7.83 (m, 2H), 7.54-7.34 (2H), 7.06-6.89 (m, 1H), 5.36 (s, 2H), 3.70-3.55 (m, 3H), 1.69-1.51 (m, 6H)

[0716] Preparation Example 56: Methyl 3-(3-(2-aminopyridin-4-yl)phenyl)propanoate

[0717]

[0718] The desired product was obtained in a similar manner to Preparation 26 using methyl 3-(3-bromophenyl)propanoate (1 g, 4.11 mmol) (yield 69% over 2 steps).

[0719] 1 H-NMR (500MHz, chloroform-D) δ8.13(d,J=5.2Hz,1H),7.45(d,J=7.9Hz,2H),7.40(t,J=7.6Hz,1H),7.27(s,1H),6. 89(d,J=5.5Hz,1H),6.72(s,1H),4.64-4.42(2H),3.70(s,3H),3.04(t,J=7.8Hz,2H),2.70(t,J=7.8Hz,2H)

[0720] Preparation Example 57: Methyl 3-(3-(2-aminopyrimidin-4-yl)phenyl)propanoate

[0721]

[0722] The desired product was obtained in a similar manner to Step 1 of Preparation 28 using methyl 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (0.200 g, 0.689 mmol) prepared in Preparation 56 (43% yield over 3 steps).

[0723] 1 H-NMR (500MHz, chloroform-D) δ8.33(d,J=5.2Hz,1H),7.86(s,1H),7.84-7.74(m,1H),7.47-7.37(1H),7.32(d,J=7.3Hz, 1H),7.01(d,J=5.2Hz,1H),5.57-5.31(2H),3.70(d,J=22.6Hz,3H),3.03(t,J=7.8Hz,2H),2.69(t,J=7.8Hz,2H)

[0724] Preparation Example 58: Methyl 3-(3-(2-aminopyridin-4-yl)phenyl)-2,2-dimethylpropanoate

[0725]

[0726] Step 1: Methyl 3-(3-bromophenyl)-2,2-dimethylpropanoate

[0727] To 400mL anhydrous tetrahydrofuran, add diisopropylamine (20.5ml, 144mmol), and at-78 ℃, slowly add 2.5M n-butyl lithium (57.6ml, 144mmol) dropwise.Reaction soln was stirred 20 minutes at the same temperature.The temperature was raised to room temperature and stirred 10 minutes, then reduced to-78 ℃ and stirred 10 minutes.The reaction soln was dropwise added to the methyl isobutyrate (16.5ml, 144mmol) dissolved in 100mL anhydrous tetrahydrofuran.Reaction soln was stirred 1 hour at-78 ℃, and slowly added dropwise 1-bromo-3-(bromomethyl) benzene (30.0g, 120mmol) dissolved in 100mL anhydrous tetrahydrofuran.Reaction soln was raised to room temperature and stirred 20 minutes.By adding 1N aqueous hydrochloric acid termination reaction to reaction soln, then extracted with diethyl ether. The organic layer was concentrated under reduced pressure and then purified by silica gel column (ethyl acetate:hexane) to obtain the desired product (yield 72%).

[0728] 1 H-NMR (chloroform-D) δ7.35 (d, J=7.9 Hz, 1H), 7.26-7.20 (1H), 7.13 (t, J=7.8 Hz, 1H), 7.03 (d, J=7.6 Hz, 1H), 3.67 (s, 3H), 2.81 (s, 2H), 1.18 (s, 6H)

[0729] Step 2: 2,2-Dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane Methyl ester

[0730] The desired product was obtained in a similar manner to Step 1 of Preparation 52 using methyl 3-(3-bromophenyl)-2,2-dimethylpropanoate obtained in Step 1 (yield 73%).

[0731] 1 H-NMR (chloroform-D) δ7.65 (d, J=7.3 Hz, 1H), 7.54 (s, 1H), 7.29-7.23 (m, 1H), 7.19 (d, J=7.6 Hz, 1H), 3.66 (s, 3H), 2.86 (s, 2H), 1.33 (s, 12H), 1.18 (s, 6H)

[0732] Step 3: Methyl 3-(3-(2-aminopyridin-4-yl)phenyl)2,2-dimethylpropanoate

[0733] The desired product was obtained in a similar manner to Step 2 of Preparation Example 52 using 4-bromopyridin-2-amine (109 mg, 0.628 mmol) and 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-propionic acid methyl ester (200 mg, 0.628 mmol) obtained in Step 2, and the next reaction was carried out without purification.

[0734] 1 H-NMR (chloroform-D) δ8.11(d,J=5.5Hz,1H),7.43(d,J=7.6Hz,1H),7.37-7.29(m,2H),7.15(d,J=7.6Hz ,1H),6.85(d,J=4.0Hz,1H),6.67(s,1H),4.56-4.43(2H),3.66(s,3H),2.92(s,2H),1.21(s,6H)

[0735] Preparation Example 59: Methyl 3-(3-(2-aminopyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0736]

[0737] Step 1: Methyl 3-(3-(2-chloropyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0738] The desired product was obtained in a similar manner to Step 2 of Preparation Example 52 using 2,4-dichloropyrimidine (1.40 g, 9.43 mmol) and 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl-propionic acid methyl ester (3.00 g, 9.43 mmol) obtained in Step 2 of Preparation Example 58 (yield 76%).

[0739] 1 H-NMR (chloroform-D) δ8.62(d,J=5.2Hz,1H),7.91(d,J=7.9Hz,1H),7.87(s,1H),7.62(d,J=5.5Hz ,1H),7.41(t,J=7.6Hz,1H),7.29(d,J=7.6Hz,1H),3.70(s,3H),2.96(s,2H),1.22(s,6H)

[0740] Step 2: Methyl 3-(3-(2-aminopyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0741] The desired product was obtained in a similar manner to Steps 3 and 4 of Preparation 19 using methyl 3-(3-(2-chloropyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate (2.18 g, 7.15 mmol) obtained in Step 1 (yield 44% over 2 steps).

[0742] 1 H-NMR (400MHz, chloroform-D) δ8.32(d,J=5.5Hz,1H),7.85(d,J=7.8Hz,1H),7.80-7.69(1H),7.38(t,J=7.8Hz,1 H),7.23(d,J=7.8Hz,1H),7.12-6.97(1H),5.31(d,J=22.0Hz,2H),3.67(s,3H),2.94(s,2H),1.21(s,6H)

[0743] Preparation Example 60: Methyl 2-(2-aminopyridin-4-yl)-2-methylpropanoate

[0744]

[0745] The desired product was obtained in a similar manner to Preparation 19 using 2-(2-chloropyridin-4-yl)acetic acid (5.00 g, 29.1 mmol) (5% yield over 4 steps).

[0746] 1H-NMR (chloroform-D) δ8.00 (d, J=4.6 Hz, 1H), 6.66-6.54 (m, 1H), 6.44 (s, 1H), 4.45 (s, 2H), 3.67 (s, 3H), 1.52 (s, 6H)

[0747] Preparation Example 61: Ethyl 2-(6-aminopyridin-2-yl)-2-methylpropanoate

[0748]

[0749] Step 1: Ethyl 2-(6-chloropyridin-2-yl)acetate

[0750] To 20mL anhydrous tetrahydrofuran, diisopropylamine (1.77ml, 12.4mmol) was added, and 2.5M n-butyl lithium (4.97ml, 12.4mmol) was slowly added dropwise at -78°C. The reaction solution was stirred at the same temperature for 20 minutes. The temperature was raised to room temperature and stirred for 10 minutes, then lowered to -78°C and stirred for 10 minutes. 2-chloro-6-methylpyridine (0.57ml, 5.2mmol) dissolved in 100mL anhydrous tetrahydrofuran was added dropwise to the reaction solution. The reaction solution was stirred at -78°C for 1 hour, and diethyl carbonate (0.75ml, 6.2mmol) dissolved in 100mL anhydrous tetrahydrofuran was slowly added dropwise. The reaction solution was warmed to 0°C and stirred for 4 hours. The reaction was terminated by adding saturated aqueous ammonium chloride to the reaction solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure, then purified by silica gel column (ethyl acetate: hexane) to obtain the desired product (yield 88%).

[0751] 1 H-NMR (chloroform-D) δ7.61 (t, J = 7.8 Hz, 1H), 7.22 (d, J = 7.6 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.80 (s, 2H), 1.29-1.20 (m, 3H)

[0752] Step 2: Ethyl 2-(6-aminopyridin-2-yl)-2-methylpropanoate

[0753] The desired product was obtained in a similar manner to Preparation Example 19 (step 2, step 3, step 4) using ethyl 2-(6-chloropyridin-2-yl)acetate (903 mg, 4.52 mmol) obtained in step 1 (yield 5% over 3 steps).

[0754] 1H-NMR (chloroform-D) δ7.38(t,J=7.9Hz,1H),6.62(d,J=7.3Hz,1H),6.34(d,J=7.9 Hz,1H),4.34(s,2H),4.19-4.12(m,2H),1.53(s,6H),1.19(t,J=7.0Hz,3H)

[0755] Preparation Example 62: tert-Butyl 3-(6-aminopyridin-2-yl)-2,2-dimethylpropanoate

[0756]

[0757] Step 1: 2-(Bromomethyl)-6-chloropyridine

[0758] 2-Chloro-6-methylpyridine (3.00 g, 23.5 mmol), N-bromosuccinimide (4.19 g, 23.5 mmol), and 2,2'-azobis(2-methylpropionitrile) (0.077 g, 0.47 mmol) were dissolved in 50 mL of 1,2-dichloroethane, heated at 80°C for 3 hours, and washed with brine. The organic solvent was dehydrated over magnesium sulfate and removed under reduced pressure. Purification on a silica gel column (ethyl acetate:hexane) gave the desired product (yield 25%).

[0759] 1 H-NMR (400 MHz, chloroform-D) δ 7.67 (t, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.28 (s, 1H), 4.50 (s, 2H)

[0760] Step 2: tert-Butyl 3-(6-chloropyridin-2-yl)-2,2-dimethylpropanoate

[0761] The desired product was obtained in a similar manner to Step 1 of Preparation 58 using 2-(bromomethyl)-6-chloropyridine (1.23 g, 5.96 mmol) obtained in Step 1 and tert-butyl isobutyrate (1.03 g, 7.15 mmol) (yield 84%).

[0762] 1 H-NMR (400 MHz, chloroform-D) δ 7.52 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 7.8 Hz, 1H), 7.06 (d, J = 7.8 Hz, 1H), 3.00 (s, 2H), 1.44 (s, 9H), 1.18 (s, 6H)

[0763] Step 3: tert-Butyl 3-(6-aminopyridin-2-yl)-2,2-dimethylpropanoate

[0764] The desired product was obtained in a similar manner to Preparation 19 (step 3, step 4) using tert-butyl 3-(6-chloropyridin-2-yl)-2,2-dimethylpropanoate (1.35 g, 5.00 mmol) obtained in step 2 (yield 9% over 2 steps).

[0765] 1 H-NMR (chloroform-D) δ7.31 (t, J = 7.8 Hz, 1H), 6.48 (d, J = 7.3 Hz, 1H), 6.34-6.29 (1H), 4.27 (s, 2H), 2.84 (s, 2H), 1.44 (s, 9H), 1.20-1.13 (6H)

[0766] Preparation Example 63: tert-Butyl 3-(2-aminopyridin-4-yl)-2,2-dimethylpropanoate

[0767]

[0768] The desired product was obtained in a similar manner to Preparation 62 using 2-chloro-4-methylpyridine (3.00 g, 23.5 mmol) (3% yield over 4 steps).

[0769] 1 H-NMR (400 MHz, chloroform-D) δ 7.94 (d, J = 5.5 Hz, 1H), 6.47 (d, J = 5.5 Hz, 1H), 6.30 (s, 1H), 4.30 (s, 2H), 2.70 (s, 2H), 1.44 (s, 9H), 1.14 (s, 6H)

[0770] Preparation Example 64: tert-Butyl 3-amino-1H-pyrazole-1-carboxylate

[0771]

[0772] After dissolving 1H-pyrazol-3-amine (0.500 g, 6.02 mmol), TEA (1.677 ml, 12.03 mmol), and 4-dimethylaminopyridine (0.049 g, 0.403 mmol) in 1,4-dioxane (20.06 ml), di-tert-butyl dicarbonate (1.590 ml, 6.92 mmol) was added dropwise at room temperature. After stirring at room temperature for 4 hours, the organic solvent was removed under reduced pressure. The mixture was diluted with ethyl acetate and washed with brine. The organic solvent was dried over magnesium sulfate and used in the next reaction without further purification (yield 84%).

[0773] 1H-NMR (500 MHz, chloroform-D) δ 7.86 (d, J = 2.7 Hz, 1H), 5.84 (d, J = 2.7 Hz, 1H), 4.01 (s, 2H), 1.64 (s, 9H)

[0774] Preparation Example 65: Ethyl 1-(6-aminopyridin-2-yl)piperidine-3-carboxylate

[0775]

[0776] The desired product was obtained in a similar manner to Preparation 29 using ethyl piperidine-3-carboxylate (0.500 g, 3.18 mmol) (24% yield over 3 steps).

[0777] 1 H-NMR (500MHz, chloroform-D) δ7.49(t,J=8.4Hz,1H),5.97(dd,J=20.1,8.2Hz,2H),4.18(q,J=7.1Hz,2H),4.05-3.93(m,1H),3.86(d,J=13.1Hz,1H),3.38(d d,J=13.1,9.8Hz,1H),3.19(dd,J=13.0,9.9Hz,1H),2.84-2.59(m,1H),2. 16(d,J=9.5Hz,1H),1.89(s,1H),1.83-1.65(m,2H),1.28(t,J=7.2Hz,3H)

[0778] Preparation Example 66: Methyl 3-(3-amino-1H-pyrazol-1-yl)-2,2-dimethylpropanoate

[0779]

[0780] Using methyl 3-hydroxy-2,2-dimethylpropanoate (0.70 g, 5.31 mmol) and 3-nitro-1H-pyrazole (0.50 g, 4.42 mmol), a procedure similar to Step 1 of Preparation 1 and Step 3 of Preparation 94 was used to obtain the desired product (yield 63%).

[0781] 1 H-NMR (400 MHz, chloroform-d): δ7.09 (d, J=2.3 Hz, 1H), 5.55 (d, J=2.3 Hz, 1H), 4.07 (s, 2H), 3.69 (s, 3H), 1.19 (s, 6H)

[0782] Preparation Example 67: Methyl 3-(3-(3-amino-1H-pyrazol-1-yl)phenyl)-2,2-dimethylpropanoate

[0783]

[0784] 1H-pyrazole-3-amine (0.20 g, 2.41 mmol), copper (I) iodide (0.046 g, 0.24 mmol), cesium carbonate (1.186 g, 3.61 mmol) and tert-butyl 3-(3-bromophenyl)-2,2-dimethylpropanoate (0.75 g, 2.41 mmol) obtained in step 1 of Preparation Example 79 were added to DMF (2.4 ml) and stirred at 120 ° C for 12 hours. Water was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with brine and dehydrated on magnesium sulfate. The solvent was removed under reduced pressure and purified by column chromatography to obtain the title compound (yield 59%).

[0785] 1 H-NMR (400 MHz, chloroform-d): δ7.66 (d, J = 2.3 Hz, 1H), 7.48-7.33 (m, 2H), 7.30-7.25 (m, 1H), 6.99 (d, J = 7.8 Hz, 1H), 5.83 (d, J = 2.3 Hz, 1H), 3.31 (s, 2H), 2.86 (s, 2H), 1.43 (s, 9H), 1.15 (s, 6H)

[0786] Preparation Example 68: Ethyl 2-(3-(2-aminopyrimidin-4-yl)phenoxy)-2-methylpropanoate

[0787]

[0788] Step 1: Ethyl 2-(3-bromophenoxy)-2-methylpropanoate

[0789] 3-bromophenol (1g, 5.78mmol), 2-bromo-2-methyl ethyl propionate (1.24g, 6.36mmol) and salt of wormwood (1.598g, 11.56mmol) are dissolved in 10mL DMF and stirred at room temperature 4 hours.After confirming that reaction is completed by TLC, remove organic solvent under reduced pressure.After extracting with ethyl acetate (2x20ml), it is washed with salt water (20ml), organic solvent is dehydrated and removed under reduced pressure on magnesium sulfate.By obtaining required product (yield 42%) with silica gel column purification (ethyl acetate: hexane=1:9).

[0790] 1 H-NMR (400 MHz, chloroform-D) δ7.13-6.92 (m, 3H), 6.79-6.67 (m, 1H), 4.24-4.13 (m, 2H), 1.71-1.43 (m, 6H), 1.25-1.15 (m, 3H)

[0791] Step 2: Ethyl 2-(3-(2-aminopyrimidin-4-yl)phenoxy)-2-methylpropanoate

[0792] The desired product was obtained in a manner similar to Preparation Example 53 (step 1, step 2) and Preparation Example 19 (step 3, step 4) using ethyl 2-(3-bromophenoxy)-2-methylpropanoate (0.7 g, 2.56 mmol) obtained in step 1 (yield 34% over 4 steps).

[0793] 1 H-NMR (400 MHz, chloroform-D) δ 8.39-8.25 (1H), 7.66-7.58 (m, 1H), 7.55-7.50 (m, 1H), 7.40-7.26 (m, 1H), 7.03-6.87 (2H), 5.01 (d, J = 31.6 Hz, 2H), 4.34-4.16 (m, 2H), 1.62 (s, 6H), 1.28-1.19 (m, 3H)

[0794] Preparation Example 69: Ethyl 2-(4-(2-aminopyrimidin-4-yl)phenoxy)-2-methylpropanoate

[0795]

[0796] The desired product was obtained in a similar manner to Preparation 68, Step 1, Preparation 53 (Step 1, Step 2) and Preparation 19 (Step 3, Step 4) using 4-bromophenol (1 g, 5.78 mmol) (yield 21% over 5 steps).

[0797] 1 H-NMR (400 MHz, chloroform-D) δ 8.32-8.19 (m, 1H), 7.96-7.81 (m, 2H), 6.98-6.89 (m, 1H), 6.89-6.77 (m, 2H), 5.34 (s, 2H), 4.29-4.14 (m, 2H), 1.63-1.54 (m, 6H), 1.25-1.14 (m, 3H)

[0798] Preparation Example 70: Methyl 2-(3-(2-aminopyrimidin-4-yl)phenyl)acetate

[0799]

[0800] Step 1: Methyl 2-(3-bromophenyl)acetate

[0801] 2-(3-bromophenyl)acetic acid (2g, 9.30mmol) and 2.79mL sulfuric acid were dissolved in 18.6mL methanol and stirred at 80°C for 4 hours. After confirming that the reaction was complete by TLC, the organic solvent was removed under reduced pressure. After extraction with ethyl acetate (2×20ml), it was washed with brine (20ml), and the organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 96%) was obtained by purification with a silica gel column (ethyl acetate: hexane = 1:9).

[0802] 1 H-NMR (400 MHz, chloroform-D) δ 7.46-7.38 (m, 1H), 7.38-7.26 (m, 1H), 7.26-7.02 (m, 2H), 3.71-3.59 (m, 3H), 3.59-3.48 (m, 2H)

[0803] Step 2: Methyl 2-(3-(2-aminopyrimidin-4-yl)phenyl)acetate

[0804] The desired product was obtained in a similar manner to Preparation Example 53 (step 1, step 2) and Preparation Example 19 (step 3, step 4) using methyl 2-(3-bromophenyl)acetate (2.042 g, 8.94 mmol) obtained in step 1 (yield 21% over 4 steps).

[0805] 1 H-NMR (400 MHz, chloroform-D) δ 8.37-8.30 (m, 1H), 7.94 (d, J = 14.6 Hz, 1H), 7.90-7.81 (m, 1H), 7.44-7.36 (m, 2H), 7.00 (t, J = 5.7 Hz, 1H), 5.26 (t, J = 43.7 Hz, 2H), 3.69 (s, 5H)

[0806] Preparation Example 71: tert-Butyl 3-(4-(2-aminopyridin-4-yl)phenyl)-2,2-dimethylpropanoate

[0807]

[0808] Step 1: 2,2-Dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane Tert-butyl ester

[0809] The desired product was obtained in a manner similar to Preparation 58 (Step 1, Step 2) using 1-bromo-4-(bromomethyl)benzene (2.00 g, 8.00 mmol) and tert-butyl isobutyrate (1.39 g, 9.60 mmol) (yield 64% over 2 steps).

[0810] 1H-NMR (chloroform-D) δ7.70(d,J=7.6Hz,2H),7.16(d,J=7.9Hz,2H),2.84(s,2H),1.43(s,9H),1.34(s,12H),1.11(s,6H)

[0811] Step 2: tert-Butyl 3-(4-(2-aminopyridin-4-yl)phenyl)-2,2-dimethylpropanoate

[0812] The desired product was obtained in a similar manner to Step 2 of Preparation Example 52 using 4-bromopyridin-2-amine (106 mg, 0.611 mmol) and tert-butyl 2,2-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (220 mg, 0.611 mmol) obtained in Step 1 (yield 86%).

[0813] 1 H-NMR (chloroform-D) δ8.11(d,J=5.2Hz,1H),7.49(d,J=7.6Hz,2H),7.24(d,J=7.6Hz,2H),6.88(d, J=5.2Hz,1H),6.70(s,1H),4.46(s,2H),2.87(s,2H),1.52-1.36(m,9H),1.21-1.07(m,6H)

[0814] Preparation Example 72: Ethyl 6-(2-aminopyrimidin-4-yl)picolinate

[0815]

[0816] Step 1: Ethyl 6-(tributylstannyl)picolinate

[0817] Ethyl 6-bromopicolinate (300 mg, 1.304 mmol) was dissolved in toluene, and bis(tributyltin) (791 μl, 1.57 mmol) and potassium acetate (384 mg, 3.91 mmol) were added. After removing dissolved oxygen from the reaction mixture, it was filled with nitrogen and the inflow of external air was blocked. 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (53.2 mg, 0.065 mmol) was added and reacted at 90°C for 18 hours. After the reaction was complete, it was filtered through diatomaceous earth and concentrated under reduced pressure, and the mixture was immediately used for the next reaction.

[0818] 1H-NMR (400MHz, chloroform-D) δ7.90 (dd, J=7.8, 1.4Hz, 1H), 7.59 (t, J=7.5Hz, 1H), 7.51 (dd, J=7.3, 1.4Hz, 1H), 4.42 (q, J=7.2Hz ,2H),1.68-1.45(m,9H),1.41(t,J=7.1Hz,3H),1.33(td,J=14.8,7.5Hz,6H),1.25-1.02(m,6H),0.88(q,J=7.3Hz,10H)

[0819] Step 2: Ethyl 6-(2-chloropyrimidin-4-yl)picolinate

[0820] The ethyl 6-(tributylstannyl)picolinate synthesized in step 1 was dissolved in toluene and 2,4-dichloropyrimidine (18.6 mg, 0.125 mmol) and sodium carbonate (39.7 mg, 0.375 mmol) were added. After removing dissolved oxygen from the reaction mixture, it was filled with nitrogen and the inflow of external air was blocked. (Triphenylphosphine) palladium (0) (14.4 mg, 0.012 mmol) was added, and a reflux cooler was connected at 130 ° C and heated for 12 hours. After the reaction was completed, it was filtered through celite and concentrated under reduced pressure, and the mixture was purified by column chromatography (hexane: ethyl acetate) to synthesize the desired compound (yield 49%).

[0821] 1 H-NMR (400MHz, chloroform-D) δ8.76(d,J=5.0Hz,1H),8.66(dd,J=7.8,0.9Hz,1H),8.47(d,J=5.0Hz,1 H),8.23(dd,J=7.5,1.1Hz,1H),8.02(t,J=7.8Hz,1H),4.58-4.40(2H),1.46(t,J=7.1Hz,3H)

[0822] Step 3: Ethyl 6-(2-aminopyrimidin-4-yl)picolinate

[0823] The desired product was synthesized in a similar manner to Preparation Example 19 (step 3, step 4) using ethyl 6-(2-chloropyrimidin-4-yl)picolinate (76 mg, 0.288 mmol) synthesized in step 2 (yield 24% over 2 steps).

[0824] 1H-NMR (400MHz, chloroform-D) δ8.52(dd,J=7.8,0.9Hz,1H),8.46(d,J=5.0Hz,1H),8.17(dd,J=7.8,0.9Hz,1H), 7.96(t,J=7.8Hz,1H),7.81(d,J=5.0Hz,1H),5.19(s,2H),4.48(q,J=7.2Hz,2H),1.46(t,J=7.1Hz,3H)

[0825] Preparation 73: tert-Butyl (6-bromopyridin-2-yl)carbamate

[0826]

[0827] 6-Bromopyridin-2-amine (15.0 g, 87.0 mmol) and 1.3 M lithium hexamethyldisilazide (147 ml, 191 mmol) were dissolved in THF 93 ml, and di-tert-butyl dicarbonate (21.9 ml, 95.0 mmol) diluted in 100 mL of THF was added dropwise thereto at -78°C under nitrogen purge. After stirring at room temperature overnight, the organic solvent was removed under reduced pressure, diluted with ethyl acetate, washed with 1N aqueous hydrochloric acid solution, dehydrated on magnesium sulfate, and purified by silica gel column (ethyl acetate: hexane) to give the desired product (yield 98%).

[0828] 1 H-NMR (chloroform-D) δ7.88 (d, J = 8.2 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.24-7.16 (1H), 7.12 (d, J = 7.6 Hz, 1H), 1.52-1.50 (9H)

[0829] Preparation 74: Methyl 2-(4-(2-aminopyrimidin-4-yl)phenyl)acetate

[0830]

[0831] Step 1: Methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

[0832] The desired product was obtained in a similar manner to Step 1 of Preparation 53 using methyl 2-(4-bromophenyl)acetate (2.07 g, 9.04 mmol) (yield 96%).

[0833] 1 H-NMR (400 MHz, chloroform-D) δ 7.76 (dd, J = 23.1, 15.3 Hz, 2H), 7.34-7.26 (m, 2H), 3.67 (s, 3H), 3.61 (t, J = 7.5 Hz, 2H), 1.43-1.29 (m, 12H)

[0834] Step 2: Methyl 2-(4-(2-chloropyrimidin-4-yl)phenyl)acetate

[0835] The desired product was obtained in a similar manner to Step 2 of Preparation 53 using methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (2.4 g, 8.69 mmol) obtained in Step 1 (yield 14%).

[0836] 1 H-NMR (400 MHz, chloroform-d) δ 8.62 (d, J = 5.5 Hz, 1H), 8.13-7.97 (m, 2H), 7.62 (d, J = 5.0 Hz, 1H), 7.43 (d, J = 8.2 Hz, 2H), 3.71 (dd, J = 15.8, 14.4 Hz, 5H)

[0837] Step 3: Methyl 2-(4-(2-aminopyrimidin-4-yl)phenyl)acetate

[0838] The desired product was obtained in a similar manner to Preparation 19 (step 3, step 4) using methyl 2-(4-(2-chloropyrimidin-4-yl)phenyl)acetate (0.32 g, 1.218 mmol) obtained in step 2 (yield 28% over 2 steps).

[0839] 1 H-NMR (400 MHz, chloroform-D) δ 8.63 (q, J = 2.6 Hz, 1H), 8.04-7.96 (m, 2H), 7.79 (d, J = 13.3 Hz, 1H), 7.39 (d, J = 8.2 Hz, 2H), 7.36-7.29 (m, 2H), 3.69 (s, 3H), 3.68 (s, 2H)

[0840] Preparation 75: Methyl 2-(4-(6-amino-3-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methylpropanoate

[0841]

[0842] Step 1: Methyl 2-(4-(6-chloro-3-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methylpropanoate

[0843] The desired product was obtained in a similar manner to Step 2 of Preparation Example 53 using methyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (0.5 g, 1.644 mmol) and 2,6-dichloro-3-(trifluoromethyl)pyridine (0.426 g, 1.972 mmol) obtained in Step 1 of Preparation Example 54 (yield 78%).

[0844] 1H-NMR (400 MHz, chloroform-D) δ 8.08-8.01 (m, 1H), 7.99 (dt, J = 8.7, 2.1 Hz, 2H), 7.72 (d, J = 8.2 Hz, 1H), 7.48-7.41 (m, 2H), 3.66 (s, 3H), 1.66-1.61 (m, 6H)

[0845] Step 2: Methyl 2-(4-(6-amino-3-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methylpropanoate

[0846] The desired product was obtained in a manner similar to Preparation Example 19 (step 3, step 4) using methyl 2-(4-(6-chloro-5-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methylpropanoate (0.46 g, 1.286 mmol) obtained in step 1 (yield 41% over 2 steps).

[0847] 1 H-NMR (400 MHz, chloroform-d) δ 7.90 (d, J = 8.7 Hz, 2H), 7.74 (d, J = 8.2 Hz, 1H), 7.41 (dd, J = 21.5, 12.8 Hz, 2H), 7.17-7.03 (m, 1H), 5.05 (d, J = 43.0 Hz, 2H), 3.72-3.56 (m, 3H), 1.62 (d, J = 15.1 Hz, 6H)

[0848] Preparation Example 76: Methyl 3-(4-(2-aminopyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0849]

[0850] Step 1: tert-Butyl 3-(4-(2-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate ester

[0851] The desired product was obtained in a similar manner to Step 2 of Preparation Example 52 and Step 3 of Preparation Example 19 using 2,4-dichloropyrimidine (4.30 g, 28.9 mmol) and tert-butyl 2,2-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (10.4 g, 28.9 mmol) obtained in Step 1 of Preparation Example 71 (yield 9% for 2 steps).

[0852] m / z(M+H) + C 24 H 34 The calculated value of N3O4 is 428, and the measured value is 428

[0853] Step 2: Methyl 3-(4-(2-aminopyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0854] tert-Butyl 3-(4-(2-((tert-butoxycarbonyl)amino)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate (1.63 g, 3.81 mmol) obtained in Step 1 was dissolved in 63.5 mL of methanol, and sulfuric acid (1.02 ml, 19.1 mmol) was slowly added dropwise. The mixture was stirred under reflux at 100°C for 2 hours, cooled, and washed with sodium bicarbonate solution. The organic solvent was dehydrated over magnesium sulfate and removed under reduced pressure. The desired product was obtained by purification on a silica gel column (ethyl acetate:hexane) (yield 73%).

[0855] 1 H-NMR (400 MHz, chloroform-D) δ 8.33 (d, J = 5.0 Hz, 1H), 7.98-7.82 (m, 2H), 7.21 (d, J = 8.2 Hz, 2H), 7.02 (d, J = 5.5 Hz, 1H), 5.03 (s, 2H), 3.67 (s, 3H), 2.92 (s, 2H), 1.20 (s, 6H)

[0856] Preparation Example 77: tert-Butyl 3-(4-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0857]

[0858] The desired product was obtained in a similar manner to Step 2 of Preparation Example 52 using 6-chloropyridin-2-amine (143 mg, 1.11 mmol) and tert-butyl 2,2-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (500 mg, 1.39 mmol) obtained in Step 1 of Preparation Example 71 (yield 40%).

[0859] 1 H-NMR (400 MHz, chloroform-D) δ 7.82 (d, J = 8.7 Hz, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 6.4 Hz, 2H), 7.15-6.99 (1H), 6.44 (d, J = 7.8 Hz, 1H), 4.46 (s, 2H), 2.87 (s, 2H), 1.45 (s, 9H), 1.13 (s, 6H)

[0860] Preparation Example 78: Methyl 3-(3-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0861]

[0862] Step 1: Methyl 3-(3-(6-((tert-Butoxycarbonyl)amino)pyridin-2-yl)-phenyl)-2,2-dimethylpropanoate

[0863] The desired product was obtained in a similar manner to Step 2 of Preparation Example 52 using tert-butyl (6-bromopyridin-2-yl)carbamate (17.3 g, 63.5 mmol) obtained in Preparation Example 73 and methyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (20.2 g, 63.5 mmol) obtained from Step 2 of Preparation Example 58 (yield 66%).

[0864] 1 H-NMR (400 MHz, chloroform-D) δ 7.85 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.75-7.67 (m, 2H), 7.35 (q, J = 7.8 Hz, 2H), 7.14 (d, J = 7.3 Hz, 1H), 3.66 (s, 3H), 2.93 (s, 2H), 1.54 (s, 9H), 1.22 (s, 6H)

[0865] Step 2: Methyl 3-(3-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0866] The desired product was obtained in a similar manner to Step 4 of Preparation 19 using methyl 3-(3-(6-((tert-butoxycarbonyl)amino)pyridin-2-yl)-phenyl)-2,2-dimethylpropanoate (16.2 g, 42.1 mmol) obtained in Step 1 (yield 86%).

[0867] 1 H-NMR (400 MHz, chloroform-D) δ 7.78 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.57-7.40 (m, 1H), 7.32 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 7.3 Hz, 1H), 7.08-6.99 (m, 1H), 6.53-6.37 (m, 1H), 4.45 (s, 2H), 3.67 (s, 3H), 3.00-2.85 (2H), 1.21 (s, 6H)

[0868] Preparation Example 79: tert-Butyl 3-(3-(2-chloro-5-fluoropyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0869]

[0870] Step 1: tert-Butyl 3-(3-bromophenyl)-2,2-dimethylpropanoate

[0871] The title compound was synthesized in a similar manner to Step 1 of Preparation 58 using 1-bromo-3-(bromomethyl)benzene (5 g, 20.01 mmol) and tert-butyl isobutyrate (4.00 ml, 24.01 mmol) (yield 70%).

[0872] 1 H-NMR (400 MHz, chloroform-D) δ 7.40-7.27 (m, 2H), 7.11 (t, J = 7.3 Hz, 1H), 7.08-6.99 (m, 1H), 2.84-2.70 (2H), 1.43 (s, 9H), 1.12 (s, 6H)

[0873] Step 2: 2,2-Dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane Tert-butyl ester

[0874] The title compound was synthesized in a similar manner to Step 2 of Preparation Example 58 using tert-butyl 3-(3-bromophenyl)-2,2-dimethylpropanoate (4.38 g, 13.98 mmol) synthesized in Step 1 (yield 72%).

[0875] 1 H-NMR (400 MHz, chloroform-D) δ 7.69-7.54 (2H), 7.23 (d, J = 1.4 Hz, 2H), 2.82 (s, 2H), 1.55 (d, J = 1.4 Hz, 2H), 1.43 (s, 9H), 1.31 (s, 12H), 1.12 (s, 6H)

[0876] Step 3: tert-Butyl 3-(3-(2-chloro-5-fluoropyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0877] The title compound was synthesized in a similar manner to Step 2 of Preparation Example 52 using tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (500 mg, 1.39 mmol) synthesized in Step 2 (yield 46%).

[0878] 1 H-NMR (400 MHz, chloroform-D) δ 8.49 (d, J = 3.2 Hz, 1H), 8.00-7.88 (m, 2H), 7.49-7.31 (m, 2H), 2.92 (s, 2H), 1.43 (s, 9H), 1.15 (s, 6H)

[0879] Preparation Example 80: tert-Butyl 3-(3-(2-aminopyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0880]

[0881] The desired product was obtained in a manner similar to Step 2 of Preparation Example 52 and Preparation Example 19 (Step 3, Step 4) using 2,4-dichloropyrimidine (0.620 g, 4.16 mmol) and tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (1.50 g, 4.16 mmol) obtained in Step 2 of Preparation Example 79 (yield 49% over 3 steps).

[0882] 1 H-NMR (chloroform-D) δ8.34 (s, 1H), 7.83 (d, J=8.8 Hz, 2H), 7.36 (s, 1H), 7.28 (s, 1H), 7.03 (s, 1H), 5.02 (s, 2H), 2.91 (s, 2H), 1.43 (s, 9H), 1.16 (s, 6H)

[0883] Preparation Example 81: tert-Butyl 3-(4-(2-aminopyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0884]

[0885] The desired product was obtained in a manner similar to Step 2 of Preparation Example 52 and Preparation Example 19 (Step 3, Step 4) using 2,4-dichloropyrimidine (182 mg, 1.22 mmol) and tert-butyl 2,2-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (440 mg, 1.22 mmol) obtained in Step 1 of Preparation Example 71 (yield 19% over 3 steps).

[0886] 1 H-NMR (400 MHz, chloroform-D) δ 8.33 (d, J = 5.5 Hz, 1H), 7.98-7.82 (m, 2H), 7.28 (s, 2H), 7.03 (d, J = 5.5 Hz, 1H), 5.04 (s, 2H), 2.88 (d, J = 9.1 Hz, 2H), 1.44 (s, 9H), 1.14 (s, 6H)

[0887] Preparation Example 82: tert-Butyl 3-(3-(6-aminopyrazin-2-yl)phenyl)-2,2-dimethylpropanoate

[0888]

[0889] Step 1: tert-Butyl 3-(3-(6-chloropyrazin-2-yl)phenyl)-2,2-dimethylpropanoate

[0890] The desired product was obtained in a similar manner to Step 2 of Preparation Example 52 using 2,6-dichloropyrazine (124 mg, 0.833 mmol) and tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (300 mg, 0.833 mmol) obtained in Step 2 of Preparation Example 79 (yield 52%).

[0891] 1 H-NMR (400 MHz, chloroform-D) δ 8.90 (s, 1H), 8.50 (s, 1H), 7.93-7.78 (m, 2H), 7.49-7.34 (m, 1H), 7.30 (d, J = 7.3 Hz, 1H), 2.93 (s, 2H), 1.45 (s, 9H), 1.24-1.10 (6H)

[0892] Step 2: tert-Butyl 3-(3-(6-aminopyrazin-2-yl)phenyl)-2,2-dimethylpropanoate

[0893] The desired product was obtained in a manner similar to Preparation Example 19 (step 3, step 4) using tert-butyl 3-(3-(6-chloropyrazin-2-yl)phenyl)-2,2-dimethylpropanoate (151 mg, 0.435 mmol) synthesized in step 1 (yield 69% over 2 steps).

[0894] 1 H-NMR (400 MHz, chloroform-D) δ 8.35 (s, 1H), 7.92 (s, 1H), 7.77 (t, J = 7.3 Hz, 2H), 7.36 (t, J = 7.8 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 4.57 (s, 2H), 2.91 (s, 2H), 1.43 (s, 9H), 1.16 (s, 6H)

[0895] Preparation Example 83: Methyl 3-(3-(5-aminopyridin-3-yl)phenyl)-2,2-dimethylpropanoate

[0896]

[0897] Step 1: tert-Butyl 3-(3-(5-bromopyridin-3-yl)phenyl)-2,2-dimethylpropanoate

[0898] The desired product was obtained in a similar manner to Step 2 of Preparation Example 52 using 3,5-bromopyridine (197 mg, 0.833 mmol) and tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (300 mg, 0.833 mmol) obtained in Step 2 of Preparation Example 79 (yield 54%).

[0899] 1H-NMR (400 MHz, chloroform-D) δ 8.73 (d, J = 1.8 Hz, 1H), 8.64 (d, J = 2.3 Hz, 1H), 7.99 (t, J = 2.1 Hz, 1H), 7.44-7.32 (m, 3H), 7.23 (d, J = 6.9 Hz, 1H), 2.91 (s, 2H), 1.43 (s, 9H), 1.16 (s, 6H)

[0900] Step 2: Methyl 3-(3-(5-aminopyridin-3-yl)phenyl)-2,2-dimethylpropanoate

[0901] The desired product was obtained in a similar manner to Step 3 of Preparation Example 19 and Step 2 of Preparation Example 76 using tert-butyl 3-(3-(5-bromopyridin-3-yl)phenyl)-2,2-dimethylpropanoate (176 mg, 0.451 mmol) synthesized in Step 1 (yield 13% over 2 steps).

[0902] 1 H-NMR (400 MHz, chloroform-D) δ 8.23 ​​(d, J = 1.8 Hz, 1H), 8.14-8.00 (1H), 7.40 (dd, J = 7.8, 1.4 Hz, 1H), 7.34 (t, J = 7.5 Hz, 1H), 7.28 (s, 1H), 7.12 (q, J = 2.3 Hz, 2H), 3.78 (s, 2H), 3.66 (s, 3H), 2.92 (s, 2H), 1.22 (s, 6H)

[0903] Preparation Example 84: tert-Butyl 3-(3-(6-amino-4-(trifluoromethyl)pyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0904]

[0905] Step 1: tert-Butyl 3-(3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0906] The desired product was obtained in a similar manner to Step 2 of Preparation Example 52 using 2,6-dichloro-4-(trifluoromethyl)pyridine (0.115 ml, 0.799 mmol) and tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (288 mg, 0.799 mmol) obtained in Step 2 of Preparation Example 79 (yield 66%).

[0907] 1H-NMR (400 MHz, chloroform-D) δ 7.87 (d, J = 8.7 Hz, 2H), 7.81 (s, 1H), 7.46 (s, 1H), 7.40 (t, J = 7.5 Hz, 1H), 7.28 (d, J = 7.8 Hz, 1H), 2.94 (s, 2H), 1.45 (s, 9H), 1.17 (s, 6H)

[0908] Step 2: tert-Butyl 3-(3-(6-amino-4-(trifluoromethyl)pyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0909] The desired product was obtained in a manner similar to Preparation Example 19 (step 3, step 4) using tert-butyl 3-(3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)phenyl)-2,2-dimethylpropanoate (218 mg, 0.527 mmol) synthesized in step 1 (yield 63% over 2 steps).

[0910] 1 H-NMR (400 MHz, chloroform-d) δ 7.79 (dd, J = 7.8, 1.4 Hz, 1H), 7.75 (s, 1H), 7.35 (t, J = 7.5 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 6.62 (s, 1H), 4.74 (s, 2H), 2.91 (s, 2H), 1.44 (s, 9H), 1.16 (s, 6H)

[0911] Preparation Example 85: tert-Butyl 3-(3-(6-amino-5-fluoropyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0912]

[0913] Step 1: tert-Butyl 3-(3-(6-chloro-5-fluoropyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0914] The title compound was synthesized in the same manner as in Step 2 of Preparation Example 52 using tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (500 mg, 1.39 mmol) and 2,6-dichloro-3-fluoropyridine (230 mg, 1.39 mmol) obtained in Step 2 of Preparation Example 79 (yield 10%).

[0915] 1 H-NMR (chloroform-D) δ7.79 (d, J=8.5Hz, 2H), 7.66 (dd, J=8.4, 3.2Hz, 1H), 7.60-7.46 (1H), 7. 38(t,J=7.5Hz,1H),7.27-7.18(1H),2.94(s,2H),1.45(d,J=9.8Hz,9H),1.19(s,6H)

[0916] Step 2: tert-Butyl 3-(3-(6-amino-5-fluoropyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0917] The title compound was synthesized in a similar manner to Preparation Example 19 (step 3, step 4) using tert-butyl 3-(3-(6-chloro-5-fluoropyridin-2-yl)phenyl)-2,2-dimethylpropanoate (500 mg, 1.39 mmol) obtained in step 1 (yield 49% over 2 steps).

[0918] 1 H-NMR (chloroform-D) δ7.74(d,J=7.6Hz,1H),7.70(s,1H),7.34(t,J=7.8Hz,1H),7.32-7.25(m,1H),7.19(d,J=7. 6Hz,1H),7.04(dd,J=7.9,3.1Hz,1H),4.83(s,2H),2.92(d,J=6.7Hz,2H),1.49-1.41(m,9H),1.18(s,6H)

[0919] Preparation Example 86: tert-Butyl 3-(3-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0920]

[0921] Step 1: tert-Butyl 3-(3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0922] The title compound was synthesized in the same manner as in Step 2 of Preparation Example 52 using tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenylpropanoate (500 mg, 1.39 mmol) and 2,6-dichloro-5-(trifluoromethyl)pyrimidine (301 mg, 1.39 mmol) obtained in Step 2 of Preparation Example 79 (yield 13%).

[0923] 1 H-NMR (chloroform-D) δ7.79 (d, J=8.5Hz, 2H), 7.66 (dd, J=8.4, 3.2Hz, 1H), 7.60-7.46 (1H), 7. 38(t,J=7.5Hz,1H),7.27-7.18(1H),2.94(s,2H),1.45(d,J=9.8Hz,9H),1.19(s,6H)

[0924] Step 2: tert-Butyl 3-(3-(2-amino-5-(trifluoromethyl)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0925] The title compound was synthesized in the same manner as in Preparation Example 19 (step 3, step 4) using tert-butyl 3-(3-(2-chloro-5-(trifluoromethyl)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate (232 mg, 0.64 mmol) obtained in step 1 (yield 43% over 2 steps).

[0926] m / z(M+H) + C 20 H 25 The calculated value of F3N3O2 is 396, and the measured value is 396

[0927] Preparation Example 87: tert-Butyl 3-(3-(6-amino-3-fluoropyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0928]

[0929] Step 1: tert-Butyl 3-(3-(6-chloro-3-fluoropyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0930] The title compound was synthesized in the same manner as in Step 2 of Preparation Example 52 using tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (500 mg, 1.39 mmol) and 2,6-dichloro-3-fluoropyridine (230 mg, 1.39 mmol) obtained in Step 2 of Preparation Example 79 (yield 68%).

[0931] 1 H-NMR (400 MHz, chloroform-d) δ 7.81 (dd, J = 7.9, 1.5 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.44 (dd, J = 10.1, 8.2 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 2.7 Hz, 1H), 7.22 (d, J = 3.2 Hz, 0H), 2.91 (s, 2H), 1.46-1.33 (m, 9H), 1.16 (d, J = 8.2 Hz, 6H)

[0932] Step 2: tert-Butyl 3-(3-(6-amino-3-fluoropyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0933] The title compound was synthesized in a manner similar to Preparation Example 19 (step 3, step 4) using tert-butyl 3-(3-(6-chloro-3-fluoropyridin-2-yl)phenyl)-2,2-dimethylpropanoate (192 mg, 0.53 mmol) synthesized in step 1 (yield 12% over 2 steps).

[0934] 1H-NMR (chloroform-D) δ7.85(d,J=7.6Hz,1H),7.82(s,1H),7.57(d,J=8.5Hz,1H),7.46(t,J=9.6Hz,1H ),7.41(t,J=7.6Hz,2H),7.26(s,1H),2.96(s,2H),1.50-1.43(m,11H),1.22(d,J=8.5Hz,6H)

[0935] Preparation Example 88: Ethyl 2-(3-(6-aminopyridin-2-yl)phenoxy)-2-methylpropanoate

[0936]

[0937] Step 1: Ethyl 2-(3-bromophenoxy)-2-methylpropanoate

[0938] 3-Bromophenol (2.00 g, 11.6 mmol), ethyl 2-bromo-2-methylpropionate (2.48 g, 12.7 mmol) and potassium carbonate (3.20 g, 23.1 mmol) were dissolved in 23.1 mL of DMF and stirred at room temperature overnight. After extraction with ethyl acetate, the organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 42%) was obtained by silica gel column purification (ethyl acetate: hexane).

[0939] 1 H-NMR (400 MHz, chloroform-D) δ 7.16-7.05 (m, 2H), 7.03 (t, J = 2.1 Hz, 1H), 6.76 (td, J = 4.6, 2.6 Hz, 1H), 4.24 (q, J = 7.0 Hz, 2H), 1.59 (s, 6H), 1.25 (t, J = 7.1 Hz, 3H)

[0940] Step 2: 2-Methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoic acid Ethyl ester

[0941] The desired product was obtained in a similar manner to Step 1 of Preparation Example 52 using ethyl 2-(3-bromophenoxy)-2-methylpropanoate (1.39 g, 4.84 mmol) synthesized in Step 1 (yield 80%).

[0942] 1 H-NMR (400 MHz, chloroform-D) δ 7.43 (d, J = 7.3 Hz, 1H), 7.30 (d, J = 2.7 Hz, 1H), 7.23 (d, J = 7.8 Hz, 1H), 6.94 (dq, J = 8.2, 1.2 Hz, 1H), 4.25 (q, J = 7.2 Hz, 2H), 1.58 (s, 6H), 1.32 (s, 12H), 1.27-1.25 (3H)

[0943] Step 3: Ethyl 2-(3-(6-aminopyridin-2-yl)phenoxy)-2-methylpropanoate

[0944] The desired product was obtained in a manner similar to Preparation Example 78 (step 1, step 2) using tert-butyl (6-bromopyridin-2-yl)carbamate (1.06 g, 3.89 mmol) obtained in Preparation Example 73 and ethyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoate (1.30 g, 3.89 mmol) synthesized in step 2 (yield 53% for 2 steps).

[0945] 1 H-NMR (400 MHz, chloroform-d) δ 7.57 (d, J = 7.8 Hz, 1H), 7.53-7.40 (2H), 7.29 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H), 6.92-6.77 (m, 1H), 6.45 (d, J = 8.2 Hz, 1H), 4.45 (s, 2H), 4.25 (q, J = 7.2 Hz, 2H), 1.62 (s, 6H), 1.25 (t, J = 7.1 Hz, 3H)

[0946] Preparation Example 89: tert-Butyl 3-(3-(6-aminopyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoate

[0947]

[0948] Step 1: tert-Butyl 3-(3-bromo-4-fluorophenyl)-2,2-dimethylpropanoate

[0949] The title compound was synthesized in a similar manner to Step 1 of Preparation 58 using 2-bromo-4-(bromomethyl)-1-fluorobenzene (5 g, 18.66 mmol) and tert-butyl isobutyrate (3.73 ml, 22.39 mmol) (yield 79%).

[0950] 1 H-NMR (400 MHz, chloroform-D) δ 7.35 (dd, J = 6.6, 2.1 Hz, 1H), 7.12-7.02 (1H), 6.98 (t, J = 8.5 Hz, 1H), 2.75 (s, 2H), 1.47-1.34 (9H), 1.11 (s, 6H)

[0951] Step 2: 3-(4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,2-dioxaborolan-2-yl tert-Butyl methylpropionate

[0952] The title compound was synthesized in a similar manner to Step 2 of Preparation Example 58 using tert-butyl 3-(3-bromo-4-fluorophenyl)-2,2-dimethylpropanoate (4.86 g, 14.67 mmol) synthesized in Step 1 (yield 58%).

[0953] 1 H-NMR (400 MHz, chloroform-d) δ 7.52 (q, J = 2.7 Hz, 1H), 7.22-7.10 (m, 1H), 6.90 (t, J = 8.7 Hz, 1H), 2.78 (s, 2H), 1.42 (d, J = 6.4 Hz, 10H), 1.31 (d, J = 15.1 Hz, 13H), 1.11 (d, J = 4.1 Hz, 6H)

[0954] Step 3: tert-Butyl 3-(3-(6-aminopyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoate

[0955] The title compound was synthesized in a similar manner to Step 2 of Preparation Example 52 using tert-butyl 3-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,2-dimethylpropanoate (500 mg, 1.32 mmol) and 6-chloropyridin-2-amine (170 mg, 1.32 mmol) synthesized in Step 2 (yield 76%).

[0956] 1H-NMR (400 MHz, chloroform-D) δ 7.78 (d, J = 7.3 Hz, 1H), 7.74-7.60 (m, 1H), 7.07 (dd, J = 11.2, 8.5 Hz, 2H), 6.71 (d, J = 8.7 Hz, 1H), 2.98-2.89 (2H), 1.42 (s, 11H), 1.15 (s, 6H)

[0957] Preparation Example 90: Methyl 3-(3-(4-aminopyrimidin-2-yl)phenyl)-2,2-dimethylpropanoate

[0958]

[0959] Step 1: tert-Butyl (2-chloropyrimidin-4-yl)carbamate

[0960] 2-Chloropyrimidin-4-amine (15.0 g, 116 mmol) and di-tert-butyl dicarbonate (31.9 ml, 139 mmol) were dissolved in 257 mL of anhydrous DCM, followed by the addition of 4-dimethylaminopyridine (2.83 g, 23.2 mmol) and stirred at room temperature overnight. After removing the organic solvent, it was purified by silica gel column (DCM) to obtain the desired product (yield 5%).

[0961] 1H-NMR (chloroform-D) δ8.42 (d, J=5.8 Hz, 1H), 7.86 (d, J=5.8 Hz, 1H), 7.35 (s, 1H), 1.53 (s, 9H)

[0962] Step 2: Methyl 3-(3-(4-aminopyrimidin-2-yl)phenyl)-2,2-dimethylpropanoate

[0963] The desired product was obtained in a manner similar to Step 2 of Preparation Example 52 and Step 4 of Preparation Example 19 using tert-butyl (2-chloropyrimidin-4-yl)carbamate (361 mg, 1.57 mmol) synthesized in Step 1 and methyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (500 mg, 1.57 mmol) obtained in Step 2 of Preparation Example 58 (yield 14% for 2 steps).

[0964] 1 H-NMR (400 MHz, chloroform-D) δ8.34 (d, J=4.1 Hz, 1H), 8.26 (d, J=6.9 Hz, 1H), 8.16 (s, 1H), 7.44-7.35 (m, 1H), 7.20 (s, 1H), 6.46 (s, 1H), 5.30 (s, 2H), 3.68 (s, 3H), 2.96 (s, 2H), 1.22 (s, 6H)

[0965] Preparation Example 91: tert-Butyl 3-(3-(6-amino-3-methylpyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0966]

[0967] Step 1: tert-Butyl 3-(3-(6-chloro-3-methylpyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0968] The title compound was synthesized in the same manner as in Step 2 of Preparation Example 52 using tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (289 mg, 0.80 mmol) and 2,6-dichloro-3-methylpyridine (260 mg, 1.61 mmol) obtained in Step 2 of Preparation Example 79 (yield 16%).

[0969] 1 H-NMR (400 MHz, chloroform-d) δ 7.51 (d, J = 8.2 Hz, 1H), 7.42-7.26 (m, 3H), 7.18 (dd, J = 7.5, 2.5 Hz, 2H), 2.87 (s, 2H), 2.30 (s, 3H), 1.40 (s, 9H), 1.12 (d, J = 5.5 Hz, 6H)

[0970] Step 2: tert-Butyl 3-(3-(6-amino-3-methylpyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[0971] The title compound was synthesized in a similar manner to Preparation Example 19 (step 3, step 4) using tert-butyl 3-(3-(6-chloro-3-methylpyridin-2-yl)phenyl)-2,2-dimethylpropanoate (47 mg, 0.13 mmol) obtained in step 1 (yield 54% over 2 steps).

[0972] 1 H-NMR (chloroform-D) δ7.39 (dd, J = 8.2, 2.7 Hz, 1H), 7.36-7.29 (m, 2H), 7.19 (d, J = 6.1 Hz, 1H), 6.56-6.40 (m, 1H), 4.70 (s, 2H), 2.90 (s, 2H), 2.20 (s, 3H), 1.46 (d, J = 13.4 Hz, 9H), 1.24-1.08 (m, 6H)

[0973] Preparation Example 92: Ethyl 2-(3-(6-aminopyridin-2-yl)-4-fluorophenoxy)-2-methylpropanoate

[0974]

[0975] Step 1: Ethyl 2-(3-bromo-4-fluorophenoxy)-2-methylpropanoate

[0976] 3-bromo-4-fluorophenol (2g, 10.47mmol) is dissolved in DMF, 2-bromo-2-methylethyl propionate (2.25g, 11.52mmol) and cesium carbonate (6.82g, 20.94mmol) are added, and stirred at room temperature for 12 hours. After the reaction is complete, water is added, extracted with ethyl acetate and washed with salt water to remove excessive DMF. After removing water with magnesium sulfate and distilling under reduced pressure, the mixture is purified by column chromatography (hexane: ethyl acetate) to obtain the desired compound (yield 58%).

[0977] 1 H-NMR (400 MHz, chloroform-D) δ 7.09 (q, J = 2.9 Hz, 1H), 6.98 (t, J = 8.5 Hz, 1H), 6.86-6.70 (m, 1H), 4.23 (q, J = 7.0 Hz, 2H), 1.55 (s, 6H), 1.26 (t, J = 7.1 Hz, 3H)

[0978] Step 2: 2-(4-Fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methyl Ethyl propionate

[0979] The title compound was synthesized in a similar manner to Step 1 of Preparation Example 52 using ethyl 2-(3-bromo-4-fluorophenoxy)-2-methylpropanoate (1.86 g, 6.10 mmol) synthesized in Step 1 (yield 91%).

[0980] 1 H-NMR (400 MHz, chloroform-d) δ 7.22 (dd, J = 4.6, 3.2 Hz, 1H), 7.01-6.80 (2H), 4.23 (q, J = 7.2 Hz, 2H), 1.54 (s, 6H), 1.32 (s, 12H), 1.24 (d, J = 7.8 Hz, 7H)

[0981] Step 3: Ethyl 2-(3-(6-aminopyridin-2-yl)-4-fluorophenoxy)-2-methylpropanoate

[0982] The title compound was synthesized in a similar manner to Step 2 of Preparation Example 52 using ethyl 2-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)-2-methylpropanoate (400 mg, 1.136 mmol) synthesized in Step 2 (yield 59%).

[0983] 1 H-NMR (400 MHz, chloroform-D) δ 7.57-7.39 (m, 2H), 7.10 (dd, J = 7.5, 2.1 Hz, 1H), 6.98 (dd, J = 10.5, 8.7 Hz, 1H), 6.90-6.75 (1H), 6.49 (d, J = 8.2 Hz, 1H), 4.73 (s, 2H), 4.24 (q, J = 7.2 Hz, 2H), 1.65-1.43 (6H), 1.26 (t, J = 7.1 Hz, 3H)

[0984] Preparation Example 93: Methyl 3-(3-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0985]

[0986] Step 1: Methyl 3-(3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0987] The title compound was synthesized in the same manner as in Step 2 of Preparation Example 52 using methyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (1 g, 3.14 mmol) and 2,4-dichloro-6-(trifluoromethyl)pyrimidine (682 mg, 3.14 mmol) obtained in Step 2 of Preparation Example 58 (yield 63%).

[0988] 1H-NMR (400 MHz, chloroform-d) δ 7.95 (dd, J = 7.8, 1.8 Hz, 1H), 7.93-7.83 (2H), 7.44 (t, J = 7.5 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 3.77-3.58 (m, 3H), 2.96 (s, 2H), 1.21 (d, J = 5.9 Hz, 6H)

[0989] Step 2: Methyl 3-(3-(2-amino-6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate

[0990] The title compound was synthesized in a manner similar to Preparation Example 19 (step 3, step 4) using methyl 3-(3-(2-chloro-6-(trifluoromethyl)pyrimidin-4-yl)phenyl)-2,2-dimethylpropanoate (735 mg, 1.97 mmol) obtained in step 1 (yield 29% over 2 steps).

[0991] 1 H-NMR (400 MHz, chloroform-d) δ 7.86 (d, J = 7.8 Hz, 1H), 7.78 (d, J = 6.9 Hz, 1H), 7.47-7.33 (m, 1H), 7.28 (s, 1H), 7.27 (s, 1H), 5.49 (s, 2H), 3.65 (d, J = 6.4 Hz, 3H), 2.94 (s, 2H), 1.23 (q, J = 7.8 Hz, 6H)

[0992] Preparation Example 94: tert-Butyl 3-(3'-amino-[1,1'-biphenyl]-4-yl)-2,2-dimethylpropanoate

[0993]

[0994] Step 1: 2,2-Dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane Tert-butyl ester

[0995] The desired product was obtained in a similar manner to Preparation 71, Step 1, using 1-bromo-4-(bromomethyl)benzene (2 g, 8 mmol) (77% yield over 2 steps).

[0996] 1 H-NMR (chloroform-D) δ7.70(d,J=7.6Hz,2H),7.16(d,J=7.9Hz,2H),2.84(s,2H),1.43(s,9H),1.34(s,12H),1.11(s,6H)

[0997] Step 2: tert-Butyl 2,2-dimethyl-3-(3'-nitro-[1,1'-biphenyl]-4-yl)propanoate

[0998] Tert-butyl 2,2-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (0.15 g, 0.416 mmol), 1-bromo-3-nitrobenzene (0.084 g, 0.416 mmol), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium(II) dichloromethane complex (0.007 g, 8.33 μmol), and 0.555 mL of 2N sodium carbonate were dissolved in 1.4 mL of ethylene glycol dimethyl ether and stirred at 90°C for 15 hours. After TLC confirmed the completion of the reaction, the organic solvent was removed under reduced pressure. After extraction with ethyl acetate (60 mL), it was washed with brine (20 mL) and dehydrated over magnesium sulfate, and the organic solvent was concentrated under reduced pressure. The desired product (yield 88%) was obtained by purification on a silica gel column (ethyl acetate:hexane = 1:9).

[0999] 1 H-NMR (400 MHz, chloroform-D) δ 8.43 (d, J = 1.8 Hz, 1H), 8.21-8.13 (m, 1H), 7.90 (t, J = 7.3 Hz, 1H), 7.64-7.55 (m, 1H), 7.55-7.48 (m, 2H), 7.32-7.26 (m, 2H), 2.90 (d, J = 15.1 Hz, 2H), 1.45 (s, 9H), 1.16 (s, 6H)

[1000] Step 3: tert-Butyl 3-(3'-amino-[1,1'-biphenyl]-4-yl)-2,2-dimethylpropanoate

[1001] tert-Butyl 2,2-dimethyl-3-(3'-nitro-[1,1'-biphenyl]-4-yl)propanoate (0.255 g, 0.717 mmol) obtained in Step 2 was dissolved in 2 mL of methanol, and Pd / C (3.82 mg, 0.036 mmol) was added, followed by reduction using a hydrogen balloon. After confirming the completion of the reaction, the mixture was filtered through a Celite filter, and the organic solvent was removed under reduced pressure to obtain the desired product (yield 73%).

[1002] 1 H-NMR (400 MHz, chloroform-D) δ 7.53-7.44 (m, 2H), 7.28-7.17 (m, 3H), 7.05-6.96 (1H), 6.94-6.87 (m, 1H), 6.72-6.62 (m, 1H), 3.73 (s, 2H), 2.96-2.74 (m, 2H), 1.54-1.38 (9H), 1.26-1.12 (m, 6H)

[1003] Preparation Example 95: Ethyl 2-(3-(4-aminopyrimidin-2-yl)phenoxy)-2-dimethylpropanoate

[1004]

[1005] The desired product was obtained in a similar manner to Step 2 of Preparation Example 52 and Step 4 of Preparation Example 19 using tert-butyl (2-chloropyrimidin-4-yl)carbamate (344 mg, 1.50 mmol) obtained from Step 1 of Preparation Example 90 and ethyl 2-methyl-2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)propanoate (500 mg, 1.50 mmol) obtained from Step 2 of Preparation Example 88 (yield 22% over 2 steps).

[1006] 1 H-NMR (chloroform-D) δ8.33(d,J=5.8Hz,1H),8.01(d,J=7.9Hz,1H),7.92(d,J=1.8Hz,1H),7.33(t,J=7.9Hz,1H),6.96(dd ,J=8.1,2.6Hz,1H),6.34(d,J=5.8Hz,1H),4.90(s,2H),4.27(q,J=7.1Hz,2H),1.64(s,6H),1.27(t,J=7.0Hz,3H)

[1007] Preparation Example 96: Methyl 3-(4-(4-aminopyrimidin-2-yl)phenyl)-2,2-dimethylpropanoate

[1008]

[1009] Step 1: 2,2-Dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propane Methyl ester

[1010] The desired product was obtained in a manner similar to Preparation 58 (step 1, step 2) using 1-bromo-4-(bromomethyl)benzene (30.0 g, 120 mmol) (yield 75% over 2 steps).

[1011] 1 H-NMR (400 MHz, chloroform-D) δ 7.70 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 7.8 Hz, 2H), 3.64 (s, 3H), 2.86 (s, 2H), 1.34 (s, 12H), 1.17 (s, 6H)

[1012] Step 2: Methyl 3-(4-(4-aminopyrimidin-2-yl)phenyl)-2,2-dimethylpropanoate

[1013] The desired product was obtained in a manner similar to Step 2 of Preparation Example 52 and Step 4 of Preparation Example 19 using tert-butyl (2-chloropyrimidin-4-yl)carbamate (578 mg, 2.51 mmol) obtained from Step 1 of Preparation Example 90 and methyl 2,2-dimethyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (800 mg, 2.51 mmol) synthesized in Step 1 (yield 68% over 2 steps).

[1014] 1 H-NMR (400MHz, chloroform-D) δ8.33(d,J=5.9Hz,1H),8.25(d,J=8.2Hz,2H),7.20(d,J=8.2 Hz,2H),6.37(d,J=5.9Hz,1H),5.12(s,2H),3.66(s,3H),2.91(s,2H),1.20(s,6H)

[1015] Preparation Example 97: Ethyl 2-(4-(6-aminopyridin-2-yl)phenoxy)-2-methylpropanoate

[1016]

[1017] The desired product was obtained in a similar manner to Preparation 88 using 4-bromophenol (2.00 g, 11.6 mmol) (24% yield over 4 steps).

[1018] 1 H-NMR (400MHz, chloroform-D) δ7.82(dt,J=9.6,2.5Hz,2H),7.55-7.38(m,1H),7.10-6.96(m,1H),6.89(dt,J=9. 5,2.5Hz,2H),6.49-6.33(m,1H),4.44(s,2H),4.24(q,J=7.0Hz,2H),1.62(s,6H),1.25(t,J=7.3Hz,3H)

[1019] Preparation 98: Ethyl 2-((4-(6-aminopyridin-2-yl)phenyl)amino)-2-methylpropanoate

[1020]

[1021] Step 1: Ethyl 2-((4-bromophenyl)amino)-2-methylpropanoate

[1022] 4-Bromoaniline (3.00 g, 17.44 mmol) was dissolved in DMF, ethyl 2-bromo-2-methylpropionate (3.40 g, 17.44 mmol) and potassium carbonate (3.62 g, 26.2 mmol) were added, and stirred at 100° C. for 6 hours. After the reaction was completed, it was cooled to room temperature and water was added, extracted with ethyl acetate, washed with brine, and excess DMF was removed. After removing water with magnesium sulfate and distilling under reduced pressure, the mixture was purified by column chromatography (hexane:ethyl acetate) to obtain the desired compound (yield 22%).

[1023] 1 H-NMR (chloroform-D) δ7.25(d,J=8.5Hz,2H),6.50(d,J=8.5Hz,2H),4.19(q,J=7.0Hz,2H),1.59(d,J=22.3Hz,7H),1.22(t,J=7.2Hz,3H)

[1024] Step 2: 2-Methyl-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino) Ethyl propionate

[1025] The title compound was synthesized in a similar manner to Step 1 of Preparation Example 52 using ethyl 2-((4-bromophenyl)amino)-2-methylpropanoate (1.82 g, 6.36 mmol) synthesized in Step 1 (yield 65%).

[1026] 1 H-NMR (400 MHz, chloroform-D) δ7.64-7.49 (2H), 6.58-6.38 (2H), 4.44-4.20 (1H), 4.20-4.11 (2H), 1.32-1.27 (12H), 1.19-1.07 (3H)

[1027] Step 3: Ethyl 2-((4-(6-aminopyridin-2-yl)phenyl)amino)-2-methylpropanoate

[1028] The title compound was synthesized in a similar manner to Step 2 of Preparation Example 52 using ethyl 2-methyl-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)propanoate (500 mg, 1.50 mmol) and 6-chloropyridin-2-amine (183 mg, 1.422 mmol) synthesized in Step 2 (yield 34%).

[1029] 1H-NMR (chloroform-D) δ7.83 (d, J = 8.5Hz, 2H), 7.54 (t, J = 7.9Hz, 1H), 6.99 (d, J = 7.6Hz, 1H), 6.65 (d, J = 8.5Hz, 2H),6.45(d,J=8.2Hz,1H),4.63-4.33(1H),4.20(q,J=7.0Hz,2H),1.61(s,6H),1.22(t,J=7.2Hz,3H)

[1030] Preparation Example 99: Ethyl 2-((4-(2-aminopyrimidin-4-yl)phenyl)amino)-2-methylpropanoate

[1031]

[1032] Step 1: Ethyl 2-((4-(2-chloropyrimidin-4-yl)phenyl)amino)-2-methylpropanoate

[1033] The title compound was synthesized in a similar manner to Step 2 of Preparation Example 52 using ethyl 2-methyl-2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)amino)propanoate (400 mg, 1.20 mmol) and 2,4-dichloropyrimidine (179 mg, 1.20 mmol) obtained in Step 2 of Preparation Example 98 (yield 59%).

[1034] 1 H-NMR (400 MHz, methanol-D4) δ 8.47-8.38 (1H), 8.00-7.88 (2H), 7.74-7.66 (1H), 6.64-6.49 (2H), 4.21-4.02 (2H), 1.58-1.48 (6H), 1.22-1.07 (3H)

[1035] Step 2: Ethyl 2-((4-(2-aminopyrimidin-4-yl)phenyl)amino)-2-methylpropanoate

[1036] The title compound was synthesized in a manner similar to Preparation Example 19 (step 3, step 4) using ethyl 2-((4-(2-chloropyrimidin-4-yl)phenyl)amino)-2-methylpropanoate (83 mg, 0.21 mmol) synthesized in step 1 (yield 27% over 2 steps).

[1037] m / z(M+H) + C 16 H 21 The calculated value of N4O2 is 301, and the measured value is 301

[1038] Preparation 100: Ethyl (4-(6-aminopyridin-2-yl)phenyl)glycine

[1039]

[1040] Step 1: (4-Bromophenyl)glycine ethyl ester

[1041] The title compound was synthesized in a similar manner to Step 1 of Preparation 98 using 4-bromoaniline (3.00 g, 17.44 mmol) (yield 44%).

[1042] 1 H-NMR (chloroform-D) δ7.32-7.23 (m, 2H), 6.59-6.45 (m, 2H), 4.34-4.19 (m, 2H), 4.12 (s, 1H), 3.89 (s, 2H), 1.39-1.23 (m, 3H)

[1043] Step 2: (4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)glycine ethyl ester

[1044] The title compound was synthesized in a similar manner to Step 1 of Preparation Example 52 using (4-bromophenyl)glycine ethyl ester (1.99 g, 7.71 mmol) synthesized in Step 1 (yield 44%).

[1045] 1 H-NMR (400 MHz, chloroform-D) δ 7.73-7.58 (m, 2H), 6.63 (d, J = 8.2 Hz, 2H), 4.24 (t, J = 7.1 Hz, 2H), 4.22-4.04 (m, 1H), 3.93 (d, J = 1.4 Hz, 2H), 1.31 (s, 12H), 1.28 (t, J = 7.1 Hz, 3H)

[1046] Step 3: (4-(6-aminopyridin-2-yl)phenyl)glycine ethyl ester

[1047] The title compound was synthesized in a similar manner to Step 2 of Preparation Example 52 using (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)glycine ethyl ester (700 mg, 2.30 mmol) and 6-chloropyridin-2-amine (295 mg, 2.30 mmol) synthesized in Step 2 (yield 32%).

[1048] 1 H-NMR (400MHz, methanol-D4) δ7.63(dt,J=9.3,2.3Hz,2H),7.42(t,J=7.8Hz,1H),6.87(d,J=6.9Hz,1H),6. 63(dt,J=9.3,2.3Hz,2H),6.47-6.32(1H),4.18(q,J=7.2Hz,2H),3.93(s,2H),1.24(t,J=7.1Hz,3H)

[1049] Preparation Example 101: Methyl 5-(2-aminopyrimidin-4-yl)bicyclo[2.2.1]heptane-2-carboxylate

[1050]

[1051] Step 1: Methyl bicyclo[2.2.1]hept-5-ene-2-carboxylate

[1052] The desired product was obtained in a similar manner to Step 1 of Preparation 50 using bicyclo[2.2.1]hept-5-ene-2-carboxylic acid (1 g, 7.24 mmol) (yield 100%).

[1053] 1 H-NMR (400 MHz, chloroform-D) δ 6.18 (q, J = 3.0 Hz, 1H), 5.91 (q, J = 2.9 Hz, 1H), 3.61 (s, 3H), 3.18 (d, J = 1.4 Hz, 1H), 2.98-2.76 (m, 2H), 1.97-1.81 (m, 1H), 1.57 (t, J = 1.6 Hz, 1H), 1.45-1.37 (2H)

[1054] Step 2: Methyl 5-(2-chloropyrimidin-4-yl)bicyclo[2.2.1]heptane-2-carboxylate

[1055] 2,4-Dichloropyrimidine (0.775 g, 5.20 mmol) was dissolved in THF (23.6 ml) and methyl bicyclo[2.2.1]hept-5-ene-2-carboxylate (0.720 g, 4.73 mmol) prepared in step 1 was added. Palladium (II) acetate (0.212 g, 0.946 mmol), triphenylphosphine (0.496 g, 1.892 mmol) and formic acid (0.907 ml, 23.65 mmol) were added to the reaction solution, and TEA (4.29 ml, 30.8 mmol) was added dropwise. After stirring at 60 ° C for 16 hours, the reaction was terminated with water, diluted with ethyl acetate, washed with brine, and the organic solvent was dehydrated over magnesium sulfate. The desired product was obtained by purification on a silica gel column (yield 24%).

[1056] 1 H-NMR (400MHz, chloroform-D) δ8.42(q,J=2.6Hz,1H),7.08(q,J=4.9Hz,1H),3.77-3.62(m,3H),3.01-2.80(m ,2H),2.80-2.66(m,1H),2.52-2.39(m,1H),2.10-1.85(m,1H),1.85-1.67(m,4H),1.41-1.31(m,1H)

[1057] Step 3: Methyl 5-(2-aminopyrimidin-4-yl)bicyclo[2.2.1]heptane-2-carboxylate

[1058] The desired product was obtained in a similar manner to Preparation 2 using methyl 5-(2-chloropyrimidin-4-yl)bicyclo[2.2.1]heptane-2-carboxylate (0.428 g, 1.605 mmol) prepared in Step 2 (13% yield over 2 steps).

[1059] 1 H-NMR (500MHz, chloroform-D) δ8.48(q,J=5.3Hz,1H),7.49(s,1H),6.81(td,J=14.5,5.2Hz,1H),4.51(s,1H),3.73(d,J=11.3Hz,3H),2.9 3-2.80(m,2H),2.80-2.61(m,1H),2.53-2.35(m,1H),2.11-1.97(m,1H),1.85-1.77(m,2H),1.77-1.67(m,2H),1.40-1.20(m,1H)

[1060] Preparation Example 102: Methyl 3-(3-(5-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[1061]

[1062] The desired product was obtained in a manner similar to Step 2 of Preparation Example 52, Step 3 of Preparation Example 19, and Step 2 of Preparation Example 76 using 2,5-dibromopyridine (189 mg, 0.799 mmol) and tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (288 mg, 0.799 mmol) obtained in Step 2 of Preparation Example 79 (yield 20% over 3 steps).

[1063] 1 H-NMR (400MHz, chloroform-D) δ8.17(d,J=2.7Hz,1H),7.74(dt,J=7.8,1.4Hz,1H),7.65(d,J=1.8Hz,1H),7.51(d,J= 7.8Hz,1H),7.31(t,J=7.9Hz,1H),7.14-6.97(m,2H),3.72(s,2H),3.66(s,3H),2.99-2.85(2H),1.21(s,6H)

[1064] Preparation 103: Methyl 2-(4-((2-aminopyrimidin-4-yl)oxy)phenyl)acetate

[1065]

[1066] The desired product was obtained in a similar manner to Preparation 104, Step 1 and Preparation 19 (Step 3, Step 4) using methyl 2-(4-hydroxyphenyl)acetate (1 g, 6.02 mmol) (yield 57% over 3 steps).

[1067] 1 H-NMR (400 MHz, chloroform-d) δ 8.11 (d, J = 5.5 Hz, 1H), 7.30 (dd, J = 8.9, 2.5 Hz, 2H), 7.08 (dt, J = 9.1, 2.4 Hz, 2H), 6.18-6.02 (1H), 5.01 (s, 2H), 3.77-3.67 (3H), 3.62 (d, J = 16.0 Hz, 2H)

[1068] Preparation Example 104: Methyl 4-((6-aminopyridin-2-yl)oxy)benzoate

[1069]

[1070] Step 1: Methyl 4-((6-chloropyridin-2-yl)oxy)benzoate

[1071] Methyl 4-hydroxybenzoate (1g, 6.57mmol), 2,6-dichloropyridine (0.875g, 5.92mmol) and cesium carbonate (2.57g, 7.89mmol) are dissolved in 27.4mL DMF and stirred at 120°C for 4 hours. After confirming that the reaction is complete by TLC, the organic solvent is removed under reduced pressure. After being extracted with ethyl acetate (2×20ml), it is washed with salt water (20ml), and the organic solvent is dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 75%) is obtained by purification with a silica gel column (ethyl acetate: hexane=1:9).

[1072] 1 H-NMR (400 MHz, chloroform-D) δ 8.14-7.94 (m, 2H), 7.74-7.52 (m, 1H), 7.20-7.10 (m, 2H), 7.10-6.96 (m, 1H), 6.89-6.76 (m, 1H), 3.95-3.80 (m, 3H)

[1073] Step 2: Methyl 4-((6-aminopyridin-2-yl)oxy)benzoate

[1074] The desired product was obtained in a similar manner to Preparation 19 (step 3, step 4) using methyl 4-((6-chloropyridin-2-yl)oxy)benzoate (1.3 g, 4.93 mmol) synthesized in step 1 (yield 76% over 2 steps).

[1075] 1H-NMR (400 MHz, chloroform-D) δ 8.15-7.89 (m, 2H), 7.52-7.37 (m, 1H), 7.12 (dt, J = 9.3, 2.3 Hz, 2H), 6.33-6.10 (2H), 4.58-4.26 (m, 2H), 3.97-3.72 (m, 3H)

[1076] Preparation 105: Methyl 2-(4-((6-aminopyridin-2-yl)oxy)phenyl)acetate

[1077]

[1078] Step 1: Methyl 2-(4-((6-chloropyridin-2-yl)oxy)phenyl)acetate

[1079] 2,6-Dichloropyridine (2.67 g, 18.1 mmol), methyl 2-(4-hydroxyphenyl)acetate (3.00 g, 18.1 mmol), and cesium carbonate (7.06 g, 21.7 mmol) were dissolved in 75.0 mL of DMF and stirred at 120° C. overnight. This was extracted with DCM, and the organic solvent was dried over magnesium sulfate and removed under reduced pressure. The desired product was obtained by purification on a silica gel column (ethyl acetate:hexane) (yield 50%).

[1080] 1 H-NMR (400 MHz, chloroform-d) δ 7.61 (t, J = 7.8 Hz, 1H), 7.39-7.28 (2H), 7.10 (td, J = 5.7, 3.2 Hz, 2H), 7.03 (d, J = 7.8 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 3.72 (s, 3H), 3.64 (s, 2H)

[1081] Step 2: Methyl 2-(4-((6-aminopyridin-2-yl)oxy)phenyl)acetate

[1082] The desired product was obtained in a similar manner to Preparation Example 19 (step 3, step 4) using methyl 2-(4-((6-chloropyridin-2-yl)oxy)phenyl)acetate (1.25 g, 4.50 mmol) synthesized in step 1 (yield 5% over 2 steps).

[1083] 1 H-NMR (400 MHz, chloroform-D) δ 7.46 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 8.7 Hz, 2H), 7.09 (dd, J = 6.6, 2.1 Hz, 2H), 6.28-6.22 (1H), 6.02 (d, J = 8.2 Hz, 1H), 3.72 (s, 3H), 3.66-3.60 (2H)

[1084] Preparation 106: Methyl 2-(4-((6-aminopyridin-2-yl)oxy)phenyl)-2-methylpropanoate

[1085]

[1086] The desired product was obtained in a similar manner to Preparation Example 19 (step 2, step 3, step 4) using methyl 2-(4-((6-chloropyridin-2-yl)oxy)phenyl)acetate (1.25 g, 4.50 mmol) obtained in Step 1 of Preparation Example 105 (yield 41% over 3 steps).

[1087] 1 H-NMR (chloroform-D) δ7.40 (t, J=7.6 Hz, 1H), 7.37-7.29 (m, 2H), 7.09-7.00 (m, 2H), 6.23-6.14 (m, 1H), 6.06 (dd, J=7.9, 5.2 Hz, 1H), 3.67 (s, 3H), 1.59 (s, 6H)

[1088] Preparation 107: Methyl 3-((6-aminopyridin-2-yl)oxy)benzoate

[1089]

[1090] Step 1: Methyl 3-((6-chloropyridin-2-yl)oxy)benzoate

[1091] The desired product was obtained in a similar manner to Preparation 104, Step 1, using methyl 3-hydroxybenzoate (0.2 g, 1.315 mmol) (yield 75%).

[1092] 1 H-NMR (400 MHz, chloroform-D) δ 7.99-7.82 (m, 1H), 7.82-7.72 (m, 1H), 7.72-7.54 (m, 1H), 7.54-7.39 (m, 1H), 7.39-7.28 (1H), 7.08-6.95 (1H), 6.87-6.65 (1H), 3.96-3.81 (3H)

[1093] Step 2: Methyl 3-((6-aminopyridin-2-yl)oxy)benzoate

[1094] The desired product was obtained in a similar manner to Preparation Example 19 (step 3, step 4) using methyl 3-((6-chloropyridin-2-yl)oxy)benzoate (0.26 g, 0.986 mmol) synthesized in step 1 (yield 54% over 2 steps).

[1095] 1H-NMR (400 MHz, chloroform-d) δ 7.84 (dd, J = 7.8, 1.4 Hz, 1H), 7.76 (t, J = 1.8 Hz, 1H), 7.42 (td, J = 7.9, 3.4 Hz, 2H), 7.30 (dq, J = 8.0, 1.2 Hz, 1H), 6.21 (d, J = 8.2 Hz, 1H), 6.10 (d, J = 7.8 Hz, 1H), 3.89 (d, J = 3.2 Hz, 3H)

[1096] Preparation Example 108: Methyl 2-(3-((6-aminopyridin-2-yl)oxy)phenyl)acetate

[1097]

[1098] Step 1: Methyl 2-(3-hydroxyphenyl)acetate

[1099] The desired product was obtained in a similar manner to Step 2 of Preparation 76 using 2-(3-hydroxyphenyl)acetic acid (3.00 g, 19.7 mmol) (yield 99%).

[1100] 1 H-NMR (400 MHz, chloroform-D) δ 7.19 (t, J = 7.8 Hz, 1H), 6.84 (d, J = 7.3 Hz, 1H), 6.80-6.66 (m, 2H), 5.10-4.91 (m, 1H), 3.70 (s, 3H), 3.58 (s, 2H)

[1101] Step 2: Methyl 2-(3-((6-aminopyridin-2-yl)oxy)phenyl)acetate

[1102] The desired product was obtained in a similar manner to Preparation 105 using 2,6-dichloropyridine (2.90 g, 19.6 mmol) and methyl 2-(3-hydroxyphenyl)acetate (3.26 g, 19.6 mmol) synthesized in Step 1 (yield 12% over 3 steps).

[1103] 1 H-NMR (400 MHz, chloroform-D) δ 7.44 (t, J = 8.0 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.11 (d, J = 7.8 Hz, 1H), 7.09-6.96 (m, 2H), 6.23 (d, J = 8.2 Hz, 1H), 6.05 (d, J = 7.8 Hz, 1H), 3.70 (s, 3H), 3.65-3.62 (2H)

[1104] Preparation Example 109: Methyl 2-(3-((6-aminopyridin-2-yl)oxy)phenyl)-2-methylpropanoate

[1105]

[1106] The desired product was obtained in a similar manner to Preparation 106 using methyl 2-(3-hydroxyphenyl)acetate (1.45 g, 5.22 mmol) obtained in Step 1 of Preparation 108 (35% yield over 3 steps).

[1107] 1 H-NMR (400 MHz, chloroform-D) δ 7.49-7.35 (m, 1H), 7.35-7.27 (m, 1H), 7.17-7.07 (m, 2H), 7.04-6.90 (m, 1H), 6.25-6.15 (m, 1H), 6.06 (d, J = 7.8 Hz, 1H), 4.44 (s, 2H), 3.65 (s, 3H), 1.44-1.40 (6H)

[1108] Preparation 110: Methyl 4-(((6-aminopyridin-2-yl)oxy)methyl)benzoate

[1109]

[1110] Step 1: Methyl 4-(((6-chloropyridin-2-yl)oxy)methyl)benzoate

[1111] Methyl 4-(hydroxymethyl)benzoate (0.5 g, 3.01 mmol) and 2,6-dichloropyridine (0.445 g, 3.01 mmol), cesium carbonate (1.176 g, 3.61 mmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthine (0.244 g, 0.421 mmol) and palladium (II) acetate (0.054 g, 0.241 mmol) were dissolved in 12 ml of toluene and stirred at 120 ° C for 4 hours. After confirming that the reaction was complete by TLC, the organic solvent was removed under reduced pressure. After extraction with ethyl acetate (2×20 ml), it was washed with brine (20 ml), and the organic solvent was dehydrated on magnesium sulfate and removed under reduced pressure. The desired product (yield 24%) was obtained by purification with a silica gel column (ethyl acetate: hexane = 1:9).

[1112] 1 H-NMR (400 MHz, chloroform-D) δ 8.07-7.98 (m, 2H), 7.53 (q, J = 7.8 Hz, 3H), 7.00-6.83 (m, 1H), 6.82-6.66 (m, 1H), 5.52-5.34 (m, 2H), 3.89 (d, J = 16.0 Hz, 3H)

[1113] Step 2: Methyl 4-(((6-aminopyridin-2-yl)oxy)methyl)benzoate

[1114] The method was similar to Preparation Example 19 (Step 3, Step 4) using methyl 4-(((6-chloropyridin-2-yl)oxy)methyl)benzoate (0.2 g, 0.72 mmol) synthesized in Step 1 to obtain the product (yield 19% over 2 steps).

[1115] 1 H-NMR (400 MHz, chloroform-D) δ 8.12-7.91 (m, 2H), 7.60-7.42 (m, 2H), 7.42-7.30 (m, 1H), 6.26-6.11 (m, 1H), 6.11-5.99 (m, 1H), 5.46-5.28 (m, 2H), 3.96-3.81 (m, 3H)

[1116] Preparation Example 111: Methyl 2-(3-(4-aminopyrimidin-2-yl)phenyl)-2-methylpropanoate

[1117]

[1118] The desired product was obtained in a similar manner to Preparation 53 (step 1, step 2) and Preparation 19 (step 3, step 4) using methyl 2-(3-bromophenyl)-2-methylpropanoate (0.25 g, 0.972 mmol) (yield 36% over 4 steps).

[1119] 1 H-NMR (400 MHz, chloroform-D) δ 8.40-8.27 (m, 2H), 8.27-8.16 (m, 1H), 7.45-7.35 (m, 2H), 6.32 (d, J = 5.9 Hz, 1H), 5.14 (s, 2H), 3.70-3.49 (m, 3H), 1.72-1.56 (m, 6H)

[1120] Preparation Example 112: Methyl 2-(4-(4-aminopyrimidin-2-yl)phenyl)-2-methylpropanoate

[1121]

[1122] The desired product was obtained in a similar manner to Preparation 53 (step 1, step 2) and Preparation 19 (step 3, step 4) using methyl 2-(4-bromophenyl)-2-methylpropanoate (5 g, 19.45 mmol) (yield 36% over 4 steps).

[1123] 1H-NMR (400 MHz, chloroform-D) δ 8.37-8.28 (m, 1H), 8.26 (d, J = 8.2 Hz, 2H), 7.46-7.34 (m, 2H), 6.35-6.23 (m, 1H), 4.99 (s, 2H), 3.77-3.46 (m, 3H), 1.67-1.52 (m, 6H)

[1124] Preparation Example 113: tert-Butyl 3-(3-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate

[1125]

[1126] The title compound was synthesized in a similar manner to Step 2 of Preparation Example 52 using tert-butyl 2,2-dimethyl-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate (500 mg, 1.39 mmol) and 6-chloropyridin-2-amine (178 mg, 1.39 mmol) obtained in Step 2 of Preparation Example 79 (yield 66%).

[1127] 1 H-NMR (400MHz, chloroform-D) δ7.86(t,J=7.3Hz,1H),7.71(s,1H),7.66(d,J=16.0Hz,1H),7.38-7.30(m,1H),7.02(d,J=7.8Hz, 1H),6.64(d,J=7.3Hz,2H),6.36(d,J=8.2Hz,1H),4.52(s,2H),2.91(s,2H),1.40(d,J=6.9Hz,9H),1.14(t,J=4.6Hz,6H)

[1128] Preparation Example 114: tert-Butyl 3-(3-(6-amino-3-fluoropyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoate

[1129]

[1130] Step 1: tert-Butyl 3-(3-(6-chloro-3-fluoropyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoate

[1131] The title compound was synthesized in a similar manner to Step 2 of Preparation Example 52 using tert-butyl 3-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,2-dimethylpropanoate (1.52 g, 4.01 mmol) and 2,6-dichloro-3-fluoropyridine (799 mg, 4.81 mmol) obtained in Step 2 of Preparation Example 89 (yield 21%).

[1132] m / z(M+H) + C 20 H 23 The calculated value of ClF2NO2 is 382, ​​and the measured value is 382

[1133] Step 2: tert-Butyl 3-(3-(6-amino-3-fluoropyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoate

[1134] The title compound was synthesized in a similar manner to Preparation Example 19 (step 3, step 4) using tert-butyl 3-(3-(6-chloro-3-fluoropyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoate (327 mg, 0.86 mmol) obtained in step 1 (yield 17% over 2 steps).

[1135] 1 H-NMR (400 MHz, chloroform-D) δ 7.66 (dd, J = 7.5, 2.5 Hz, 1H), 7.34-7.15 (m, 1H), 7.15-7.04 (m, 2H), 7.04-6.90 (1H), 4.89-4.60 (2H), 2.84 (s, 2H), 1.40 (d, J = 6.9 Hz, 9H), 1.17-1.03 (m, 6H)

[1136] Preparation Example 115: Tert-butyl 3-(3-(6-amino-5-fluoropyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoate

[1137]

[1138] Step 1: tert-Butyl 3-(3-(6-chloro-5-fluoropyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoate

[1139] The title compound was synthesized in a similar manner to Step 2 of Preparation Example 52 using tert-butyl 3-(4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2,2-dimethylpropanoate (1.52 g, 4.01 mmol) and 2,6-dichloro-3-fluoropyridine (799 mg, 4.81 mmol) obtained in the step of Preparation Example 89 (yield 49%).

[1140] 1 H-NMR (400MHz, chloroform-D) δ7.46(t,J=8.5Hz,1H),7.38(dd,J=7.1,2.5Hz,1H),7.32(dd,J=8.7,3.2Hz,1H),7.22(t d,J=5.5,2.7Hz,1H),7.04(dd,J=9.8,8.5Hz,1H),2.85(s,2H),1.54(s,2H),1.40(d,J=7.8Hz,9H),1.14(s,6H)

[1141] Step 2: tert-Butyl 3-(3-(6-amino-5-fluoropyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoate

[1142] The title compound was synthesized in a manner similar to Preparation Example 19 (step 3, step 4) using tert-butyl 3-(3-(6-chloro-3-fluoropyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoate (756 mg, 1.98 mmol) obtained in step 1 (yield 38% over 2 steps).

[1143] 1 H-NMR (400MHz, chloroform-D) δ7.57-7.41(m,2H),7.39(dd,J=6.9,1.8Hz,1H),7.22-7.11(m,1H),7.06(t,J=9.1H z,1H),6.70(dd,J=8.9,3.0Hz,1H),4.38(d,J=22.9Hz,1H),2.86(s,2H),1.42-1.34(9H),1.16-1.06(6H)

[1144] Preparation Example 116: Methyl 3-(4-(6-aminopyridin-2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropanoate

[1145]

[1146] Using methyl 3-hydroxy-2,2-dimethylpropanoate (1.08 g, 8.16 mmol) and 4-bromo-1H-pyrazole (1.00 g, 6.80 mmol), a method similar to Step 1 of Preparation Example 1, Step 2 of Preparation Example 58, and Preparation Example 19 (Step 3 and Step 4) was used sequentially to obtain the desired product (yield 0.3% over 4 steps).

[1147] 1 H-NMR (400 MHz, chloroform-d): δ7.84 (d, J=7.8 Hz, 2H), 7.43-7.30 (m, 1H), 6.84-6.75 (m, 1H), 6.30 (d, J=7.8 Hz, 1H), 4.52 (s, 2H), 4.27 (s, 2H), 3.70 (s, 3H), 1.21 (s, 6H)

[1148] Preparation Example 117: Ethyl 4-((2-aminopyrimidin-4-yl)oxy)cyclohexane-1-carboxylate

[1149]

[1150] Step 1: Ethyl 4-((2-chloropyrimidin-4-yl)oxy)cyclohexane-1-carboxylate

[1151] 2,4-Dichloropyrimidine (0.300 g, 2.014 mmol) was dissolved in DMF (10 ml), followed by the addition of ethyl 4-hydroxycyclohexane-1-carboxylate (0.357 ml, 2.215 mmol) and cesium carbonate (1.640 g, 5.03 mmol). After stirring at 80°C for 3 hours, the mixture was diluted with diethyl ether and washed with water. After the organic solvent was dehydrated with magnesium sulfate, the mixture was purified by silica gel column to obtain the desired product (yield 29%).

[1152] 1 H-NMR (400 MHz, chloroform-D) δ 8.29-8.17 (m, 1H), 6.64-6.46 (m, 1H), 5.46-4.97 (m, 1H), 4.18-4.00 (m, 2H), 2.46-2.21 (m, 1H), 2.14 (dt, J = 9.0, 3.5 Hz, 1H), 2.08-1.89 (m, 2H), 1.89-1.79 (m, 1H), 1.79-1.70 (1H), 1.70-1.51 (m, 2H), 1.51-1.32 (m, 1H), 1.29-1.12 (m, 3H)

[1153] Step 2: Ethyl 4-((2-aminopyrimidin-4-yl)oxy)cyclohexane-1-carboxylate

[1154] The desired product was obtained in a similar manner to Preparation 2 using ethyl 4-((2-chloropyrimidin-4-yl)oxy)cyclohexane-1-carboxylate (0.165 g, 0.579 mmol) prepared in Step 1 (98% yield over 2 steps).

[1155] m / z(M+H) + C 13 H 20 The calculated value of N3O3 is 266.32, and the measured value is 266.1

[1156] Preparation 118: (R)-2-chloro-6-(3-(2-ethoxy-4-fluorophenoxy)piperidin-1-yl)pyrazine

[1157]

[1158] Step 1: 1-(Benzyloxy)-2-ethoxy-4-fluorobenzene

[1159] 2-(Benzyloxy)-5-fluorophenol (1.00 g, 4.58 mmol), iodoethane (0.44 ml, 5.5 mmol) and cesium carbonate (2.24 g, 6.87 mmol) were added to 6.74 mL of acetone and stirred at room temperature for 24 hours. The reaction mixture was filtered and water was added, then extracted with ethyl acetate. After washing with water and brine, the organic layer was dehydrated over magnesium sulfate and concentrated under reduced pressure. The desired product was obtained by purification on a silica gel column (yield 82%).

[1160] 1 H-NMR (400MHz, chloroform-D) δ7.43(d,J=7.3Hz,2H),7.40-7.33(m,2H),7.33-7.27(m,1H),6.82(dd,J=9.1,5.5Hz,1H),6 .64(dd,J=10.1,2.7Hz,1H),6.51(td,J=8.3,3.0Hz,1H),5.09(s,2H),4.08(q,J=7.0Hz,2H),1.47(t,J=7.1Hz,3H)

[1161] Step 2: 2-Ethoxy-4-fluorophenol

[1162] 1-(Benzyloxy)-2-ethoxy-4-fluorobenzene (921 mg, 3.74 mmol) obtained in step 1 was dissolved in methanol, Pd / C (19.9 mg, 0.187 mmol) was added, and then stirred under hydrogen. After the reaction was completed, it was filtered through celite to obtain the desired product (yield 92%).

[1163] 1 H-NMR (400 MHz, chloroform-D) δ 6.83 (dd, J = 8.7, 5.5 Hz, 1H), 6.68-6.48 (m, 2H), 5.45-5.31 (1H), 4.09 (q, J = 7.0 Hz, 2H), 1.50-1.37 (3H)

[1164] Step 3: (R)-2-chloro-6-(3-(2-ethoxy-4-fluorophenoxy)piperidin-1-yl)pyrazine

[1165] The desired product was obtained in a similar manner to Preparation Example 1 (step 1, step 2, step 3) using 2-ethoxy-4-fluorophenol (539 mg, 3.45 mmol) obtained in step 2 (3-step yield 37%).

[1166] 1H-NMR (400 MHz, chloroform-D) δ 7.95 (s, 1H), 7.74 (d, J = 5.0 Hz, 1H), 6.92 (dd, J = 8.7, 5.9 Hz, 1H), 6.70-6.47 (m, 2H), 4.28-4.14 (1H), 4.07-3.89 (3H), 3.72 (q, J = 6.4 Hz, 1H), 3.67-3.46 (m, 2H), 2.15-1.85 (m, 3H), 1.59 (qd, J = 8.5, 4.3 Hz, 1H), 1.41 (t, J = 7.1 Hz, 3H)

[1167] Preparation 119: Methyl 2-(4-(4-aminopyrimidin-2-yl)phenoxy)-2-methylpropanoate

[1168]

[1169] The desired product was obtained in a similar manner to Preparation 68, Step 1, Preparation 53 (Step 1, Step 2) and Preparation 19 (Step 4) using 4-bromophenol (1 g, 5.78 mmol) (6% yield over 4 steps).

[1170] 1 H-NMR (400 MHz, chloroform-D) δ 8.31-8.00 (m, 3H), 6.96-6.60 (m, 2H), 6.33-6.07 (m, 1H), 5.26 (d, J = 44.4 Hz, 2H), 4.22-4.09 (m, 2H), 1.63-1.50 (m, 6H), 1.29-1.07 (m, 3H)

[1171] Example 1: (R)-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)thiazole-5-carboxylic acid

[1172]

[1173] (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (20 mg, 0.06 mmol) and methyl 2-aminothiazole-5-carboxylate (0.011 g, 0.072 mmol) prepared in Preparation Example 1 were dissolved in 1,4-dioxane, and cesium carbonate (49 mg, 0.150 mmol), tris(dibenzylideneacetone)dipalladium(0) (4.39 mg, 0.005 mmol) and 4,5-bis(diphenylphosphine)-9,9-dimethylxanthine (3.47 mg, 0.006 mmol) were added, followed by reflux stirring for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, then dehydrated over magnesium sulfate, and the organic solvent was removed under reduced pressure. The desired product (yield 81%) was obtained by purification on a silica gel column (hexane:ethyl acetate = 2:1).

[1174] The resulting ester compound (22 mg, 0.05 mmol) was dissolved in THF:water:methanol = 1:1:1, lithium hydroxide (2 mg, 0.074 mmol) was added, and then stirred at 60°C for 12 hours. After the reaction was cooled to room temperature, the pH was adjusted to 4.5, and then extracted with an organic solvent. The organic layer was dehydrated over magnesium sulfate, removed under reduced pressure, and then purified by silica gel column chromatography to proceed with synthesis.

[1175] 1 H NMR (300 MHz, methanol-D): δ 11.5 (bs, 1H), 7.77 (s, 1H), 7.70 (s, 1H), 7.01 (d, 1H), 6.78-6.87 (m, 3H), 4.36 (bs, 1H), 3.75-3.91 (m, 8H), 1.82-1.97 (m, 4H), 1.55 (m, 1H), 1.18 (m, 5H)

[1176] Example 2: (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4,5-dimethylthiazol-2-amine

[1177]

[1178] The title compound was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.10 g, 0.30 mmol) and 2-amino-4,5-dimethylthiazole (0.038 g, 0.30 mmol) prepared in Preparation Example 1 (yield 63%).

[1179] 1H-NMR (400MHz, chloroform-D): δ8.80(brs,1H),7.61(s,1H),7.41(s,1H),6.82-7.01(m,4H),4.30-4.36(m,2H),3.98-4.05( m,3H),3.49(m,1H),3.38(m,1H),2.21(s,3H),2.19(s,3H),2.20(m,1H),1.78(m,1H),1.61-1.69(m,2H),1.39(t,3H)

[1180] Example 3: (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)thiazol-2-amine

[1181]

[1182] The title compound was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.10 g, 0.30 mmol) and 2-aminothiazole (0.03 g, 0.30 mmol) prepared in Preparation Example 1 (yield 25%).

[1183] 1 H-NMR (400 MHz, chloroform-D): δ10.97 (s, 1H), 7.64 (s, 1H), 7.59 (s, 1H), 7.45 (s, 1H), 7.02 (m, 2H), 6.86 (m, 2H), 6.71 (s, 1H), 4.46 (m, 1H), 4.34 (m, 1H), 4.03 (m, 3H), 3.34-3.45 (m, 2H), 2.24 (m, 1H), 2.02 (m, 1H), 1.91 (m, 1H), 1.71 (m, 1H), 1.39 (t, 3H)

[1184] Example 4: (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4-phenylthiazol-2-amine

[1185]

[1186] The title compound was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.10 g, 0.30 mmol) and 2-amino-4-benzothiazole (0.053 g, 0.30 mmol) prepared in Preparation Example 1 (yield 28%).

[1187] 1H-NMR (400MHz, chloroform-D): δ8.72(brs,1H),7.85(d,2H),7.63(s,1H),7.40(t,2H),7.35(s,1H),7.29(t,1H),7.02(m,2H),6.87(m,3H) ,4.44(m,1H),4.33(m,1H),3.95-4.06(m,3H),3.35-3.47(m,2H),2.23(m,1H),2.02(m,1H),1.89(m,1H),1.70(m,1H),1.39(t,3H)

[1188] Example 5: (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[d]thiazol-2-amine

[1189]

[1190] The title compound was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.10 g, 0.30 mmol) and 2-aminobenzothiazole (0.045 g, 0.30 mmol) prepared in Preparation Example 1 (yield 37%).

[1191] 1 H-NMR (400MHz, chloroform-D): δ9.20(brs,1H),7.73(s,1H),7.64-7.71(m,2H),7.42(s,1H),7.38(m,1H),7.22(m,1H),7.04(d,1H),6.83-6. 93(m,3H),4.31-4.40(m,2H),4.03(m,3H),3.63(m,1H),3.59(m,1H),2.21(m,1H),2.09(m,1H),1.97(m,1H),1.74(m,1H),1.39(t,3H)

[1192] Example 6: (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-6-methoxybenzo[d]thiazol-2-amine

[1193]

[1194] The title compound was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.10 g, 0.30 mmol) and 2-amino-(6-methoxy)benzothiazole (0.054 g, 0.30 mmol) prepared in Preparation Example 1 (yield 28%).

[1195] 1 H-NMR (400MHz, chloroform-D): δ9.90(brs,1H),7.70(s,1H),7.61(d,1H),7.52(s,1H),7.15(s,1H),6.82-7.06(m,4H),4.40(m,2H) ,3.99-4.06(m,3H),3.86(s,3H),3.60(m,1H),3.48(m,1H),2.20(m,1H),2.07(m,1H),1.96(m,1H),1.73(m,1H),1.39(t,3H)

[1196] Example 7: (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-6-(methylsulfonyl)benzo[d]thiazol-2-amine

[1197]

[1198] The title compound was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.10 g, 0.3 mmol) and 2-amino-(6-methylsulfonyl)benzothiazole (0.068 g, 0.30 mmol) prepared in Preparation Example 1 (yield 19%).

[1199] 1 H-NMR (400MHz, chloroform-D): δ9.70(brs,1H),8.24(s,1H),7.89(m,1H),7.80(s,1 H),7.76(m,1H),7.53(s,1H),7.03(d,1H),6.96(m,2H),6.83(m,1H),4.45( m,1H),4.29(m,1H),4.03(m,3H),3.89(m,1H),3.72(m,1H),3.59(m,1H),3. 11(s,3H),2.19(m,1H),2.11(m,1H),2.01(m,1H),1.76(m,1H),1.39(t,3H)

[1200] Example 8: (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-3-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)iso 5-Azolidine

[1201]

[1202] The title compound was prepared in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.15 g, 0.45 mmol) and 3-(1-(2-methoxyethoxy)-2-methylpropan-2-yl)isothiazolin-1-yl)pyrazine prepared in Preparation Example 1. The product was obtained by adding oxazol-5-amine (0.1 g, 0.49 mmol) (yield 57%).

[1203] 1 H-NMR (500 MHz, chloroform-D): δ7.73 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.03-6.90 (m, 2H), 6.89-6.75 (m, 2H), 5.99 (s, 1H), 4.36-4.25 (m, 1H), 4.08 (dd, J=12.8, 3.1 Hz, 1H), 4.03-3.88 (m, 2H), 3.88-3.76 (m, 1H), 3.59-3 .52(m,3H),3.52-3.46(m,4H),3.46-3.38(m,1H),3.33(d,J=6.1Hz,3H),2.17-2.07(m,1H),1.99(td,J=6 .6,3.5Hz,1H),1.90(q,J=4.3Hz,1H),1.62(q,J=4.5Hz,1H),1.36(t,J=7.0Hz,3H),1.29(d,J=2.6Hz,6H)

[1204] Example 9: (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4-phenyl Azol-2-amine

[1205]

[1206] The title compound was prepared in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.03 g, 0.09 mmol) prepared in Preparation Example 1 and 4-phenylbenzene prepared in Preparation Example 25. The product was obtained by adding oxazol-2-amine (0.016 g, 0.099 mmol) (yield 4%).

[1207] 1 H-NMR (500MHz, chloroform-D) δ7.92(s,1H),7.87(s,1H),7.72(d,J=7.6Hz,1H),7.66(s,1H),7.41(t,J=7.6Hz ,1H),7.34(d,J=7.3Hz,1H),7.28(m,2H),7.01-6.84(m,3H),6.84-6.74(m,1H),4.29-4.18(m,1H),4.0 6(dd,J=13.4,3.4Hz,1H),4.01(q,J=7.0Hz,2H),3.75(td,J=8.9,4.3Hz,1H),3.35(dd,J=13.1,8.2Hz, 1H),3.30-3.16(m,1H),2.20-2.02(m,1H),1.98-1.75(m,2H),1.57-1.51(m,1H),1.39(t,J=6.9Hz,3H)

[1208] Example 10: (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[d] Azol-2-amine

[1209]

[1210] The title compound was prepared in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.1 g, 0.30 mmol) and 2-aminobenzoic acid prepared in Preparation Example 1. It was obtained by adding oxazole (0.05 g, 0.36 mmol) (yield 19%).

[1211] 1 H-NMR (500MHz, chloroform-D) δ8.77(s,1H),7.87(s,1H),7.55(d,J=7.3Hz,1H),7.44-7.34( m,1H),7.17(t,J=7.6Hz,1H),7.06(d,J=16.5Hz,1H),6.97(t,J=7.9Hz,2H),6.88(q, J=7.1Hz,2H),4.32(s,1H),4.10-3.90(m,3H),3.78(d,J=14.1Hz,1H),3.62(q,J=6.9 Hz,1H),3.43(d,J=9.8Hz,1H),2.21-1.87(m,4H),1.61(s,1H),1.37(t,J=7.0Hz,3H)

[1212] Example 11: (R)-5-chloro-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[d] Azol-2-amine

[1213]

[1214] The title compound was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.14 g, 0.42 mmol) and 2-amino-(5-chloro)benzothiazole (0.071 g, 0.42 mmol) prepared in Preparation Example 1 (yield 51%).

[1215] 1 H-NMR (400MHz, chloroform-D): δ8.73(s,1H),7.89(s,1H),7.52(s,1H),7.16(m,1H),7.13(m,2H),6.99(m,2h),6.86-6.91(m,2H),4.34(m ,1H),3.93-4.03(m,3H),3.75(m,1H),3.67(m,1H),3.49(m,1H),2.11(m,1H),2.02(m,1H),1.93(m,1H),1.63(m,1H),1.37(t,3H)

[1216] Example 12: (R)-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-5-yl)acetic acid

[1217]

[1218] To 20 mL of 1,4-dioxane were added (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.777 g, 2.328 mmol) obtained in Preparation Example 1 and 2-(2-aminobenzo[d] To the reaction mixture was added methyl 2-oxazol-5-yl)acetate (0.4 g, 1.940 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.178 g, 0.194 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthine (0.135 g, 0.233 mmol) and cesium carbonate (1.580 g, 4.85 mmol), and stirred under reflux for 4 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution and brine, dehydrated over magnesium sulfate, and the organic solvent was removed under reduced pressure. The desired ester product (yield 36%) was obtained by purification on a silica gel column (ethyl acetate: hexane = 4:1).

[1219] 1 H-NMR (400 MHz, chloroform-D) δ 8.81-8.66 (m, 1H), 8.03 (d, J = 50.8 Hz, 1H), 7.95-7.77 (m, 1H), 7.54-7.38 (m, 1H), 7.26 (q, J = 7.8 Hz, 1H), 7.12-7.01 (m, 1H), 6.99-6.87 (m, 2H), 6.87-6.77 (m, 2H), 4.36-4.20 (m, 1H), 4.06-3.99(m,1H),3.99-3.89(m,2H),3.75(td,J=9.6,3.8Hz,1H),3.69(d,J=9.6Hz,5H),3.61-3.46( m,1H),3.46-3.30(m,1H),2.18-2.03(m,1H),2.01-1.74(m,2H),1.68-1.44(m,1H),1.44-1.28(m,3H)

[1220] The ester compound (0.330g, 0.655mmol) obtained is dissolved in 5mL THF, 2mL MeOH and 2mL water. After adding sodium hydroxide (0.786g, 19.66mmol), the mixture is stirred at room temperature for 15 hours. After confirming that the reaction is complete by TLC, 1N hydrochloric acid aqueous solution is used to be adjusted to pH 4.5, diluted with ethyl acetate, and the water layer is removed. After the reaction product is dried over magnesium sulfate, the organic solvent is removed under reduced pressure to obtain the title compound (yield 3%).

[1221] 1H-NMR (400 MHz, methanol-D4) δ8.51 (s, 1H), 7.68 (s, 1H), 7.44-7.34 (1H), 7.25 (d, J = 8.2 Hz, 1H), 7.11 (q, J = 7.3 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H), 6.86 (d, J = 3.7 Hz, 2H), 6.84-6.71 (m, 2H), 4.40 (s, 1H), 3 .89-3.83(m,2H),3.82-3.74(m,2H),3.62(dd,J=16.9,12.8Hz,1H),3.55-3.50(2H),2.63(s,1H ),2.00(dd,J=13.5,3.4Hz,2H),1.90(d,J=8.2Hz,1H),1.64-1.48(m,1H),1.25(t,J=6.9Hz,3H)

[1222] Example 13: (R)-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-5-yl)-2-methylpropionic acid

[1223]

[1224] Ester product was prepared in a similar manner to Example 12 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.855 g, 2.56 mmol) obtained in Preparation Example 1 and 2-(2-aminobenzo[d] The product was obtained by adding methyl 2-oxazol-5-yl)-2-methylpropanoate (0.5 g, 2.134 mmol) (yield 66%).

[1225] 1H-NMR (400 MHz, chloroform-D) δ8.82 (q, J = 14.8 Hz, 1H), 8.62 (s, 1H), 7.86 (t, J = 15.1 Hz, 1H), 7.56-7.46 (m, 1H), 7.34-7.20 (m, 1H), 7.21-7.03 (m, 1H), 7.03-6.83 (m, 2H), 6.83-6.69 (m, 2H), 4.33-4.15 (m, 1H), 4.16-3.97 (m, 1H), 3. 90(td,J=15.4,8.1Hz,2H),3.82-3.68(m,1H),3.68-3.58(m,3H),3.58-3.45(m,1H),3.45-3.29(m,1H),2.16- 2.02(m,1H),1.98-1.87(m,1H),1.87-1.71(m,1H),1.68-1.56(m,6H),1.56-1.48(m,1H),1.30(t,J=6.9Hz,3H)

[1226] The title compound was obtained by hydrolysis of the obtained ester compound in a similar manner to Example 12 (yield 56%).

[1227] m / z(M+H) + C 28 H 32 The calculated value of N5O5 is 518, and the measured value is 518

[1228] Example 14: (R)-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-5-yl)-2,2-dimethylpropionic acid

[1229]

[1230] The title compound was prepared in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.30 g, 0.90 mmol) prepared in Preparation Example 1 and 3-(2-aminobenzo[d] The product was obtained by adding methyl 2,2-dimethylpropanoate (0.22 g, 0.90 mmol) (32% yield over 2 steps).

[1231] 1H-NMR (400 MHz, chloroform-D) δ8.27 (s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 7.21 (d, J = 8.2 Hz, 1H), 6.96 (d, J = 8.2 Hz, 2H), 6.93-6.81 (m, 2H), 6.77 (t, J = 7.5 Hz, 1H), 4.36-4.25 (m, 1H), 4.12 (d, J = 16.5 Hz, 1H), 4.04-3.90 (m, 2 H),3.84(d,J=13.3Hz,1H),3.59(dd,J=13.0,7.5Hz,1H),3.43(t,J=9.6Hz,1H),2.99(s,2H),2.13(t,J= 5.9Hz,1H),2.06-1.95(m,1H),1.95-1.83(m,1H),1.68-1.54(m,1H),1.35(t,J=6.9Hz,3H),1.29(s,6H)

[1232] Example 15: (R,E)-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-5-yl)acrylic acid

[1233]

[1234] Ester product was prepared in a similar manner to Example 12 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.973 g, 2.91 mmol) obtained in Preparation Example 1 and (E)-3-(2-aminobenzo[d] The product was obtained by adding methyl 2-oxazol-5-yl)acrylate (0.53 g, 2.429 mmol) (yield 6%).

[1235] 1H-NMR (400 MHz, chloroform-D) δ 8.74 (s, 1H), 7.88 (s, 1H), 7.80-7.68 (m, 2H), 7.35 (dd, J = 10.5, 8.7 Hz, 2H), 7.23-7.18 (1H), 6.99-6.91 (m, 2H), 6.91-6.84 (m, 2H), 6.42 (dd, J = 16.7, 6.6 Hz, 1H), 4. 41-4.24(m,1H),4.06-3.87(m,3H),3.85-3.79(m,3H),3.79-3.70(m,1H),3.69-3.54(m,1H), 3.54-3.35(m,1H),2.21-2.07(m,1H),2.02-1.86(2H),1.70-1.58(1H),1.36(t,J=7.1Hz,3H)

[1236] The title compound was obtained by hydrolysis of the obtained ester compound in a similar manner to Example 12 (yield 1%).

[1237] m / z(M+H) + C 27 H 28 The calculated value of N5O5 is 502, and the measured value is 502

[1238] Example 16: (R)-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-5-yl)propionic acid

[1239]

[1240] Ester product was prepared in a similar manner to Example 12 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (1 g, 3.00 mmol) obtained in Preparation Example 1 and 3-(2-aminobenzo[d] The product was obtained by adding methyl 2-oxazol-5-yl)propanoate (0.550 g, 2.496 mmol) (yield 28%).

[1241] 1H-NMR (400 MHz, chloroform-D) δ8.61 (d, J = 4.1 Hz, 1H), 7.81 (s, 1H), 7.43-7.32 (m, 1H), 7.27 (d, J = 8.2 Hz, 1H), 7.04-6.90 (m, 3H), 6.84 (t, J = 7.1 Hz, 2H), 4.34-4.22 (m, 1H), 4.20-4.09 (m, 1H), 4.09-3. 87(m,3H),3.88-3.70(m,1H),3.65-3.49(m,3H),3.50-3.32(m,1H),3.14-2.97(m,2H),2.71(t ,J=7.8Hz,2H),2.27-2.11(m,1H),2.02-1.81(m,2H),1.72-1.52(m,1H),1.36(t,J=6.9Hz,3H)

[1242] The title compound was obtained by hydrolysis of the obtained ester compound in a similar manner to Example 12 (yield 5%).

[1243] m / z(M+H) + C 27 H 30 The calculated value of N5O5 is 504, and the measured value is 504

[1244] Example 17: (R)-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-6-yl)-2-methylpropionic acid

[1245]

[1246] The title compound was prepared in a similar manner to Example 12 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.293 g, 0.878 mmol) obtained in Preparation Example 1 and 2-(2-aminobenzo[d] The product was obtained by adding methyl 2-oxazol-6-yl)-2-methylpropanoate (0.187 g, 0.798 mmol) (7% yield over 2 steps).

[1247] 1H-NMR (400 MHz, chloroform-D) δ8.55 (d, J = 11.9 Hz, 1H), 7.82 (d, J = 10.1 Hz, 1H), 7.55-7.44 (m, 1H), 7.44-7.36 (m, 1H), 7.31 (d, J = 7.3 Hz, 1H), 7.02-6.87 (2H), 6.86-6.74 (m, 2H), 4.29 (t, J = 3.4 Hz, 1H), 4. 15-4.06(m,1H),4.06-3.83(m,3H),3.81-3.67(m,1H),3.66-3.50(1H),3.50-3.35(m,1H),2.15- 2.04(m,1H),2.03(d,J=2.7Hz,1H),2.01-1.82(m,2H),1.62(d,J=12.3Hz,6H),1.37-1.28(m,3H)

[1248] Example 18: (R)-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-6-yl)propionic acid

[1249]

[1250] The product was prepared in a similar manner to Example 12 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.8 g, 2.398 mmol) obtained in Preparation Example 1 and 3-(2-aminobenzo[d] The product was obtained by adding methyl oxazol-6-yl)propanoate (0.44 g, 1.998 mmol) (yield 11%).

[1251] 1 H-NMR (400 MHz, chloroform-D) δ8.74 (s, 1H), 7.85 (s, 1H), 7.43 (d, J = 8.2 Hz, 1H), 7.13-7.01 (m, 1H), 6.97 (t, J = 7.1 Hz, 3H), 6.92-6.83 (m, 3H), 4.33 (d, J = 4.1 Hz, 1H), 4.03-3.90 (3H), 3 .79(s,1H),3.66(s,3H),3.60(dd,J=13.0,7.5Hz,2H),3.03(t,J=7.8Hz,2H),2.71-2. 60(2H),2.13-2.05(1H),1.98(d,J=40.7Hz,2H),1.75-1.63(1H),1.36(t,J=7.1Hz,3H)

[1252] The title compound was obtained by hydrolysis of the obtained ester compound in a similar manner to Example 12 (yield 3%).

[1253] m / z(M+H) + C 27 H 30 The calculated value of N5O5 is 504, and the measured value is 504

[1254] Example 19: (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(1H-pyrazol-3-yl)pyrazin-2-amine

[1255]

[1256] Step 1: (R)-3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino-1H-pyrazole- tert-Butyl 1-formate

[1257] The desired product was obtained in a manner similar to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (1.540 g, 4.61 mmol) prepared in Preparation Example 1 and tert-butyl 3-amino-1H-pyrazole-1-carboxylate (0.930 g, 5.08 mmol) prepared in Preparation Example 64 (yield 1%).

[1258] 1 H-NMR (chloroform-D) δ7.91 (d, J = 2.7Hz, 1H), 7.73-7.57 (m, 2H), 7.46-7.34 (1H), 7.07-6.95 (m, 2H), 6. 95-6.80(2H),6.67-6.55(1H),4.30(td,J=8.2,3.9Hz,1H),4.21(dd,J=13.0,3.5Hz,1H),4.09- 3.95(m,2H),3.93-3.78(1H),3.41(dd,J=13.0,8.1Hz,1H),3.36-3.23(m,1H),2.20(dd,J=12. 7,5.0Hz,1H),2.00(dd,J=9.3,4.1Hz,1H),1.95-1.81(1H),1.66(s,10H),1.40(t,J=7.0Hz,3H)

[1259] Step 2: (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(1H-pyrazol-3-yl)pyrazin-2-amine

[1260] (R)-tert-Butyl 3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino-1H-pyrazole-1-carboxylate (0.0124 g, 0.026 mmol) obtained in step 1 was dissolved in DCM (0.2 ml), and trifluoroacetic acid (0.026 ml) dissolved in DCM was added, followed by stirring at room temperature for 1 hour and 30 minutes. After the solvent was removed under reduced pressure, it was dissolved in DCM and washed with water, and purified by silica gel column to give the title compound (yield 50%).

[1261] 1 H-NMR (500MHz, MeOD) δ7.49(s,1H),7.45(s,1H),7.40(s,1H),7.02(d,J=7.6Hz,1H),6.95(d,J=3.7Hz,2H),6.87(d,J=11.9Hz,1H),6.31(s,1H ),4.60(s,1H),4.46-4.34(1H),4.13-3.90(m,2H),3.75-3.66(1H),3. 66-3.52(m,2H),2.18-1.85(3H),1.75-1.56(1H),1.32(t,J=6.7Hz,3H)

[1262] Example 20: (R)-2-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H-pyrazol-1-yl)acetic acid

[1263]

[1264] Step 1: (R)-2-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H-pyrazol- Ethyl oxazol-1-yl)acetate

[1265] (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(1H-pyrazol-3-yl)pyrazin-2-amine (0.200 g, 0.526 mmol) and sodium hydride (0.025 g, 0.631 mmol) prepared in Example 19 were dissolved in tetrahydrofuran (2.63 ml) and stirred for 30 minutes. Ethyl 2-bromoacetate (0.087 ml, 0.789 mmol) dissolved in tetrahydrofuran (2.63 ml) was added dropwise to the reaction solution, followed by stirring for 2 hours. Water was added dropwise to terminate the reaction, which was then dissolved in ethyl acetate and washed with brine. The organic solvent was dehydrated over magnesium sulfate and removed under reduced pressure. The desired product was obtained by purification on a silica gel column (yield 3%).

[1266] 1H-NMR (500MHz, chloroform-D) δ7.69 (s, 1H), 7.59 (s, 1H), 7.32 (d, J = 1.8Hz, 1H), 7.09-6.81 (m, 4H), 6.66 (s, 1H),6.36(d,J=2.1Hz,1H),4.83-4.70(m,2H),4.37-4.18(m,4H),4.05(qd,J=6.8,3.1Hz,2H),3.99- 3.83(m,1H),3.35(dd,J=13.0,8.4Hz,1H),3.31-3.18(m,1H),2.29-2.12(m,1H),1.98(q,J=4.5Hz, 1H),1.93-1.78(m,1H),1.79-1.55(m,2H),1.42(t,J=7.0Hz,3H),1.31(t,J=7.2Hz,3H),1.28(s,1H)

[1267] Step 2: (R)-2-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H-pyrazol- oxazol-1-yl)acetic acid

[1268] Ethyl (R)-2-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H-pyrazol-1-yl)acetate (0.0073 g, 0.016 mmol) obtained in Step 1 was dissolved in a 50% aqueous ethanol solution (0.156 ml), and lithium hydroxide (1.124 mg, 0.047 mmol) was added thereto, followed by stirring at 0°C for 1 hour. After removing the solvent under reduced pressure, the mixture was dissolved in ethyl acetate and washed with water. The title compound was obtained by purification on a silica gel column (yield 26%).

[1269] m / z(M+H) + C 22 H 27 The calculated value of N6O4 is 439, and the measured value is 439

[1270] Example 21: (R)-3-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H-pyrazol-1-yl)-2,2-dimethylpropanoic acid

[1271]

[1272] The title compound was obtained in a manner similar to that in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.10 g, 0.30 mmol) prepared in Preparation Example 1 and methyl 3-(3-amino-1H-pyrazol-1-yl)-2,2-dimethylpropanoate (0.059 g, 0.30 mmol) obtained in Preparation Example 66 (yield 45%).

[1273] 1 H-NMR (400MHz, chloroform-D): δ9.32 (s, 1H), 7.45 (d, J = 7.3Hz, 2H), 7.13 (d, J = 2.3H) z,1H),7.06-6.77(m,5H),6.47(d,J=2.3Hz,1H),4.35-4.14(m,4H),4.06-3 .89(m,2H),3.89-3.78(m,1H),3.37-3.08(m,2H),2.17(q,J=4.3Hz,1H),1. 99-1.71(m,2H),1.71-1.53(m,1H),1.36(t,J=6.9Hz,3H),1.22-1.09(m,6H)

[1274] Example 22: (R)-3-(3-(6-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoropyrimidin-2-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid

[1275]

[1276] (R)-2-chloro-4-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-fluoropyrimidine (54 mg, 0.15 mmol) synthesized in Preparation Example 8 and tert-butyl 3-(3-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate (50 mg, 0.15 mmol) synthesized in Preparation Example 113 were dissolved in 1,4-dioxane, and the mixture was deoxygenated and filled with nitrogen to prevent exposure to the outside air. Tris(dibenzylideneacetone)dipalladium(0) (8.4 mg, 9.19 μmol), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthine (8.0 mg, 0.01 mmol), and cesium carbonate (125 mg, 0.38 mmol) were added, and a reflux cooler was connected and heated for 12 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with ethyl acetate, dehydrated over magnesium sulfate, and the organic solvent was removed under reduced pressure. The desired product was obtained by purification with a silica gel column (hexane:ethyl acetate) (yield 15%).

[1277] The obtained ester compound (15mg, 0.02mmol) was dissolved in DCM, trifluoroacetic acid (36μl, 0.47mmol) was added, and then stirred at room temperature for 2 hours. After the reaction was completed, the mixture was distilled under reduced pressure to remove excess trifluoroacetic acid, neutralized with 1N sodium hydroxide, and extracted with ethyl acetate. The organic solvent was dehydrated on magnesium sulfate and the organic solvent was removed under reduced pressure. The desired product (yield 37%) was obtained by purification with a silica gel column (hexane: ethyl acetate).

[1278] 1 H-NMR (400 MHz, methanol-D4) δ7.81 (s, 1H), 7.78 (d, J = 7.8 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.66-7.57 (1H), 7.54 (t, J = 8.0 Hz, 1H), 7.45-7.23 (m, 5H), 7.23-7.11 (1H), 7.00-6.88 (m, 1H), 6.86 (d, J = 4.1 Hz, 2H ),6.82-6.70(m,1H),4.44(d,J=2.7Hz,1H),4.14-3.94(m,2H),3.94-3.75(m,4H),3.62(d,J=8.7H z,1H),2.90(s,2H),2.14-1.84(m,4H),1.60(d,J=7.3Hz,1H),1.34-1.20(m,3H),1.19-1.11(m,6H)

[1279] Example 23: (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(1-methyl-1H-tetrazol-5-yl)pyrazin-2-amine

[1280]

[1281] The title compound was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.15 g, 0.45 mmol) and 1-methyl-1H-tetrazol-5-amine (0.049 g, 0.49 mmol) prepared in Preparation Example 1 (yield 44%).

[1282] 1H-NMR (500MHz, chloroform-D): δ8.18(s,1H),7.79(s,1H),7.41(s,1H),7.01-6.89(m, 2H),6.88-6.75(m,2H),4.34-4.23(m,1H),4.06-3.91(m,2H),3.88(s,3H),3. 86(s,1H),3.70-3.56(2H),3.42(q,J=4.5Hz,1H),2.13-2.03(m,1H),2.02-1. 95(m,1H),1.90(q,J=4.1Hz,1H),1.57(q,J=4.5Hz,1H),1.34(t,J=7.0Hz,3H)

[1283] Example 24: (R)-N-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-phenylpyrazin-2-amine

[1284]

[1285] The title compound was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.09 g, 0.27 mmol) prepared in Preparation 1 and aniline (0.025 g, 0.27 mmol).

[1286] 1 H-NMR (400MHz, chloroform-D): δ7.56(s,1H),7.52(s,1H),7.36(d,J=8Hz,2H),7.03(d,J=8Hz,2H),6.94-7.03(m,3H),6.82-6.91(m,2H),6.20(s,1H), 4.31(m,1H),4.19(m,1H),4.04(m,3H),3.89(m,1H),3.43(m,1H),3.29( m,1H),2.15(m,1H),1.96(m,1H),1.86(m,1H),1.64(m,1H),1.39(t,3H)

[1287] Example 25: (R)-N-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)methanesulfonamide

[1288]

[1289] The title compound was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.15 g, 0.45 mmol) and N-(4-aminophenyl)methanesulfonamide (0.092 g, 0.49 mmol) prepared in Preparation Example 1 (yield 69%).

[1290] 1 H-NMR (500MHz, chloroform-D): δ7.57(s,1H),7.45(s,1H),7.42-7.33(m,2H),7.13(dd,J=9.6,2.6Hz,2H),7.03-6.93(m,2H) ,6.89(dd,J=7.9,1.2Hz,1H),6.82(td,J=7.5,1.4Hz,1H),6.48(s,1H),6.28(s,1H),4.35-4.24(m,1H),4.16(dd,J=1 3.1,3.4Hz,1H),4.07-3.95(m,2H),3.83(td,J=8.9,4.1Hz,1H),3.43(dd,J=13.4,7.9Hz,1H),3.37-3.24(m,1H),2.9 6(s,3H),2.23-2.09(m,1H),1.98(dd,J=9.8,3.7Hz,1H),1.93-1.80(m,1H),1.69-1.61(m,1H),1.38(t,J=7.0Hz,3H)

[1291] Example 26: (R)-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-N-(pyridin-4-ylmethyl)acetamide

[1292]

[1293] The title compound was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.15 g, 0.45 mmol) and 2-(4-aminophenyl)-N-(pyridin-4-ylmethyl)acetamide (0.11 g, 0.49 mmol) prepared in Preparation Example 1 (yield 54%).

[1294] 1H-NMR (500MHz, chloroform-D): δ8.49(d,J=5.5Hz,2H),7.54(s,1H),7.46(s,1H),7.38(d,J=8.6Hz,2H),7.15(d,J=7.9Hz,2H),7.07(d,J=5.5Hz,2 H),7.01-6.96(1H),6.95-6.91(m,1H),6.90-6.85(m,1H),6.80(td,J=7.6,1.4Hz,1H),6.43(s,1H),5.96(s,1H),4.40(d,J=6.1Hz,2H),4 .32-4.24(m,1H),4.17(dd,J=12.8,3.1Hz,1H),4.06-3.95(m,2H),3.83(td,J=8.6,4.1Hz,1H),3.60(s,2H),3.40(dd,J=12.8,8.0Hz,1H) ,3.34-3.24(m,1H),2.21-2.11(m,1H),1.97(dd,J=9.7,3.8Hz,1H),1.87(dd,J=9.2,3.7Hz,1H),1.67-1.55(m,1H),1.37(t,J=7.0Hz,3H)

[1295] Example 27: (R)-2-(4-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-2-methylpropanoic acid

[1296]

[1297] The desired product was obtained in a manner similar to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.30 g, 0.90 mmol) prepared in Preparation Example 1 and methyl 2-(4-aminophenyl)-2-methylpropanoate (0.19 g, 0.99 mmol) prepared in Preparation Example 14 (yield 91%).

[1298] 1H-NMR (400 MHz, chloroform-D) δ7.55 (s, 1H), 7.48 (s, 1H), 7.29-7.32 (m, 2H), 7.23 (dd, J = 6.9, 1.8 Hz, 2H), 6.81-7.01 (m, 4H), 6.18 (s, 1H), 4.26-4.30 (m, 1H), 4.19 (dd, J = 12.8, 3.7 Hz, 1H), 3.99-4.05 (m, 2H), 3.8 4-3.88(m,1H),3.64(s,3H),3.38(dd,J=12.8,8.2Hz,1H),3.24-3.30(m,1H),2.14-2.18(m,1H),1.9 7(q,J=4.6Hz,1H),1.87(dd,J=9.4,3.4Hz,1H),1.60-1.64(m,1H),1.56(s,6H),1.38(t,J=6.9Hz,3H)

[1299] The title compound was obtained by hydrolysis of the obtained ester compound (0.40 g, 0.82 mmol) in a similar manner to Example 1 (yield 23%).

[1300] 1 H-NMR (400 MHz, chloroform-D) δ7.51 (s, 1H), 7.42 (s, 1H), 7.27-7.31 (m, 4H), 6.85-6.99 (m, 4H), 6.34 (s, 1H), 4.25-4.29 (m, 1H), 4.16 (d, J = 12.8 Hz, 1H), 3.97-4.03 (m, 2H), 3 .79-3.82(m,1H),3.39(dd,J=13.0,8.0Hz,1H),3.26(t,J=10.1Hz,1H),2.12-2.1 5(m,1H),1.93-1.97(m,1H),1.81-1.89(m,1H),1.58(s,7H),1.36(t,J=6.9Hz,3H)

[1301] Example 28: (R)-2-(4-((6-(3-(2-ethoxyphenoxy)pyridin-1-yl)pyrazin-2-yl)amino)phenyl)-2-methylpropanoic acid

[1302]

[1303] The desired product was obtained in a manner similar to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyridine (0.30 g, 0.90 mmol) prepared in Preparation Example 4 and methyl 2-(4-aminophenyl)-2-methylpropanoate (0.19 g, 0.99 mmol) prepared in Preparation Example 14 (yield 88%).

[1304] 1 H-NMR (400 MHz, chloroform-D) δ7.30 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 3.2 Hz, 1H), 7.20-7.22 (m, 2H), 7.04 (dd, J = 8.0, 1.6 Hz, 1H), 6.82-6.96 (m, 3H), 6.19 (s, 1H), 6.11 (q, J = 8.4 Hz, 2H), 4.24-4.36 (m, 2H ),3.96-4.06(m,3H),3.64(s,3H),3.47(d,J=7.3Hz,0H),3.03-3.19(m,2H),2.19(dd,J=12.6 ,4.3Hz,1H),1.77-1.91(m,2H),1.38-1.63(m,12H),1.18-1.24(m,1H),-0.01(t,J=3.2Hz,3H)

[1305] The title compound was obtained in a similar manner to Example 1 by hydrolysis reaction of the obtained ester compound (0.40 g, 0.82 mmol).

[1306] 1 H-NMR (400MHz, chloroform-D) δ7.22-7.30(m,5H),7.03(d,J=7.8Hz,1H),6.89(dq,J=28.9,7.5Hz,3H ),6.14(d,J=7.8Hz,1H),6.08(d,J=7.8Hz,1H),4.24-4.32(m,2H),4.03(q,J=6.9Hz,2H),3. 95(d,J=12.8Hz,1H),3.17(dd,J=11.9,8.2Hz,1H),3.07(t,J=10.5Hz,1H),2.19(d,J=8.2Hz ,1H),1.89(q,J=4.3Hz,1H),1.78(d,J=11.9Hz,1H),1.57-1.65(m,7H),1.39(t,J=6.9Hz,3H)

[1307] Example 29: (R)-2-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)phenyl)-2-methylpropanoic acid

[1308]

[1309] The title compound was obtained in a manner similar to that in Example 12 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (1.036 g, 3.10 mmol) obtained in Preparation Example 1 and methyl 2-(3-aminophenyl)-2-methylpropanoate (0.5 g, 2.59 mmol) obtained in Preparation Example 15 (4% ​​yield over 2 steps).

[1310] 1 H-NMR (400 MHz, chloroform-D) δ 7.63 (s, 1H), 7.50 (s, 1H), 7.45 (s, 1H), 7.22 (d, J = 7.8 Hz, 1H), 7.07 (t, J = 9.8 Hz, 2H), 7.00-6.89 (m, 2H), 6.89-6.76 (m, 2H), 6.42 (s, 1H), 4.44-4.21 (m, 2H), 4.05-3. 91(m,2H),3.83(q,J=4.4Hz,1H),3.42-3.26(1H),3.26-3.05(m,1H),2.25-2.06(m,1H),1.93 (q,J=4.6Hz,1H),1.83-1.67(1H),1.67-1.59(m,1H),1.59-1.48(m,6H),1.35(t,J=6.9Hz,3H)

[1311] Example 30: (R)-3-(3'-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-[1,1'-biphenyl]-4-yl)-2,2-dimethylpropanoic acid

[1312]

[1313] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.192 g, 0.575 mmol) obtained in Preparation Example 1 and tert-butyl 3-(3'-amino-[1,1'-biphenyl]-4-yl)-2,2-dimethylpropanoate (0.17 g, 0.522 mmol) obtained in Preparation Example 94 (yield 12% over 2 steps).

[1314] 1H-NMR (400 MHz, chloroform-D) δ7.58 (s, 1H), 7.55-7.48 (2H), 7.48-7.39 (m, 2H), 7.30-7.22 (2H), 7.18 (q, J = 7.6 Hz, 3H), 6.93 (q, J = 7.6 Hz, 2H), 6.88-6.83 (m, 1H), 6.83-6.73 (m, 1H), 6.53 (s, 1H), 4.37-4.18 (m, 1H ),4.18-4.06(m,1H),4.05-3.89(m,2H),3.83(q,J=4.3Hz,1H),3.53-3.36(1H),3.36-3.19(m,1H),2 .90(s,2H),2.25-2.06(1H),1.99-1.74(m,2H),1.70-1.48(m,1H),1.34(q,J=7.3Hz,3H),1.23(s,6H)

[1315] Example 31: (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(pyridin-2-yl)pyrazin-2-amine

[1316]

[1317] The title compound was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.20 g, 0.60 mmol) and 2-aminopyridine (0.06 g, 0.66 mmol) prepared in Preparation Example 1 (yield 94%).

[1318] 1 H-NMR (500MHz, chloroform-D): δ8.24(d,J=4.9Hz,1H),7.89(s,1H),7.66(s,1H),7.62(d,J=8.6Hz,1H),7.54-7.42( m,1H),7.09(s,1H),6.99(d,J=7.9Hz,1H),6.95(t,J=7.0Hz,1H),6.90-6.72(m,3H),4.36-4.25(m,1H),4.1 9(dd,J=13.2,3.3Hz,1H),4.08-3.94(m,2H),3.89-3.81(m,1H),3.44(dd,J=13.4,7.9Hz,1H),3.38-3.25(m ,1H),2.17(t,J=5.8Hz,1H),2.05-1.95(1H),1.93-1.79(m,1H),1.67(d,J=6.1Hz,1H),1.37(t,J=7.0Hz,3H)

[1319] Example 32: (R)-6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)nicotinic acid

[1320]

[1321] The desired product was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.30 g, 0.90 mmol) and methyl 6-aminonicotinate (0.15 g, 0.99 mmol) prepared in Preparation 1 (yield 72%).

[1322] 1 H-NMR (500MHz, chloroform-D): δ8.87(d,J=2.4Hz,1H),8.08(dd,J=8.9,2.1Hz,1H),7.90(s,1H),7.73(s,1H),7.65(d,J =8.6Hz,1H),7.36(s,1H),7.04-6.92(m,2H),6.90-6.68(m,2H),4.32(td,J=7.9,3.7Hz,1H),4.12(dd,J=13.1, 3.4Hz,1H),4.07-3.95(m,2H),3.91(s,3H),3.80(td,J=9.2,4.5Hz,1H),3.53(dd,J=13.1,7.6Hz,1H),3.46-3. 31(m,1H),2.27-2.11(m,1H),2.09-1.99(m,1H),1.97-1.84(m,1H),1.66(q,J=4.5Hz,1H),1.36(t,J=6.7Hz,3H)

[1323] The title compound was obtained by hydrolysis of the obtained ester compound (0.29 g, 0.65 mmol) in a similar manner to Example 1 (yield 21%).

[1324] 1H-NMR (500MHz, DMSO-D6): δ12.99-12.26(1H),10.00(s,1H),8.71(s,1H),8.12(s,1H),7.95(d,J=7.9Hz,1 H),7.76(s,1H),7.61(d,J=8.6Hz,1H),7.00(d,J=7.9Hz,1H),6.89(d,J=6.7Hz,1H),6.84(d,J=7.3Hz,1H) ,6.76(t,J=7.0Hz,1H),4.40-4.24(1H),4.03(d,J=11.6Hz,1H),3.96-3.80(m,2H),3.68(d,J=13.4Hz,1H) ,3.57-3.39(m,2H),2.12-1.94(1H),1.86(s,1H),1.72(d,J=9.2Hz,1H),1.54(s,1H),1.18(t,J=7.0Hz,3H)

[1325] Example 33: (R)-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)isonicotinic acid

[1326]

[1327] The desired product was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.20 g, 0.60 mmol) and methyl 2-aminoisonicotinate (0.10 g, 0.66 mmol) prepared in Preparation 1 (yield 71%).

[1328] 1H-NMR (500MHz, chloroform-D): δ8.46(s,1H),8.36(d,J=4.9Hz,1H),7.80(s,1H),7.68(s,1H),7.40(d,J=5.5Hz,1H),7.22(s ,1H),6.94(d,J=7.9Hz,1H),6.92-6.88(1H),6.86-6.82(m,1H),6.80-6.67(m,1H),4.38-4.28(1H),4.11(dd,J=13.1 ,3.4Hz,1H),4.05-3.96(m,2H),3.92(dt,J=13.4,3.8Hz,1H),3.88(s,3H),3.60(dd,J=13.1,7.6Hz,1H),3.51-3.35 (m,1H),2.13(s,1H),2.04(td,J=6.6,3.3Hz,1H),1.93(q,J=4.1Hz,1H),1.66(q,J=4.5Hz,1H),1.36(t,J=7.0Hz,3H)

[1329] The title compound was obtained by hydrolysis of the obtained ester compound (0.18 g, 0.40 mmol) in a similar manner to Example 1 (yield 57%).

[1330] 1 H-NMR (500MHz, DMSO-D6): δ9.76 (s, 1H), 8.31 (d, J = 5.5Hz, 2H), 8.04 (s, 1H), 7.66 (s, 1H), 7.24 ( d,J=5.5Hz,1H),6.96(d,J=7.3Hz,1H),6.87(s,1H),6.81(t,J=7.6Hz,1H),6.72(t,J=7.6Hz,1H) ,4.29(s,1H),3.93(d,J=13.4Hz,1H),3.89-3.76(m,2H),3.70(d,J=15.9Hz,1H),3.64-3.51(m,2 H),1.97(s,1H),1.84(s,1H),1.73(d,J=7.9Hz,1H),1.53(d,J=4.3Hz,1H),1.18(q,J=7.3Hz,3H)

[1331] Example 34: (R)-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)nicotinic acid

[1332]

[1333] The desired product was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.20 g, 0.60 mmol) and methyl 2-aminonicotinate (0.10 g, 0.66 mmol) prepared in Preparation 1 (yield 85%).

[1334] 1 H-NMR (500MHz, chloroform-D): δ10.40(s,1H),9.10(s,1H),8.46(q,J=2.2Hz,1H),8.28(dd,J=7.6,2.1Hz,1H),7.79(s ,1H),7.06(q,J=3.1Hz,1H),6.99-6.91(m,2H),6.88(q,J=3.3Hz,1H),6.83(q,J=4.3Hz,1H),4.31-4.22(m,2H) ,4.04(qd,J=6.9,2.3Hz,2H),3.98(t,J=4.6Hz,1H),3.95(s,3H),3.36(dd,J=14.1,9.2Hz,1H),3.33-3.23(m, 1H),2.22-2.13(m,1H),1.95(q,J=4.5Hz,1H),1.86(d,J=10.4Hz,1H),1.66-1.55(m,1H),1.41(t,J=7.0Hz,3H)

[1335] The title compound was obtained by hydrolysis of the obtained ester compound (0.21 g, 0.47 mmol) in a similar manner to Example 1 (yield 74%).

[1336] 1 H-NMR (500MHz, DMSO-D6): δ10.63(s,1H),8.91(s,1H),8.48(q,J=2.2Hz,1H),8.37-8.20(1 H),7.90(s,1H),7.11-6.97(m,2H),6.87(dt,J=12.2,4.9Hz,3H),4.43-4.20(m,1H),4.04(d ,J=12.8Hz,1H),3.95-3.79(m,2H),3.76-3.62(m,1H),3.59-3.42(m,2H),2.08-1.94(m,1H ),1.83(t,J=3.4Hz,1H),1.75(q,J=4.1Hz,1H),1.51(q,J=4.3Hz,1H),1.20(t,J=7.0Hz,3H)

[1337] Example 35: (R)-2-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)-2-methylpropanoic acid

[1338]

[1339] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (1.12 g, 3.35 mmol) prepared in Preparation Example 1 and methyl 2-(2-aminopyridin-4-yl)-2-methylpropanoate (650 mg, 3.35 mmol) prepared in Preparation Example 60 (1% yield over two steps).

[1340] 1 H-NMR (chloroform-D) δ8.31(s,1H),7.96(d,J=4.6Hz,1H),7.69(s,2H),6.97-6.73(5H),4.36(q,J=4.1Hz,1H),4.06-3.92(m,3H),3.89-3.75(1H),3 .46(t,J=10.2Hz,1H),3.38-3.22(m,1H),2.12(d,J=5.5Hz,1H),2.05(d,J=15.3Hz,1H),1.96(s,1H),1.80-1.54(7H),1.33(t,J=7.0Hz,3H)

[1341] Example 36: (R)-2-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)acetic acid

[1342]

[1343] The desired product was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.14 g, 0.42 mmol) prepared in Preparation Example 1 and methyl 2-(6-aminopyridin-3-yl)acetate (0.08 g, 0.46 mmol) prepared in Preparation Example 12 (yield 62%).

[1344] 1H-NMR (400MHz, chloroform-D): δ8.14(s,1H),7.87(s,1H),7.66(s,1H),7.62(d,J=8Hz ,1H),7.46(d,J=8Hz,1H),7.08(s,1H),6.99(m,2H),6.88(m,2H),4.32(m,1H), 4.29(m,1H),4.02(m,2H),3.87(m,1H),3.83(s,1H),3.56(s,2H),3.48(m,1H) ,3.34(m,1H),2.17(m,1H),2.02(m,1H),1.91(m,1H),1.66(m,1H),1.38(t,3H)

[1345] The title compound was obtained by hydrolysis of the obtained ester compound (0.11 g, 0.24 mmol) in a similar manner to Example 1 (yield 19%).

[1346] 1 H-NMR (400MHz, DMSO-D6): δ9.54(s,1H),8.10(s,1H),8.06(s,1H),7.67(s,1H ),7.60(d,J=8Hz,1H),7.41(d,J=6Hz,1H),7.04(d,J=8Hz,1H),6.95(m,2H),6 .84(m,1H),4.33(m,1H),4.10(m,1H),3.95(m,2H),3.72(m,1H),3.51(s,2H), 3.45(m,2H),2.04(m,1H),1.87(m,1H),1.75(m,1H),1.57(m,1H),1.25(t,3H)

[1347] Example 37: (R,E)-3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)acrylic acid

[1348]

[1349] The desired product was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.50 g, 1.50 mmol) prepared in Preparation Example 1 and (E)-methyl 3-(6-aminopyridin-3-yl)acrylate (0.29 g, 1.65 mmol) prepared in Preparation Example 13 (yield 70%).

[1350] 1H-NMR (500MHz, chloroform-D): δ8.35(s,1H),7.95-7.81(1H),7.71(s,1H),7.64(d,J=2.4Hz,2H),7.62(d,J=1 5.9Hz,1H),7.23(s,1H),7.01-6.92(m,2H),6.91-6.79(m,2H),6.34(d,J=16.5Hz,1H),4.33(d,J=4.3H z,1H),4.19-4.13(m,1H),4.05-3.96(m,2H),3.82(d,J=7.9Hz,4H),3.50(dd,J=12.8,7.9Hz,1H),3.36 (d,J=9.8Hz,1H),2.21-2.13(1H),2.06-1.97(1H),1.97-1.87(1H),1.66(s,1H),1.37(t,J=7.0Hz,3H)

[1351] The title compound was obtained by hydrolysis of the obtained ester compound (0.15 g, 0.32 mmol) in a similar manner to Example 1 (yield 82%).

[1352] 1 H-NMR (500MHz, DMSO-D6): δ10.71(s,1H),8.49(s,1H),8.16(s,1H),8.04(d,J=6.7 Hz,1H),7.88(s,1H),7.56-7.47(m,2H),6.97(d,J=6.1Hz,1H),6.86-6.81(1H),6.8 0-6.70(m,2H),6.47(d,J=15.9Hz,1H),4.45(s,1H),3.92-3.72(m,5H),3.61(s,1H ),1.96(d,J=7.9Hz,1H),1.84(d,J=29.3Hz,2H),1.55(s,1H),1.13(t,J=7.0Hz,3H)

[1353] Example 38: (R)-3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)propanoic acid

[1354]

[1355] (R,E)-3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)acrylic acid (0.3 g, 0.63 mmol) and Pd / C (67 mg) obtained in Example 37 were dissolved in 20 mL of methanol and reduced using a hydrogen balloon. After stirring at room temperature for 2 hours, the mixture was filtered and the organic solvent was removed under reduced pressure to provide the desired product (yield 63%).

[1356] 1 H-NMR (500 MHz, chloroform-D): δ8.09 (s, 1H), 7.83 (s, 1H), 7.63 (s, 1H), 7.58 (d, J = 8.6 Hz, 1H), 7.37-7.32 (m, 1H), 7.12 (s, 1H), 7.01-6.92 (m, 2H), 6.90-6.79 (m, 2H), 4.35-4.27 (m, 1H), 4.19 (d, J = 12.8 Hz, 1H), 4.05-3.97 (m, 2H), 3. 82(d,J=11.6Hz,1H),3.67(s,3H),3.42(dd,J=12.8,7.9Hz,1H),3.32(d,J=12.8Hz,1H),2.87(t,J=7.6Hz,2H) ,2.60(t,J=7.6Hz,2H),2.18(s,1H),2.03-1.95(1H),1.88(d,J=9.8Hz,1H),1.69(s,1H),1.37(t,J=7.0Hz,3H)

[1357] The title compound was obtained by hydrolysis of the obtained ester compound (0.15 g, 0.32 mmol) in a similar manner to Example 1 (yield 57%).

[1358] 1H-NMR (500MHz, DMSO-D6): δ9.44(s,1H),8.05(d,J=1.8Hz,1H),8.02(s,1H),7.62(s,1H),7.53(d,J=8.6Hz,1H),7.35(dd, J=8.6,2.4Hz,1H),7.00(dd,J=7.9,1.8Hz,1H),6.91(dd,J=7.9,1.2Hz,1H),6.87(td,J=7.6,1.8Hz,1H),6.78(td,J=7.6,1 .6Hz,1H),4.35-4.24(m,1H),4.06(d,J=12.8Hz,1H),3.97-3.85(m,2H),3.75-3.64(m,1H),3.47-3.31(m,2H),2.70(t,J=7 .6Hz,2H),2.47(t,J=1.5Hz,2H),2.02(s,1H),1.83(s,1H),1.70(d,J=9.2Hz,1H),1.60-1.48(m,1H),1.20(t,J=7.0Hz,3H)

[1359] Example 39: (R)-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)-2,2-dimethylpropanoic acid

[1360]

[1361] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (165 mg, 0.495 mmol) prepared in Preparation Example 1 and tert-butyl 3-(2-aminopyridin-4-yl)-2,2-dimethylpropanoate (124 mg, 0.495 mmol) prepared in Preparation Example 63 (yield 41% over 2 steps).

[1362] 1H-NMR (400 MHz, chloroform-D) δ9.06 (s, 1H), 8.01-7.82 (m, 2H), 7.60 (s, 1H), 7.55-7.45 (1H), 7.02-6.80 (m, 3H), 6.80-6.65 (m, 2H), 4.40-4.21 (m, 1H), 4.19-4.05 (m, 1H), 4.05-3.94 (m, 2H), 3.81-3.69 (m, 1H ),3.46(dd,J=13.3,7.8Hz,1H),3.40-3.22(m,1H),2.81-2.61(2H),2.15-2.03(m,1H),1.97(dd,J= 9.8,3.4Hz,1H),1.91-1.75(m,1H),1.72-1.49(m,1H),1.34(t,J=7.1Hz,3H),1.22(d,J=3.2Hz,6H)

[1363] Example 40: (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(5-phenylpyridin-2-yl)pyrazin-2-amine

[1364]

[1365] The title compound was obtained in a similar manner to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.1 g, 0.30 mmol) and 2-amino-(5-phenyl)pyridine (0.05 g, 0.30 mmol) prepared in Preparation Example 1 (yield 71%).

[1366] 1H-NMR (500MHz, chloroform-D) δ8.48(d,J=2.4Hz,1H),7.87(s,1H),7.78-7.70(2H),7.67(s,1H),7.61-7.52(m,2H),7.51-7.42(2H),7.35(t,J=7.3H z,1H),7.32(s,1H),7.06-6.98(1H),6.93(td,J=7.6,1.2Hz,1H),6.88(dd,J=7.9,1.8Hz,1H),6.82(td,J=7.5,1.6Hz,1H),4.41-4.29(m,1H) ,4.22(dd,J=12.8,3.7Hz,1H),4.10-3.94(m,2H),3.86(td,J=8.9,4.1Hz,1H),3.46(dd,J=12.8,7.9Hz,1H),3.39-3.31(m,1H),2.27-2.12( m,1H),2.08-1.98(m,1H),1.96-1.85(m,1H),1.83-1.51(m,3H),1.38(t,J=7.0Hz,3H),1.29(d,J=39.7Hz,1H),0.87(dd,J=26.3,19.6Hz,0H)

[1367] Example 41: (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(4-phenylpyridin-2-yl)pyrazin-2-amine

[1368]

[1369] The title compound was obtained in a manner similar to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.1 g, 0.30 mmol) prepared in Preparation Example 1 and 2-amino-(4-phenyl)pyridine (0.06 g, 0.36 mmol) prepared in Preparation Example 11 (yield 45%).

[1370] 1H-NMR (500MHz, chloroform-D) δ8.35(d,J=5.5Hz,1H),7.92(d,J=31.8Hz,1H),7.86-7.82(m,3H),7.65(d,J=37.3Hz,1H),7.50(s,1H) ,7.35(dt,J=19.0,7.2Hz,3H),7.29-7.26(m,1H),6.92(t,J=7.6Hz,2H),6.84(d,J=7.9Hz,1H),6.78(t,J=7.6Hz,1H),5.53(s ,1H),4.41-4.26(m,1H),4.11(q,J=7.1Hz,1H),4.06-3.88(m,3H),3.85-3.70(m,1H),3.61(q,J=6.7Hz,1H),3.54-3.39(m,1H ),2.18-2.06(m,2H),2.05-1.98(m,2H),1.97-1.85(m,1H),1.63(qd,J=8.8,4.3Hz,1H),1.44-1.30(m,3H),1.29-1.14(m,2H)

[1371] Example 42: (R)-2-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl)-2-methylpropanoic acid

[1372]

[1373] The title compound was obtained in a manner similar to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.237 g, 0.709 mmol) prepared in Preparation Example 1 and methyl 2-(3-(2-aminopyridin-4-yl)phenyl)-2-methylpropanoate (0.230 g, 0.851 mmol) prepared in Preparation Example 27 (yield 56%).

[1374] 1H-NMR (500MHz, chloroform-D) δ8.27(s,1H),8.16-8.05(1H),7.81(s,1H),7.66(s,2H),7.50(d,J=8.5Hz,2H),7.40 (t,J=7.6Hz,1H),7.05(d,J=5.5Hz,1H),6.93-6.84(m,2H),6.81(d,J=7.0Hz,1H),6.77-6.65(m,1H),4.29( d,J=3.7Hz,1H),4.10(d,J=3.1Hz,1H),3.94(t,J=7.0Hz,2H),3.90-3.79(1H),3.58(dd,J=13.1,7.6Hz,1H) ,3.42(s,1H),2.08(m,1H),1.94-1.84(m,2H),1.71(d,J=8.2Hz,6H),1.67-1.55(1H),1.33(t,J=7.0Hz,3H)

[1375] Example 43: (R)-2-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl)-2-methylpropanoic acid

[1376]

[1377] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.329 g, 0.986 mmol) prepared in Preparation Example 1 and methyl 2-(4-(2-aminopyridin-4-yl)phenyl)-2-methylpropanoate (0.32 g, 1.184 mmol) prepared in Preparation Example 26 (yield 1%).

[1378] 1H-NMR (400 MHz, chloroform-D) δ9.51 (s, 1H), 8.45 (d, J = 8.7 Hz, 1H), 8.13-7.99 (m, 1H), 7.78 (d, J = 10.1 Hz, 1H), 7.71-7.62 (m, 1H), 7.59 (d, J = 8.7 Hz, 2H), 7.49 (t, J = 9.1 Hz, 2H), 7.13-7.01 (m, 1H), 6.93 -6.66(m,4H),4.36-4.23(m,1H),4.16-4.02(m,1H),3.99-3.87(m,2H),3.87-3.77(m,1H),3.5 7(dd,J=13.0,7.5Hz,1H),3.47-3.36(m,1H),2.16-1.79(m,3H),1.61(s,7H),1.35-1.25(m,3H)

[1379] Example 44: (R)-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl)-2,2-dimethylpropanoic acid

[1380]

[1381] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (210 mg, 0.629 mmol) prepared in Preparation Example 1 and methyl 3-(3-(2-aminopyridin-4-yl)phenyl)-2,2-dimethylpropanoate (179 mg, 0.629 mmol) prepared in Preparation Example 58 (4% yield over two steps).

[1382] 1H-NMR (chloroform-D) δ10.10(s,1H),8.27(s,1H),7.68(d,J=5.5Hz,1H),7.62(s,1H),7.52(s,1H),7.37(d,J=7.9Hz,1H),7.33(t,J=7.5 Hz,1H),7.20(d,J=7.3Hz,1H),6.93(s,1H),6.80(dd,J=14.6,7.9Hz,2H),6.74(d,J=7.9Hz,1H),6.63(t,J=7.6Hz,1H),6.51(d, J=4.9Hz,1H),4.37-4.29(m,1H),4.00(dd,J=13.1,2.7Hz,1H),3.93-3.87(m,2H),3.86-3.79(m,1H),3.65(dd,J=12.4,7.8Hz,1 H),3.56-3.47(m,1H),2.94(dd,J=29.1,13.0Hz,2H),2.16-2.11(m,1H),2.07-1.90(m,2H),1.73-1.62(m,1H),1.36-1.29(m,9H)

[1383] Example 45: (R)-3-(4-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl)-2,2-dimethylpropanoic acid

[1384]

[1385] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (175 mg, 0.524 mmol) prepared in Preparation Example 1 and tert-butyl 3-(4-(2-aminopyridin-4-yl)phenyl)-2,2-dimethylpropanoate (171 mg, 0.524 mmol) prepared in Preparation Example 71 (20% yield over 2 steps).

[1386] 1H-NMR (400 MHz, chloroform-D) δ9.13 (s, 1H), 8.43-8.28 (1H), 8.08 (d, J = 5.5 Hz, 1H), 7.70 (s, 1H), 7.59 (s, 1H), 7.46 (d, J = 8.2 Hz, 2H), 7.23 (d, J = 8.2 Hz, 2H), 7.02 (d, J = 5.5 Hz, 1H), 6.96-6.64 (m, 4H), 4.34-4.18 (m, 1H), 4.01 (d, J =12.8Hz,1H),3.93(q,J=7.0Hz,2H),3.79(d,J=12.8Hz,1H),3.50(dd,J=12.8,7.8Hz,1H),3.43-3.25(1H),2 .90(s,2H),2.09-1.99(m,1H),1.98-1.87(m,1H),1.87-1.73(m,1H),1.66-1.45(m,1H),1.29(q,J=6.9Hz,9H)

[1387] Example 46: (R)-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl)propanoic acid

[1388]

[1389] Step 1: (R)-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrrolidone Methyl 4-pyridin-4-yl)phenyl)propanoate

[1390] The desired product was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.189 g, 0.568 mmol) prepared in Preparation Example 1 and methyl 3-(3-(2-aminopyridin-4-yl)phenyl)propanoate (0.160 g, 0.624 mmol) prepared in Preparation Example 56 (yield 64%).

[1391] 1H-NMR (chloroform-D) δ8.32(d,J=5.2Hz,1H),8.03(s,1H),7.92(s,1H),7.75-7.63(1H),7.56-7.45(m,2H),7.37(t,J=7.5Hz,1H),7.28-7.24 (1H),7.22(s,1H),7.17-7.02(m,1H),7.01-6.89(m,2H),6.89-6.83(m,1H),6.79(td,J=7.6,1.5Hz,1H),4.40-4.25(m,1H),4.22-4. 09(m,1H),4.04-3.95(m,2H),3.93(dt,J=13.1,4.8Hz,1H),3.70(s,3H),3.58(dd,J=13.1,7.9Hz,1H),3.51-3.37(m,1H),3.03(t,J= 7.9Hz,2H),2.69(t,J=7.8Hz,2H),2.24-2.11(m,1H),2.05-1.97(m,1H),1.97-1.84(m,1H),1.76-1.66(m,1H),1.37(t,J=6.9Hz,3H)

[1392] Step 2: (R)-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrrolidone (4-pyridin-4-yl)phenyl)propionic acid

[1393] Methyl (R)-3-(3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-4-yl)phenyl)propanoate (0.090 g, 0.163 mmol) obtained in Step 1 was dissolved in methanol (0.813 ml) and THF (0.813 ml), and then a 7N aqueous sodium hydroxide solution (0.232 ml, 1.626 mmol) was added and stirred at room temperature for 4 hours. After removing the solvent under reduced pressure, it was dissolved in ethyl acetate and washed with water. The title compound was obtained by purification on a silica gel column (yield 29%).

[1394] m / z(M+H) + C 31 H 34 The calculated value of N5O4 is 540, and the measured value is 540

[1395] Example 47: (R)-3-(3-(5-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)phenyl)-2,2-dimethylpropanoic acid

[1396]

[1397] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (20.3 mg, 0.0610 mmol) prepared in Preparation Example 1 and methyl 3-(3-(5-aminopyridin-3-yl)phenyl)-2,2-dimethylpropanoate (17.3 mg, 0.0610 mmol) prepared in Preparation Example 83 (yield 29% over 2 steps).

[1398] 1 H-NMR (400MHz, chloroform-D) δ8.50(s,1H),8.24(d,J=17.4Hz,2H),7.81(s,1H),7.47(s,1H),7.43(s,1H),7.32( t,J=7.5Hz,2H),7.24(s,1H),7.14(d,J=7.3Hz,1H),6.90(d,J=7.8Hz,1H),6.84(t,J=7.8Hz,1H),6.77(d ,J=6.9Hz,1H),6.74-6.61(1H),4.40(s,1H),4.04-3.70(m,4H),3.59(d,J=12.8Hz,1H),3.48(d,J=6.9Hz ,1H),3.06-2.80(m,2H),2.15-1.81(m,3H),1.56(d,J=4.6Hz,1H),1.32-1.30(3H),1.29(d,J=3.7Hz,6H)

[1399] Example 48: (R)-3-(3-(5-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid

[1400]

[1401] The title compound was obtained in a manner similar to that in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (51.9 mg, 0.155 mmol) prepared in Preparation Example 1 and methyl 3-(3-(5-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate (44.2 mg, 0.155 mmol) prepared in Preparation Example 102 (yield 60% over 2 steps).

[1402] 1H-NMR (400 MHz, chloroform-D) δ8.54 (d, J = 2.7 Hz, 1H), 7.87-7.70 (m, 3H), 7.41 (s, 1H), 7.40-7.31 (m, 2H), 7.20 (d, J = 7.3 Hz, 1H), 7.14 (s, 1H), 6.98-6.84 (m, 3H), 6.84-6.74 (m, 1H), 6.70 (s, 1H), 4.37-4.19 (1H), 4.11-3.94 (m, 2H), 3.94-3.84 (m,1H),3.62-3.53(m,1H),3.49(dd,J=12.6,7.5Hz,1H),3.31-3.15(m,1H),2.99(dd,J=19.7,13.3Hz,2H),2.05(d, J=4.6Hz,1H),2.00-1.90(m,1H),1.90-1.77(m,1H),1.64-1.48(m,1H),1.35(t,J=7.1Hz,3H),1.30(d,J=4.6Hz,6H)

[1403] Example 49: (R)-2-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-3-yl)phenyl)-2-methylpropanoic acid

[1404]

[1405] The title compound was obtained in a manner similar to that in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (137 mg, 0.409 mmol) prepared in Preparation Example 1 and methyl 2-(6-aminopyridin-3-yl)-2-methylpropanoate (79.5 mg, 0.409 mmol) prepared in Preparation Example 19 (30% yield over 2 steps).

[1406] 1H-NMR (400 MHz, chloroform-D) δ 10.36 (s, 1H), 8.21 (s, 1H), 8.07 (d, J = 9.1 Hz, 1H), 7.71 (s, 1H), 7.67-7.51 (2H), 7.06-6.70 (m, 4H), 4.42-4.25 (m, 1H), 4.19 (dd, J = 13.0, 3.4 Hz, 1H), 4.09-3.89 (m, 2H ),3.81(td,J=8.8,4.1Hz,1H),3.42(dd,J=12.8,8.2Hz,1H),3.36-3.21(m,1H),2.17(t,J=6. 2Hz,1H),2.01(dd,J=9.6,3.7Hz,1H),1.95-1.78(m,1H),1.77-1.46(m,7H),1.44-1.19(m,3H)

[1407] Example 50: (R)-2-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-2-methylpropanoic acid

[1408]

[1409] The title compound was obtained in the same manner as in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (56.1 mg, 0.168 mmol) prepared in Preparation Example 1 and ethyl 2-(6-aminopyridin-2-yl)-2-methylpropanoate (35.0 mg, 0.168 mmol) prepared in Preparation Example 61 (yield 39% over 2 steps).

[1410] 1 H-NMR (400 MHz, chloroform-D) δ 8.05 (s, 1H), 7.65 (s, 1H), 7.62-7.49 (m, 2H), 7.45 (d, J = 8.7 Hz, 1H), 7.06-6.73 (m, 5H), 4.41-4.22 (m, 1H), 4.11 (dd, J = 13.0, 3.4 Hz, 1H), 4.06-3.87 (m, 2H), 3.77 (td ,J=8.9,4.1Hz,1H),3.51(dd,J=13.3,7.8Hz,1H),3.44-3.26(m,1H),2.24-2.10(m,1H),2.04 -1.94(m,1H),1.94-1.79(m,1H),1.65(d,J=2.7Hz,6H),1.63-1.44(m,1H),1.40-1.30(m,3H)

[1411] Example 51: (R)-3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-2,2-dimethylpropanoic acid

[1412]

[1413] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (151 mg, 0.451 mmol) prepared in Preparation Example 1 and tert-butyl 3-(6-aminopyridin-2-yl)-2,2-dimethylpropanoate (113 mg, 0.451 mmol) prepared in Preparation Example 62 (27% yield over 2 steps).

[1414] 1 H-NMR (chloroform-D) δ9.67(s,1H),7.91(d,J=8.2Hz,1H),7.61(s,1H),7.56(s,1H),7.42(t,J=7.9Hz,1H),7.04-6.90(m,2H),6. 87(d,J=7.6Hz,1H),6.80(t,J=7.6Hz,1H),6.69(d,J=7.3Hz,1H),4.28(td,J=8.1,4.0Hz,1H),4.23-4.14(m,1H),4.05-3 .90(m,2H),3.81(q,J=4.4Hz,1H),3.37(dd,J=13.0,8.1Hz,1H),3.26(t,J=9.9Hz,1H),2.99(t,J=14.5Hz,2H),2.18-2.1 1(m,1H),1.97(dd,J=9.2,4.0Hz,1H),1.92-1.78(m,1H),1.72-1.54(m,1H),1.36(t,J=6.9Hz,3H),1.26(d,J=4.0Hz,6H)

[1415] Example 52: 1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)pyrrolidine-3-carboxylic acid

[1416]

[1417] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.093 g, 0.280 mmol) prepared in Preparation Example 1 and 1-(6-aminopyridin-2-yl)pyrrolidine-3-carboxylic acid methyl ester (0.065 g, 0.294 mmol) prepared in Preparation Example 38 (yield 22%).

[1418] 1 H-NMR (500MHz, chloroform-D) δ8.58(s,1H),7.65(s,1H),7.33(t,J=7.9Hz,1H),7.09-6.92(m,2H),6.92-6.81(m,2H),6.42(d,J=6. 4Hz,1H),5.94(d,J=8.2Hz,1H),4.40-4.25(1H),4.16(d,J=12.8Hz,1H),4.10-3.97(2H),3.92(t,J=9.0Hz,1H),3.88-3.77 (m,2H),3.68-3.55(m,1H),3.52-3.42(m,2H),3.42-3.29(m,1H),3.23(t,J=7.0Hz,1H),2.40(dt,J=20.0,7.6Hz,1H),2.30 (td,J=12.2,7.0Hz,1H),2.23-2.13(m,1H),2.05-1.95(m,1H),1.95-1.81(m,1H),1.76-1.50(m,1H),1.39(t,J=7.0Hz,3H)

[1419] Example 53: 1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-3-methylpyrrolidine-3-carboxylic acid

[1420]

[1421] The title compound was obtained in a manner similar to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.068 g, 0.202 mmol) prepared in Preparation Example 1 and 1-(6-aminopyridin-2-yl)-3-methylpyrrolidine-3-carboxylic acid methyl ester (0.050 g, 0.213 mmol) prepared in Preparation Example 49 (yield 40%).

[1422] 1H-NMR (500MHz, chloroform-D) δ11.21-9.78(1H),8.62(d,J=16.5Hz,1H),7.75-7.62(m,1H),7.33(t,J=7.9Hz,1H),7.04-6.99(m,1H ),6.99-6.93(m,1H),6.93-6.83(2H),6.48-6.32(m,1H),6.02-5.86(m,1H),4.40-4.24(m,1H),4.17(dd,J=13.1,3.1Hz,1H ),4.12-3.91(m,3H),3.82(td,J=8.8,4.1Hz,1H),3.66-3.53(m,2H),3.50(s,1H),3.48(t,J=6.7Hz,1H),3.43-3.25(m,1H) ,2.70-2.53(m,1H),2.16(dd,J=12.4,5.6Hz,1H),2.03-1.80(m,3H),1.75-1.57(m,1H),1.47(s,3H),1.39(t,J=6.9Hz,3H)

[1423] Example 54: 1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidine-3-carboxylic acid

[1424]

[1425] Step 1: 1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridine- 2-aminobenzoic acid ethyl ester

[1426] The desired product was obtained in a manner similar to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.224 g, 0.670 mmol) prepared in Preparation Example 1 and 1-(6-aminopyridin-2-yl)piperidine-3-carboxylic acid ethyl ester (0.192 g, 0.770 mmol) prepared in Preparation Example 65 (yield 38%).

[1427] 1H-NMR (chloroform-D) δ8.14(d,J=23.8Hz,1H),7.73-7.57(1H),7.42-7.32(1H),7.03(d,J=7.9Hz,1H),6.97(t,J=7.6Hz,1H),6.94-6.77(m,3H) ,6.70(d,J=7.9Hz,1H),6.27(d,J=8.2Hz,1H),4.32(d,J=10.4Hz,2H),4.26-4.09(m,4H),4.09-3.93(m,2H),3.88(d,J=12.8Hz,1H),3.4 2(dd,J=13.0,8.1Hz,1H),3.36-3.23(m,1H),3.23-3.08(m,1H),3.00(t,J=11.9Hz,1H),2.68-2.50(1H),2.19(d,J=7.3Hz,1H),2.09(d, J=13.1Hz,1H),1.99(d,J=9.8Hz,1H),1.94-1.84(m,1H),1.84-1.70(m,2H),1.70-1.48(m,2H),1.40(t,J=6.9Hz,3H),1.34-1.12(m,3H)

[1428] Step 2: 1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridine- 2-aminobenzoic acid

[1429] Ethyl 1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidine-3-carboxylate (0.140 g, 0.256 mmol) obtained in Step 1 was dissolved in ethanol (1.280 ml) and THF (1.280 ml), and then a 6N aqueous sodium hydroxide solution (0.427 ml, 2.56 mmol) was added and stirred at room temperature for 6 hours. After removing the solvent under reduced pressure, it was dissolved in ethyl acetate and washed with water. The title compound was obtained by purification on a silica gel column (yield 52%).

[1430] m / z(M+H) + C 28 H 35 The calculated value of N6O4 is 519, and the measured value is 519

[1431] Example 55: (R)-1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidine-3-carboxylic acid

[1432]

[1433] Step 1: (R)-1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrrolidone 2-pyridin-2-yl)piperidine-3-carboxylic acid ethyl ester

[1434] The desired product was obtained in a manner similar to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.370 g, 1.108 mmol) prepared in Preparation Example 1 and (R)-1-(6-aminopyridin-2-yl)piperidine-3-carboxylic acid ethyl ester (0.290 g, 1.163 mmol) prepared in Preparation Example 31 (yield 33%).

[1435] 1 H-NMR (500MHz, chloroform-D) δ8.13(s,1H),7.65(s,1H),7.37(t,J=7.9Hz,1H),7.08-6.84(m,4H),6.78-6.64(m,2H), 6.28(d,J=8.2Hz,1H),4.42-4.27(m,2H),4.27-4.09(m,4H),4.04(t,J=6.0Hz,2H),3.91(s,1H),3.43(dd,J=1 3.0,8.1Hz,1H),3.31(s,1H),3.24-3.09(m,1H),3.01(s,1H),2.60(s,1H),2.19(s,1H),2.10(d,J=27.2Hz,1H ),2.05-1.95(1H),1.95-1.85(1H),1.81(d,J=13.4Hz,2H),1.66(s,2H),1.46-1.38(3H),1.30(t,J=7.2Hz,3H)

[1436] Step 2: (R)-1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrrolidone pyridin-2-yl)piperidine-3-carboxylic acid

[1437] The title compound was obtained in a similar manner to step 2 of Example 54 using (R)-ethyl 1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidine-3-carboxylate (0.200 g, 0.366 mmol) obtained in step 1 (30% yield).

[1438] m / z(M+H) + C 28 H 35 The calculated value of N6O4 is 519, and the measured value is 519

[1439] Example 56: (R)-1-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidine-4-carboxylic acid

[1440]

[1441] The title compound was obtained in a manner similar to Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.306 g, 0.917 mmol) prepared in Preparation Example 1 and 1-(6-aminopyridin-2-yl)piperidine-4-carboxylic acid ethyl ester (0.240 g, 0.963 mmol) prepared in Preparation Example 29 (yield 38%).

[1442] 1 H-NMR (500MHz, chloroform-D) δ8.66 (s, 1H), 7.70-7.62 (1H), 7.39 (t, J = 7.9Hz, 1H), 7.05-6.87 (m, 4H), 6.73 (s, 1H),6.25(q,J=4.1Hz,2H),4.43-4.28(m,1H),4.24(dd,J=12.8,4.3Hz,2H),4.15(q,J=7.2Hz,2H),3.82 (d,J=18.3Hz,1H),3.54(dd,J=12.8,7.6Hz,1H),3.46-3.30(m,1H),3.04(t,J=11.4Hz,2H),2.60(d,J= 10.7Hz,1H),2.16(d,J=12.2Hz,3H),2.02(s,1H),1.96-1.79(m,3H),1.65(s,1H),1.40(t,J=7.0Hz,3H)

[1443] Example 57: (R)-2-(1-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid

[1444]

[1445] The title compound was obtained in a manner similar to that described in Example 12 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.237 g, 0.710 mmol) obtained in Preparation Example 1 and ethyl 2-(1-(6-aminopyridin-2-yl)piperidin-4-yl)acetate (0.17 g, 0.646 mmol) obtained in Preparation Example 36 (11% yield over two steps).

[1446] 1H-NMR (400 MHz, chloroform-D) δ8.25 (d, J = 15.6 Hz, 1H), 7.63-7.54 (m, 1H), 7.33 (t, J = 8.2 Hz, 1H), 7.05-6.90 (m, 2H), 6.90-6.78 (m, 2H), 6.58 (d, J = 7.8 Hz, 1H), 6.24-6.16 (m, 1H), 5.28 (s, 1H), 4.39-4.25 (m, 1H), 4.24-4.10 (m, 3H), 4.0 7-3.91(m,2H),3.88-3.75(m,1H),3.53-3.36(1H),3.36-3.24(m,1H),2.86(t,J=11.7Hz,2H),2.37-2.20(m,2H) ,2.20-2.10(m,1H),2.07-2.01(m,1H),2.01-1.92(1H),1.92-1.77(m,3H),1.73-1.53(m,1H),1.44-1.29(m,5H)

[1447] Example 58: (R)-2-(1-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidin-4-yl)-2-methylpropanoic acid

[1448]

[1449] The title compound was obtained in a manner similar to that described in Example 12 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.093 g, 0.278 mmol) obtained in Preparation Example 1 and methyl 2-(1-(6-aminopyridin-2-yl)piperidin-4-yl)-2-methylpropanoate (0.07 g, 0.252 mmol) obtained in Preparation Example 34 (yield 49% over 2 steps).

[1450] 1H-NMR (400 MHz, chloroform-D) δ8.20 (s, 1H), 7.59 (s, 1H), 7.38 (s, 1H), 7.32 (q, J = 8.1 Hz, 1H), 7.04-6.90 (m, 2H), 6.90-6.79 (2H), 6.64 (d, J = 7.8 Hz, 1H), 6.20 (d, J = 8.2 Hz, 1H), 4.29 (q, J = 4.1 Hz, 3H), 4.22-4.13 (m, 1H), 4.06-3.91 (m, 2H), 3.82 (q, J = 4.4 Hz, 1H), 3.42 (dd,J=13.0,8.0Hz,1H),3.36-3.23(1H),2.86-2.69(m,2H),2.23-2.10(m,1H),1.96(dd,J=9.6,3.7Hz,1H),1.91-1.77(m,2H) ,1.72(d,J=11.9Hz,2H),1.67-1.52(m,1H),1.52-1.40(m,1H),1.40-1.29(m,3H),1.24(q,J=7.3Hz,1H),1.15(d,J=16.9Hz,6H)

[1451] Example 59: 2-(((S)-1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidin-3-yl)acetic acid

[1452]

[1453] The desired title compound was obtained in a manner similar to Example 19 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.047 g, 0.139 mmol) prepared in Preparation Example 1 and (S)-tert-butyl 2-((1-(6-aminopyridin-2-yl)piperidin-3-yl)oxy)acetate (0.045 g, 0.146 mmol) prepared in Preparation Example 45 (yield 11.4%).

[1454] 1H-NMR (500MHz, chloroform-D) δ8.66(s,1H),7.68(s,1H),7.36(t,J=7.9Hz,1H),7.07-6.93(2H),6.89(t,J= 7.3Hz,2H),6.34(s,1H),6.25-6.15(1H),4.78-4.44(1H),4.31(s,2H),4.19-4.06(2H),4.06-3.93 (2H),3.77(s,1H),3.64(s,1H),3.59-3.44(m,2H),3.44-3.28(1H),3.15(s,1H),3.00(s,1H),2.13 (s,1H),2.08(d,J=13.1Hz,1H),2.02-1.93(1H),1.93-1.80(2H),1.60(s,3H),1.39(t,J=7.0Hz,3H)

[1455] Example 60: (R)-2-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2-methylpropanoic acid

[1456]

[1457] The desired title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (74.1 mg, 0.222 mmol) prepared in Preparation Example 1 and methyl 2-(3-(6-aminopyridin-2-yl)phenyl)-2-methylpropanoate (60.0 mg, 0.222 mmol) prepared in Preparation Example 52 (yield 66% over 2 steps).

[1458] 1H-NMR (400 MHz, chloroform-D) δ8.84 (s, 1H), 8.23 ​​(s, 1H), 7.68 (d, J = 9.1 Hz, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.51-7.36 (m, 2H), 7.33 (s, 1H), 7.28 (s, 1H), 7.05-6.92 (m, 3H), 6.88 (dq, J = 9.7, 1.9 Hz, 2H), 4.33 (td, J = 7.8, 3.8 Hz,1H),4.14(dd,J=12.8,3.2Hz,1H),4.08-3.90(2H),3.82(q,J=4.4Hz,1H),3.52(dd,J=12.8,7.8Hz,1 H),3.46-3.28(m,1H),2.00(d,J=9.6Hz,2H),1.95-1.80(m,1H),1.74-1.53(m,7H),1.38(t,J=7.1Hz,3H)

[1459] Example 61: (R)-2-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2-methylpropanoic acid

[1460]

[1461] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (61.7 mg, 0.185 mmol) prepared in Preparation Example 1 and methyl 2-(4-(6-aminopyridin-2-yl)phenyl)-2-methylpropanoate (50.0 mg, 0.185 mmol) prepared in Preparation Example 54 (16% yield over two steps).

[1462] 1H-NMR (400 MHz, chloroform-D) δ9.10 (s, 1H), 8.01 (s, 1H), 7.86-7.71 (m, 3H), 7.68 (s, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.47 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 7.3 Hz, 1H), 7.08-6.74 (m, 4H), 4.43-4.26 (m, 1H), 4.20 (dd, J = 13.3, 3.2 Hz,1H),4.11-3.93(m,2H),3.85(q,J=4.4Hz,1H),3.49(dd,J=13.0,8.0Hz,1H),3.43-3.26(m,1H),2.28- 2.09(m,1H),2.09-1.97(m,1H),1.96-1.80(m,1H),1.78-1.65(m,1H),1.63(s,6H),1.38(t,J=6.9Hz,3H)

[1463] Example 62: (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

[1464]

[1465] The title compound was obtained in a manner similar to that described in Example 12 using (R)-2-chloro-6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine (0.272 g, 0.814 mmol) obtained in Preparation Example 3 and methyl 2-(4-(6-aminopyridin-2-yl)phenyl)-2-methylpropanoate (0.2 g, 0.740 mmol) obtained in Preparation Example 54 (yield 43% over 2 steps).

[1466] 1H-NMR (400 MHz, methanol-D4) δ 8.30-8.19 (m, 1H), 7.97 (td, J = 4.3, 2.3 Hz, 2H), 7.65-7.49 (m, 3H), 7.46 (dd, J = 8.7, 2.3 Hz, 2H), 7.29 (ddd, J = 19.4, 7.8, 2.5 Hz, 2H), 7.07-6.94 (m, 1H), 6.82-6.64 (m, 1H), 5 .18(d,J=2.7Hz,1H),4.12-4.02(m,2H),3.90-3.79(m,2H),3.79-3.69(m,2H),3.66-3.48(1H),2 .20-2.00(m,2H),1.96(d,J=4.6Hz,1H),1.70-1.60(1H),1.57(d,J=2.3Hz,6H),1.22-1.19(m,3H)

[1467] Example 63: (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid

[1468]

[1469] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (81.0 mg, 0.242 mmol) prepared in Preparation Example 1 and tert-butyl 3-(3-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate (79.0 mg, 0.242 mmol) prepared in Preparation Example 113 (yield 77% over 2 steps).

[1470] 1H-NMR (400MHz, chloroform-D) δ9.57(s,1H),8.22(s,1H),7.68(d,J=7.8Hz,1H),7.65(s,1H),7.60(t,J=7.8Hz,1H),7.33(t, J=7.5Hz,2H),7.15(d,J=7.8Hz,1H),7.08-6.82(4H),6.78(s,1H),6.58(d,J=8.2Hz,1H),4.42-4.23(m,1H),4.17-4. 04(m,1H),4.04-3.88(m,2H),3.80(dt,J=13.3,4.9Hz,1H),3.56(dd,J=13.0,7.5Hz,1H),3.44-3.28(m,1H),3.01(s ,2H),2.21-2.08(m,1H),2.08-1.94(m,1H),1.94-1.80(m,1H),1.72-1.50(m,1H),1.38(t,J=7.1Hz,3H),1.25(s,6H)

[1471] Example 64: (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

[1472]

[1473] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine (205 mg, 0.613 mmol) prepared in Preparation Example 3 and tert-butyl 3-(3-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate (200 mg, 0.613 mmol) prepared in Preparation Example 113 (yield 39% over 2 steps).

[1474] 1H-NMR (chloroform-D) δ9.54(s,1H),8.24(s,1H),7.77(d,J=5.2Hz,1H),7.70(d,J=4.6Hz,2H),7.62(t,J=7.9Hz,1 H),7.36(d,J=7.6Hz,2H),7.18(d,J=7.6Hz,1H),6.93(d,J=7.6Hz,1H),6.83(dd,J=7.6,5.2Hz,1H),6.61( s,1H),6.55(d,J=7.9Hz,1H),5.30-5.14(1H),4.05-3.80(4H),3.80-3.68(1H),3.68-3.54(1H),3.12-2.9 0(2H),2.28-2.12(1H),2.12-1.93(2H),1.78-1.63(1H),1.33-1.29(3H),1.29-1.27(3H),1.27-1.24(3H)

[1475] Example 65: (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyridin-2-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid

[1476]

[1477] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyridine (204 mg, 0.613 mmol) prepared in Preparation Example 4 and tert-butyl 3-(3-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate (200 mg, 0.613 mmol) prepared in Preparation Example 113 (yield 12% over 2 steps).

[1478] 1H-NMR (400 MHz, methanol-D4) δ7.80 (d, J = 8.7 Hz, 2H), 7.63-7.47 (m, 2H), 7.44 (t, J = 8.0 Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 2H), 7.04-6.70 (m, 5H), 6.28 (d, J = 8.2 Hz, 1H), 4.41-4.22 (m, 1H), 4.12 (d, J = 1 1.4Hz,1H),4.04-3.87(m,2H),3.76(d,J=12.8Hz,1H),3.47-3.32(m,2H),2.96(s,2H),2.15-2.03(m,1H ),1.94(td,J=6.6,3.2Hz,1H),1.88-1.72(m,1H),1.71-1.53(m,1H),1.31(t,J=6.9Hz,3H),1.21(s,6H)

[1479] Example 66: (R)-3-(3-(6-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid

[1480]

[1481] The title compound was obtained in a manner similar to Example 22 using (R)-4-chloro-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine (205 mg, 0.613 mmol) prepared in Preparation Example 5 and tert-butyl 3-(3-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate (200 mg, 0.613 mmol) prepared in Preparation Example 113 (yield 49% over 2 steps).

[1482] 1H-NMR (chloroform-D) δ8.28(s,1H),7.98(d,J=5.8Hz,1H),7.76(s,1H),7.67(d,J=7.6Hz,1H),7.45(t,J=7.3Hz,2H),7.33(t,J=7.6Hz,1H),7.2 0(d,J=7.6Hz,1H),7.12(d,J=7.3Hz,1H),7.04(d,J=7.9Hz,1H),6.96-6.86(m,2H),6.83(d,J=7.6Hz,1H),6.46(s,1H),4.51(d,J=12.8 Hz,1H),4.39-4.24(m,1H),4.19(q,J=4.5Hz,1H),4.08-3.86(m,2H),3.48(d,J=21.4Hz,1H),3.37(d,J=12.8Hz,1H),2.96(s,2H),2.20 (dd,J=15.4,4.1Hz,1H),1.94(dt,J=9.2,3.8Hz,1H),1.88(dd,J=9.9,3.5Hz,1H),1.70-1.56(m,1H),1.37(t,J=6.9Hz,3H),1.24(s,6H)

[1483] Example 67: (R)-3-(3-(6-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-2-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid

[1484]

[1485] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-4-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine (205 mg, 0.613 mmol) prepared in Preparation Example 6 and tert-butyl 3-(3-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate (200 mg, 0.613 mmol) prepared in Preparation Example 113 (46% yield over 2 steps).

[1486] 1H-NMR (400MHz, methanol-D4) δ8.23(d,J=6.4Hz,1H),7.84(s,1H),7.76(t,J=7.1Hz,2H),7.48(t,J= 7.3Hz,2H),7.38(t,J=7.5Hz,1H),7.28(d,J=7.8Hz,1H),7.00(d,J=7.3Hz,1H),6.96-6.76(m, 3H),6.45(d,J=5.9Hz,1H),4.55(s,1H),4.28-4.01(m,2H),4.01-3.73(m,3H),3.59(d,J=9.1 Hz,1H),2.95(s,2H),2.15-1.98(m,3H),1.76-1.58(m,1H),1.30(t,J=6.9Hz,3H),1.21(s,6H)

[1487] Example 68: (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

[1488]

[1489] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-4-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrimidine (205 mg, 0.613 mmol) prepared in Preparation Example 7 and tert-butyl 3-(3-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate (200 mg, 0.613 mmol) prepared in Preparation Example 113 (29% yield over 2 steps).

[1490] 1 H-NMR (400 MHz, chloroform-D) δ9.40 (s, 1H), 8.16 (s, 1H), 7.82 (s, 2H), 7.70 (d, J = 7.8 Hz, 1H), 7.60 (s, 1H), 7.49 (d, J = 20.1 Hz, 1H), 7.36-7.27 (m, 2H), 7.21 (d, J = 7.3 Hz, 1H), 6.98 (d, J = 7.3 Hz, 1H ),6.69(s,1H),6.05(s,1H),5.28(t,J=2.7Hz,1H),4.09-3.82(m,4H),3.70(s,2H),3.02(d, J=13.3Hz,2H),2.16-1.94(m,3H),1.69(s,1H),1.30(t,J=7.1Hz,3H),1.26(d,J=1.4Hz,6H)

[1491] Example 69: (R)-3-(3-(3-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-1H-pyrazol-1-yl)phenyl)-2,2-dimethylpropanoic acid

[1492]

[1493] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.10 g, 0.30 mmol) prepared in Preparation Example 1 and methyl 3-(3-(3-amino-1H-pyrazol-1-yl)phenyl)-2,2-dimethylpropanoate (0.094 g, 0.30 mmol) obtained in Preparation Example 67 (yield 40%).

[1494] 1 H-NMR (400 MHz, chloroform-D): δ8.53 (s, 1H), 7.61 (s, 2H), 7.57 (s, 1H), 7.50 (s, 1H), 7.35-7.27 (m, 2H), 7.06 (t, J = 2.5 Hz, 1H), 7.00-6.88 (m, 2H), 6.88-6.72 (m, 2H), 6.51 (d, J = 2.3 Hz, 1H), 4.25 (t, J = 3.9 Hz, 1 H),4.21-4.14(m,1H),3.98(qd,J=6.9,1.5Hz,2H),3.79(q,J=4.4Hz,1H),3.42-3.17(m,2H),2.99( s,2H),2.20-2.08(m,1H),1.99-1.77(m,2H),1.64-1.54(m,1H),1.35(t,J=7.1Hz,3H),1.26(s,6H)

[1495] Example 70: (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

[1496]

[1497] The title compound was obtained in a manner similar to Example 22 using (R)-4-chloro-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-(trifluoromethyl)pyrimidine (79 mg, 0.20 mmol) from Preparation Example 9 and tert-butyl 3-(3-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate (64 mg, 0.20 mmol) synthesized in Preparation Example 113 (yield 65% over 2 steps).

[1498] 1 H-NMR (400MHz, methanol-D4) δ8.25 (s, 1H), 7.80 (d, J = 7.8Hz, 1H), 7.75 (s, 1H), 7.68 (s,0H),7.44(d,J=4.1Hz,1H),7.38-7.28(1H),7.24(d,J=7.8Hz,1H),7.06-6 .43(m,5H),4.46(s,1H),4.07(q,J=7.2Hz,2H),3.98-3.56(m,4H),2.94(s,2H ),2.13-1.88(m,4H),1.59(d,J=3.7Hz,1H),1.21(t,J=7.1Hz,3H),1.18(s,6H)

[1499] Example 71: (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

[1500]

[1501] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-4-(3-(2-ethoxyphenoxy)piperidin-1-yl)-5-(trifluoromethyl)pyrimidine (135 mg, 0.38 mmol) synthesized in Preparation Example 10 and tert-butyl 3-(3-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate (110 mg, 0.238 mmol) synthesized in Preparation Example 113 (yield 18% over 2 steps).

[1502] 1H-NMR (400MHz, methanol-D4) δ9.34(s,1H),8.89(s,1H),8.85-8.74(m,1H),8.23(d,J=2.7Hz,1H),7.91(q,J=1.4Hz,1H),7.33- 7.19(m,3H),7.19-7.06(m,4H),7.01(t,J=7.5Hz,1H),3.99(q,J=7.0Hz,2H),3.72(s,2H),2.82(s,2H),1.18-1.01(m,9H)

[1503] Example 72: (R)-3-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2,2-dimethylpropanoic acid

[1504]

[1505] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (146 mg, 0.438 mmol) prepared in Preparation Example 1 and tert-butyl 3-(4-(6-aminopyridin-2-yl)phenyl)-2,2-dimethylpropanoate (143 mg, 0.438 mmol) prepared in Preparation Example 77 (yield 71% over 2 steps).

[1506] 1 H-NMR (400MHz, chloroform-D) δ8.16(s,1H),8.02(s,1H),7.85(d,J=8.2Hz,2H),7.67(s,1H),7.55(q,J=8.1Hz,1H),7.48(d, J=8.2Hz,1H),7.40-7.29(m,2H),7.24-7.15(m,1H),7.08-6.76(m,4H),4.32(td,J=7.9,4.0Hz,1H),4.18(dd,J=13.5 ,3.4Hz,1H),4.07-3.91(m,2H),3.83(td,J=9.0,4.1Hz,1H),3.48(dd,J=13.0,8.0Hz,1H),3.42-3.25(m,1H),2.94(s ,2H),2.27-2.11(m,1H),2.04-1.95(m,1H),1.95-1.79(m,1H),1.76-1.53(m,1H),1.37(t,J=7.1Hz,3H),1.24(s,6H)

[1507] Example 73: (R)-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)glycine

[1508]

[1509] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (70 mg, 0.21 mmol) synthesized in Preparation Example 1 and (4-(6-aminopyridin-2-yl)phenyl)glycine ethyl ester (57 mg, 0.21 mmol) synthesized in Preparation Example 100 (yield 25% for 2 steps).

[1510] 1 H-NMR (400 MHz, methanol-D4) δ 8.20 (s, 1H), 7.90-7.75 (2H), 7.49 (s, 1H), 7.47 (d, J = 8.5 Hz, 1H), 7.26 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.98 (d, J = 7.8 Hz, 2H), 6.88 (d, J = 4.1 Hz, 3H), 6.81 (dt, J = 8.7,3.9Hz,1H),6.65(d,J=8.7Hz,2H),4.40(t,J=3.4Hz,1H),4.14-3.81(m,4H),3.71(d,J=6.9 Hz,1H),3.68(s,2H),3.67-3.55(m,2H),2.22-1.90(m,3H),1.70-1.50(m,1H),1.34-1.22(m,3H)

[1511] Example 74: (R)-(4-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)glycine

[1512]

[1513] The title compound was obtained in a manner similar to Example 1 using (R)-2-chloro-6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine (58 mg, 0.17 mmol) synthesized in Preparation Example 3 and (4-(6-aminopyridin-2-yl)phenyl)glycine ethyl ester (47 mg, 0.17 mmol) synthesized in Preparation Example 100 (21% yield over 2 steps).

[1514] 1H-NMR (400MHz, methanol-D4) δ8.19(s,1H),7.82(d,J=8.7Hz,2H),7.58(q,J=2.3Hz,1H),7.51(s,1H),7.48 (t,J=8.0Hz,1H),7.18(q,J=7.9Hz,2H),7.02(dd,J=7.8,1.4Hz,1H),6.72(dd,J=7.8,5.0Hz,1H),6.6 5(d,J=8.7Hz,2H),5.18(q,J=2.9Hz,1H),4.07(dd,J=13.7,5.5Hz,1H),3.93-3.76(m,5H),3.73(d,J =7.3Hz,2H),3.69-3.51(m,1H),2.19-1.95(m,4H),1.63(dd,J=9.5,6.5Hz,1H),1.21(t,J=7.1Hz,3H)

[1515] Example 75: (R)-(4-(6-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidin-4-yl)amino)pyridin-2-yl)phenyl)glycine

[1516]

[1517] The title compound was obtained in a manner similar to Example 1 using (R)-4-chloro-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine (58 mg, 0.17 mmol) synthesized in Preparation Example 5 and (4-(6-aminopyridin-2-yl)phenyl)glycine ethyl ester (47 mg, 0.17 mmol) synthesized in Preparation Example 100 (yield 18% over 2 steps).

[1518] 1 H-NMR (400 MHz, methanol-D4) δ7.98-7.85 (m, 2H), 7.81 (d, J = 9.1 Hz, 2H), 7.53 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.2 Hz, 1H), 7.31 (d, J = 7.3 Hz, 1H), 6.95 (d, J = 6.9 Hz, 1H), 6.92-6.80 (m, 3H), 6.80-6.6 8(m,2H),6.66(d,J=8.7Hz,2H),4.41(q,J=3.2Hz,1H),4.06-3.98(1H),3.97-3.84(4H),3.8 3(s,2H),3.79(d,J=13.7Hz,2H),2.12-1.84(m,4H),1.67-1.51(m,1H),1.26(t,J=6.9Hz,3H)

[1519] Example 76: (R)-(4-(6-((4-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)glycine

[1520]

[1521] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-4-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine (58 mg, 0.17 mmol) synthesized in Preparation Example 6 and (4-(6-aminopyridin-2-yl)phenyl)glycine ethyl ester (47 mg, 0.17 mmol) synthesized in Preparation Example 100 (yield 11% over 2 steps).

[1522] 1 H-NMR (400 MHz, methanol-D4) δ7.89 (d, J = 6.4 Hz, 1H), 7.65 (d, J = 8.2 Hz, 3H), 7.31 (d, J = 8.2 Hz, 1H), 7.18 (s, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.92-6.73 (m, 3H), 6.74-6.56 (2H), 6.39 (s, 1 H),4.51(s,1H),4.30-3.98(m,1H),3.97-3.81(m,2H),3.79(s,1H),3.67(d,J=7.8Hz,2 H),3.50(dd,J=11.4,6.9Hz,1H),2.00(s,3H),1.59(q,J=7.5Hz,1H),1.29-1.18(m,3H)

[1523] Example 77: (R)-2-((4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)amino)-2-methylpropanoic acid

[1524]

[1525] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.15 g, 0.45 mmol) synthesized in Preparation Example 1 and ethyl 2-((4-(6-aminopyridin-2-yl)phenyl)amino)-2-methylpropanoate (146 mg, 0.49 mmol) synthesized in Preparation Example 98 (yield 74% for 2 steps).

[1526] 1H-NMR (400 MHz, methanol-D4) δ8.29 (s, 1H), 7.80 (d, J = 8.2 Hz, 2H), 7.52-7.39 (2H), 7.24-7.12 (m, 2H), 6.97 (d, J = 8.2 Hz, 1H), 6.87 (d, J = 4.1 Hz, 2H), 6.84-6.72 (m, 1H), 6.59 (d, J = 8.2 Hz, 2H), 4.38 (t, J = 3.2 Hz, 1 H),4.14(q,J=7.0Hz,2H),4.02-3.79(m,3H),3.68(q,J=6.7Hz,1H),3.62(s,2H),2.05(d,J=12.3Hz, 2H),1.88(d,J=10.5Hz,1H),1.60(s,1H),1.52(d,J=4.1Hz,7H),1.34-1.23(m,3H),1.19-1.15(m,3H)

[1527] Example 78: (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoic acid

[1528]

[1529] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (73 mg, 0.22 mmol) synthesized in Preparation Example 1 and tert-butyl 3-(3-(6-aminopyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoate (69 mg, 0.20 mmol) synthesized in Preparation Example 89 (81% yield over 2 steps).

[1530] 1H-NMR (400MHz, methanol-D4) δ8.48(s,1H),7.84(dd,J=7.5,2.5Hz,1H),7.57(t,J=8.0Hz,1H),7.53(s,1H),7.38 -7.24(m,2H),7.24-7.15(m,1H),7.06(dd,J=11.2,8.5Hz,1H),6.98(d,J=7.3Hz,1H),6.93-6.86(m,2H),6 .86-6.74(m,1H),4.48-4.33(m,1H),4.00-3.78(m,3H),3.72(q,J=6.6Hz,1H),3.64(t,J=5.5Hz,2H),2.91 (s,2H),2.14-1.99(m,2H),1.89(d,J=8.2Hz,1H),1.61(d,J=5.9Hz,1H),1.26(t,J=7.1Hz,4H),1.18(s,6H)

[1531] Example 79: (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

[1532]

[1533] The title compound was obtained in a manner similar to Example 22 using (R)-2-chloro-6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine (73 mg, 0.22 mmol) synthesized in Preparation Example 3 and tert-butyl 3-(3-(6-aminopyridin-2-yl)-4-fluorophenyl)-2,2-dimethylpropanoate (69 mg, 0.20 mmol) synthesized in Preparation Example 89 (yield 98% for 2 steps).

[1534] 1H-NMR (400 MHz, methanol-D4) δ8.35 (s, 1H), 7.83-7.68 (2H), 7.65 (s, 1H), 7.59-7.44 (1H), 7.41-7.31 (m, 1H), 7.26 (s, 1H), 7.19 (d, J = 8.2 Hz, 1H), 7.13 (dd, J = 11.2, 8.5 Hz, 1H), 7.01 (dd, J = 7.8, 1.4 Hz, 1H), 6.78 -6.62(1H),5.15(s,1H),4.19-4.09(m,1H),3.97-3.85(m,1H),3.85-3.72(m,2H),3.69(d,J=12.8Hz ,1H),3.57(d,J=9.6Hz,1H),2.93(s,2H),2.15-1.99(m,3H),1.62(d,J=6.4Hz,1H),1.25-1.15(m,9H)

[1535] Example 80: (R)-2-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenoxy)-2-methylpropanoic acid

[1536]

[1537] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (111 mg, 0.333 mmol) prepared in Preparation Example 1 and ethyl 2-(3-(6-aminopyridin-2-yl)phenoxy)-2-methylpropanoate (100 mg, 0.333 mmol) prepared in Preparation Example 88 (61% yield over two steps).

[1538] 1H-NMR (400 MHz, chloroform-D) δ9.42 (s, 1H), 7.99 (t, J = 2.1 Hz, 1H), 7.62 (t, J = 8.5 Hz, 2H), 7.51 (d, J = 8.2 Hz, 1H), 7.44-7.28 (m, 2H), 7.09-6.93 (m, 3H), 6.89 (qd, J = 7.5, 1.6 Hz, 2H), 6.79 (s, 1H), 6.61 (d, J = 7.8 Hz, 1H), 4.42-4.24 ( m,1H),4.07(dd,J=13.3,3.7Hz,1H),4.04-3.88(m,2H),3.87-3.70(m,1H),3.58(dd,J=13.0,7.5Hz,1H),3.48 -3.30(m,1H),2.25-2.08(1H),2.08-1.95(m,1H),1.95-1.81(m,1H),1.72-1.48(m,7H),1.37(t,J=7.1Hz,3H)

[1539] Example 81: (R)-2-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenoxy)-2-methylpropanoic acid

[1540]

[1541] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine (111 mg, 0.333 mmol) prepared in Preparation 3 and ethyl 2-(3-(6-aminopyridin-2-yl)phenoxy)-2-methylpropanoate (100 mg, 0.333 mmol) prepared in Preparation 88 (76% yield over two steps).

[1542] 1H-NMR (400MHz, chloroform-D) δ9.36 (s, 1H), 7.99 (t, J = 2.1Hz, 1H), 7.74 (dd, J = 5.0, 1.4Hz, 1H), 7.65 (s, 1H), 7.60 (t, J = 7.8Hz, 1 H),7.51(d,J=7.8Hz,1H),7.43-7.29(m,2H),7.03(dd,J=7.8,2.3Hz,1H),6.94(dd,J=7.8,1.4Hz,1H),6.81(dd,J=7.8, 5.0Hz,1H),6.64(s,1H),6.57(d,J=7.8Hz,1H),5.23(q,J=3.5Hz,1H),3.91(d,J=5.0Hz,2H),3.90-3.79(m,2H),3.72(q ,J=3.7Hz,1H),3.59(t,J=3.9Hz,1H),2.16(t,J=4.3Hz,1H),2.10-1.94(m,2H),1.73-1.55(m,7H),1.27(t,J=6.9Hz,3H)

[1543] Example 82: (R)-2-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenoxy)-2-methylpropanoic acid

[1544]

[1545] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (111 mg, 0.333 mmol) prepared in Preparation Example 1 and ethyl 2-(4-(6-aminopyridin-2-yl)phenoxy)-2-methylpropanoate (100 mg, 0.333 mmol) prepared in Preparation Example 97 (69% yield over two steps).

[1546] 1H-NMR (400 MHz, chloroform-D) δ 8.07 (s, 1H), 7.74 (d, J = 8.7 Hz, 2H), 7.67 (d, J = 6.4 Hz, 2H), 7.62-7.48 (1H), 7.13 (d, J = 7.3 Hz, 1H), 7.09-7.01 (2H), 7.01-6.96 (1H), 6.93 (td, J = 7.7, 1.4 Hz, 1H), 6.89-6.74 (m, 2H), 4.42-4.24 (m, 1H) ,4.14(dd,J=12.8,3.2Hz,1H),4.07-3.89(m,2H),3.89-3.69(m,1H),3.52(dd,J=12.8,7.8Hz,1H),3.44-3.27 (m,1H),2.26-2.09(m,1H),2.09-1.96(m,1H),1.96-1.81(m,1H),1.64(t,J=16.0Hz,7H),1.36(t,J=6.9Hz,3H)

[1547] Example 83: (R)-2-(4-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)phenoxy)-2-methylpropanoic acid

[1548]

[1549] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine (111 mg, 0.333 mmol) prepared in Preparation 3 and ethyl 2-(4-(6-aminopyridin-2-yl)phenoxy)-2-methylpropanoate (100 mg, 0.333 mmol) prepared in Preparation 97 (71% yield over two steps).

[1550] 1H-NMR (400 MHz, chloroform-D) δ8.05 (s, 1H), 7.75 (d, J = 9.1 Hz, 2H), 7.71 (s, 1H), 7.66-7.46 (m, 3H), 7.12 (d, J = 7.3 Hz, 1H), 7.05 (d, J = 8.7 Hz, 2H), 6.95 (dd, J = 7.8, 1.4 Hz, 1H), 6.70 (dd, J = 7.8, 5.0 Hz, 1H), 5.26 (t, J=3.2Hz,1H),3.99(dd,J=13.5,3.0Hz,1H),3.94-3.81(m,3H),3.75(d,J=13.7Hz,1H),3.65-3.46(m ,1H),2.27-2.11(m,1H),2.11-1.89(2H),1.79-1.67(m,1H),1.65(d,J=1.8Hz,6H),1.38-1.19(m,3H)

[1551] Example 84: (R)-2-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-4-fluorophenoxy)-2-methylpropanoic acid

[1552]

[1553] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (115 mg, 0.35 mmol) synthesized in Preparation Example 1 and ethyl 2-(3-(6-aminopyridin-2-yl)-4-fluorophenoxy)-2-methylpropanoate (100 mg, 0.31 mmol) synthesized in Preparation Example 92 (yield 45% for 2 steps).

[1554] 1H-NMR (400 MHz, methanol-D4) δ8.30 (s, 1H), 7.67-7.47 (m, 3H), 7.35 (d, J = 8.2 Hz, 1H), 7.31 (dd, J = 7.5, 2.1 Hz, 1H), 7.08 (dd, J = 11.0, 9.1 Hz, 1H), 7.02-6.92 (m, 2H), 6.87 (d, J = 4.1 Hz, 2H), 6.81 (q,J=4.0Hz,1H),4.42(s,1H),4.01-3.82(m,3H),3.76(q,J=6.7Hz,1H),3.72-3.56(m,2H), 2.14-2.00(2H),1.91(d,J=8.7Hz,1H),1.70-1.58(m,1H),1.56(s,6H),1.26(t,J=7.1Hz,3H)

[1555] Example 85: (R)-2-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-4-fluorophenoxy)-2-methylpropanoic acid

[1556]

[1557] The title compound was obtained in a manner similar to Example 1 using (R)-2-chloro-6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine (116 mg, 0.35 mmol) synthesized in Preparation Example 3 and ethyl 2-(3-(6-aminopyridin-2-yl)-4-fluorophenoxy)-2-methylpropanoate (100 mg, 0.31 mmol) synthesized in Preparation Example 92 (yield 42% for 2 steps).

[1558] 1 H-NMR (400 MHz, methanol-D4) δ8.26 (s, 1H), 7.66-7.47 (m, 4H), 7.30 (dd, J = 8.2, 2.7 Hz, 2H), 7.17-6.99 (m, 2H), 6.95 (dt, J = 9.0, 3.5 Hz, 1H), 6.72 (dd, J = 7.8, 5.0 Hz, 1H), 5.1 9(q,J=2.9Hz,1H),4.17-3.98(m,2H),3.93-3.70(m,4H),3.67-3.51(m,1H),2.17- 2.00(m,2H),1.96(s,1H),1.64(t,J=3.0Hz,1H),1.56(s,6H),1.21(t,J=7.1Hz,3H)

[1559] Example 86: (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

[1560]

[1561] The title compound was obtained in a manner similar to that of Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.050 g, 0.15 mmol) prepared in Preparation Example 1 and methyl 3-(4-(6-aminopyridin-2-yl)-1H-pyrazol-1-yl)-2,2-dimethylpropanoate (0.041 g, 0.15 mmol) obtained in Preparation Example 116 (yield 14%).

[1562] 1 H-NMR (400 MHz, methanol-D4): δ8.18 (s, 1H), 8.11 (s, 1H), 7.95 (s, 1H), 7.63-7.50 (m, 2H), 7.21-7.07 (m, 2H), 6.99-6.86 (m, 1H), 6.86-6.70 (m, 3H), 4.41 (d, J=9.1 Hz, 1H), 4.35 (s, 2H), 3.94-3.68 (m, 5H), 3.64-3.54 (m, 1H), 2.12-2.00 (m, 2H), 1.98-1.88 (m, 1H), 1.68-1.53 ​​(m, 1H), 1.28-1.18 (m, 9H)

[1563] Example 87: (R)-3-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)benzoic acid

[1564]

[1565] The title compound was obtained in a manner similar to that described in Example 12 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.098 g, 0.293 mmol) obtained in Preparation Example 1 and methyl 3-((6-aminopyridin-2-yl)oxy)benzoate (0.065 g, 0.266 mmol) obtained in Preparation Example 107 (yield 50% over 2 steps).

[1566] 1H-NMR (400MHz, methanol-D4) δ7.84(d,J=7.8Hz,1H),7.70(t,J=2.1Hz,1H),7.65(s,1H),7.54(t,J=8.0Hz,1H),7.48 (t,J=8.0Hz,1H),7.42(s,1H),7.36-7.28(m,1H),7.19(d,J=7.8Hz,1H),7.02-6.93(m,1H),6.93-6.84(m,2H) ,6.80(dq,J=8.6,2.6Hz,1H),6.45(d,J=7.8Hz,1H),4.40(td,J=6.6,3.5Hz,1H),3.98-3.76(m,3H),3.71(q,J =6.7Hz,1H),3.66-3.52(m,2H),2.14-1.97(m,2H),1.94-1.80(m,1H),1.67-1.50(m,1H),1.23(t,J=6.9Hz,3H)

[1567] Example 88: (R)-3-((6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)benzoic acid

[1568]

[1569] The title compound was obtained in a manner similar to that described in Example 12 using (R)-2-chloro-6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine (0.098 g, 0.293 mmol) obtained in Preparation Example 3 and methyl 3-((6-aminopyridin-2-yl)oxy)benzoate (0.065 g, 0.266 mmol) obtained in Preparation Example 107 (21% yield over two steps).

[1570] 1H-NMR (400MHz, methanol-D4) δ7.84 (dd, J=7.8, 1.4Hz, 1H), 7.71 (t, J=2.1Hz, 1H), 7.61 (s, 1H), 7.59- 7.45(m,3H),7.42(s,1H),7.36-7.27(m,1H),7.12(d,J=8.2Hz,1H),7.02(dd,J=8.0,1.6Hz,1H ),6.73(dd,J=7.8,5.0Hz,1H),6.45(d,J=7.8Hz,1H),5.17(q,J=2.7Hz,1H),4.15-4.01(1H),3 .87-3.62(4H),3.61-3.47(m,1H),2.12-1.91(m,3H),1.65-1.53(m,1H),1.15(t,J=7.1Hz,3H)

[1571] Example 89: (R)-4-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)benzoic acid

[1572]

[1573] The title compound was obtained in a manner similar to that described in Example 12 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (0.15 g, 0.45 mmol) obtained in Preparation Example 1 and methyl 4-((6-aminopyridin-2-yl)oxy)benzoate (0.1 g, 0.409 mmol) obtained in Preparation Example 104 (yield 70% over 2 steps).

[1574] 1 H-NMR (400 MHz, chloroform-D) δ8.32-8.20 (m, 2H), 7.98 (s, 1H), 7.80 (d, J = 8.2 Hz, 1H), 7.59 (q, J = 7.6 Hz, 1H), 7.27 (t, J = 2.3 Hz, 1H), 7.04-6.78 (m, 5H), 6.62 (d, J = 8.2 Hz, 1H), 6.60-6.47 (m, 1H), 4.37-4.22 (m, 1H), 4.0 5(dd,J=13.3,3.2Hz,1H),4.01-3.83(m,2H),3.72(td,J=9.3,4.1Hz,1H),3.54(dd,J=13.3,7.8Hz,1H), 3.42-3.33(m,1H),2.19-2.05(m,1H),2.01-1.81(m,2H),1.57(qd,J=8.8,4.6Hz,1H),1.37-1.28(m,3H)

[1575] Example 90: (R)-4-((6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)benzoic acid

[1576]

[1577] The title compound was obtained in a manner similar to that described in Example 12 using (R)-2-chloro-6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine (0.151 g, 0.450 mmol) obtained in Preparation Example 3 and methyl 4-((6-aminopyridin-2-yl)oxy)benzoate (0.1 g, 0.409 mmol) obtained in Preparation Example 104 (yield 71% over 2 steps).

[1578] 1 H-NMR (400 MHz, chloroform-D) δ 8.19 (t, J = 8.9 Hz, 2H), 7.92 (d, J = 17.8 Hz, 1H), 7.75-7.66 (m, 2H), 7.58 (t, J = 7.8 Hz, 1H), 7.44-7.26 (m, 1H), 7.24-7.16 (m, 2H), 6.97-6.89 (m, 1H), 6.83-6. 68(m,2H),6.55(t,J=8.5Hz,1H),5.20(s,1H),3.96-3.82(m,3H),3.82-3.72(m,1H),3.7 2-3.52(m,2H),2.10(q,J=4.1Hz,1H),2.01(q,J=5.3Hz,2H),1.65(s,1H),1.26-1.20(3H)

[1579] Example 91: (R)-2-(3-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)phenyl)-2-methylpropanoic acid

[1580]

[1581] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazine (117 mg, 0.349 mmol) prepared in Preparation Example 1 and methyl 2-(3-((6-aminopyridin-2-yl)oxy)phenyl)-2-methylpropanoate (100 mg, 0.349 mmol) prepared in Preparation Example 109 (47% yield over two steps).

[1582] 1H-NMR (400 MHz, methanol-D4) δ7.72 (d, J = 4.1 Hz, 1H), 7.62-7.50 (1H), 7.47 (s, 1H), 7.44-7.31 (1H), 7.25 (d, J = 8.7 Hz, 1H), 7.22-7.16 (1H), 7.14 (t, J = 2.1 Hz, 1H), 7.07-6.96 (m, 2H), 6.96-6.87 (2H), 6.87-6.75 (m, 1H), 6.4 1(d,J=7.8Hz,1H),4.41(td,J=6.7,3.4Hz,1H),4.02-3.80(m,3H),3.71(q,J=6.6Hz,1H),3.63(t,J=5.3Hz ,2H),2.18-1.99(m,2H),1.91(qd,J=7.9,3.9Hz,1H),1.71-1.56(m,1H),1.54(s,6H),1.27(t,J=6.9Hz,3H)

[1583] Example 92: (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

[1584]

[1585] The title compound was obtained in a manner similar to that described in Example 1 using (R)-2-chloro-6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazine (117 mg, 0.349 mmol) prepared in Preparation 3 and methyl 2-(3-((6-aminopyridin-2-yl)oxy)phenyl)-2-methylpropanoate (100 mg, 0.349 mmol) prepared in Preparation 109 (56% yield over two steps).

[1586] 1H-NMR (400MHz, methanol-D4) δ7.68 (s, 1H), 7.61 (q, J = 2.3Hz, 1H), 7.52 (t, J = 8.0Hz, 1H), 7.48 (s, 1H), 7.43-7 .31(m,1H),7.31-7.22(m,1H),7.22-7.10(m,2H),7.06(dd,J=7.8,1.4Hz,1H),7.03-6.92(m,1H),6.77( dd,J=7.8,5.0Hz,1H),6.40(d,J=7.3Hz,1H),5.20(q,J=2.9Hz,1H),4.04(dd,J=13.7,5.9Hz,1H),3.96 -3.69(m,4H),3.69-3.53(m,1H),2.22-1.89(3H),1.77-1.58(m,1H),1.55(s,6H),1.20(t,J=7.1Hz,3H)

[1587] Example 93: (R)-2-(4-((6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)oxy)phenyl)-2-methylpropanoic acid

[1588]

[1589] The title compound was obtained in a manner similar to that de...

Claims

1. A compound of the following formula (1) or a pharmaceutically acceptable salt thereof: [Formula (1)] in A and D are each independently CH or N; B and E are each independently CH, C-halogen, C-halo-C1-C7 alkyl or N; R 1 is a C1-C7 alkyl group; R 2 is hydrogen or a halogen; R 3 Yes - GJ; Where G is C6-C 10 Aryl, C6-C 10 Arylene, C6-C 10 Arylene-C1-C7 alkylene, 5- to 12-membered heteroaryl, or 5- to 12-membered heteroarylene; J is hydrogen, C1-C7 alkoxy-C1-C7 alkyl, C3-C 10 Cycloalkyl, C3-C 10 Cycloalkyl-oxy, 5- to 12-membered heterocycloalkyl, C6-C 10 Aryl, C6-C 10 Aryl-oxy, C6-C 10 Aryl-C1-C7 alkoxy, 5- to 12-membered heteroaryl, carboxyl-C1-C7 alkyl, carboxyl-C2-C7 alkenyl, carboxyl-C1-C7 alkyl-C6-C 10 Aryl, carboxyl-C1-C7 alkoxy-C6-C 10 Aryl, carboxyl-C1-C7 alkyl-5 to 12-membered heterocycloalkyl, carboxyl-C1-C7 alkoxy-5 to 12-membered heterocycloalkyl, carboxyl-C1-C7 alkyl-amino-C6-C 10 Aryl, carboxyl-C1-C7 alkyl-C6-C 10 Aryl-oxy or carboxy-C1-C7 alkyl-5 to 12 membered heteroaryl; wherein the alkoxy, cycloalkyl, aryl, heterocycloalkyl, heteroaryl or heteroarylene is optionally substituted with 1 to 4 substituents selected from halogen, -COOH, C1-C7 alkyl, C1-C7 alkoxy, halo-C1-C7 alkyl, C1-C7 alkylsulfonyl and 5 to 12 membered heteroaryl-C1-C7 alkyl; and The heterocycloalkyl, heteroaryl and heteroarylene groups include 1 to 5 heteroatoms selected from N, O and S.

2. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from: (R)-2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)thiazole-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-(methylsulfonyl)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)iso Azol-5-amine; (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)-4-phenyl Azol-2-amine; (R)-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[d] Azol-2-amine; (R)-5-Chloro-N-(6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)benzo[d] Azol-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-2-yl)amino)benzo[d] oxazol-5-yl)-2-methylpropanoic acid; (R)-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)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] oxazol-5-yl)acrylic acid; (R)-3-(2-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)benzo[d] oxazol-5-yl)propionic 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)propionic acid; (R)-6-(3-(2-ethoxyphenoxy)piperidin-1-yl)-N-(1H-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)pyridin-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-methylpropanoic 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-methylpropanoic acid; (R)-2-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-2-methylpropanoic 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)pyrrolidine-3-carboxylic acid; 1-(6-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)-3-methylpyrrolidine-3-carboxylic acid; 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-((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)piperidine-4-carboxylic acid; (R)-2-(1-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidin-4-yl)acetic acid; (R)-2-(1-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-2-yl)piperidin-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)pyrazin-2-yl)amino)pyridin-2-yl)phenyl)-2-methylpropanoic acid; (R)-2-(4-(6-((6-(3-(2-ethoxyphenoxy)piperidin-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; (R)-3-(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)-2-methylpropanoic acid; (R)-2-(3-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-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)-2-methylpropanoic acid; (R)-2-(4-(6-((6-(3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyridin-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)pyridin-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-fluoropyridin-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-fluoropyridin-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-fluoropyridin-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-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methylpropanoic acid; (R)-3-(3-(6-((6-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)-4-(trifluoromethyl)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)pyrimidin-4-yl)-L-proline; 1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)pyrrolidine-3-carboxylic acid; 1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)-3-methylpyrrolidine-3-carboxylic acid; 1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-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)pyrimidin-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)pyrimidin-4-yl)piperidin-3-yl)propanoic acid; 2-(((S)-1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidin-3-yl)oxy)acetic acid; 2-(((R)-1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)piperidin-3-yl)oxy)acetic acid; 2-(((R)-1-(2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-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)cyclohexane-1-carboxylic acid; (1R,4r)-4-((2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)oxy)cyclohexane-1-carboxylic acid; (1R,4r)-4-((2-((6-((R)-3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)oxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-((2-((6-((R)-3-(2-ethoxyphenoxy)piperidin-1-yl)pyrazin-2-yl)amino)pyrimidin-4-yl)oxy)cyclohexane-1-carboxylic acid; (1S,4s)-4-((2-((6-((R)-3-((3-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)pyrimidin-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)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)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)pyrimidin-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-ethoxypyridin-2-yl)oxy)piperidin-1-yl)pyrazin-2-yl)amino)-5-(trifluoromethyl)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)-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; (R)-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)pyrimidin-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)pyrimidin-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)pyrimidin-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.

3. A pharmaceutical composition for treating a disease associated with diacylglycerol acyltransferase 2, comprising a compound of formula (1) as defined in any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier.

4. The pharmaceutical composition according to claim 3, wherein the disease associated with diacylglycerol acyltransferase 2 is selected from the group consisting of fatty liver, diabetes, obesity, hyperlipidemia, atherosclerosis and hypercholesterolemia. 5 . The pharmaceutical composition according to claim 3 , wherein the disease associated with diacylglycerol acyltransferase 2 is non-alcoholic steatohepatitis. The pharmaceutical composition according to claim 3 , wherein the disease associated with diacylglycerol acyltransferase 2 is non-alcoholic fatty liver disease.

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