WO2019022223A1

WO2019022223A1 - Cyclic amine derivative and use thereof for medical purposes

Info

Publication number: WO2019022223A1
Application number: PCT/JP2018/028211
Authority: WO
Inventors: 和也大角; 真幸星; 新之助林; バレットマーシャル; 慎也横坂; 拓実青木; 目黒　裕之; 戒能　美枝; こずえ高垣
Original assignee: 東レ株式会社
Priority date: 2017-07-28
Filing date: 2018-07-27
Publication date: 2019-01-31
Also published as: JPWO2019022223A1; TW201910312A

Abstract

The present invention addresses the problem of providing a novel compound which has a retinoid-related orphan receptor γ antagonistic activity and exhibits a therapeutic effect or a prophylactic effect on an autoimmune disease such as multiple sclerosis or psoriasis or an allergic disease such as an allergic dermatitis including contact dermatitis or atopic dermatitis. The present invention provides a cyclic amine derivative (I) typified by a compound shown below, or a stereoisomer of the derivative, or a hydrate of the derivative or the stereoisomer, or a pharmacologically acceptable salt of the derivative, the stereoisomer or the hydrate.

Description

Cyclic amine derivative and pharmaceutical use thereof

The present invention relates to cyclic amine derivatives and their pharmaceutical uses.

Autoimmune disease is a general term for diseases in which excessive immune reaction causes symptoms by attacking normal cells and tissues of the patient. For example, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory Intestinal diseases, ankylosing spondylitis, uveitis or polymyalgia rheumatica can be mentioned.

Allergic diseases are diseases resulting from excessive immune reaction to specific antigens, such as allergic dermatitis, atopic dermatitis, allergic rhinitis (hay fever), allergic conjunctivitis, allergy Gastroenteritis, bronchial asthma, childhood asthma or food allergy are included.

Various mechanisms have been proposed for the onset and progression of autoimmune diseases and allergic diseases, one of which is Th17 cells, which is a subset of helper T cells, and inflammatory cytokines produced by them. It is known that IL-17 plays an important role in the onset and development of autoimmune diseases (Non-patent Documents 1 and 2).

IL-17 acts on various cells such as fibroblasts, epithelial cells, vascular endothelial cells and macrophages, and is involved in induction of inflammatory cytokines, chemokines, metalloproteases and other inflammatory mediators and neutrophil migration. ing. Therefore, if it is possible to suppress the production or function of IL-17, a strong anti-inflammatory effect is considered to be exerted, and clinical trials of anti-IL-17 antibodies with indications for various autoimmune diseases are conducted. It is done.

In recent years, it has been clarified that the nuclear receptor retinoid-related orphan receptor γ (hereinafter referred to as RORγ) functions as a transcription factor essential for differentiation and proliferation of Th17 cells and expression of IL-17 (non-patent) Reference 3), it was shown that suppressing the expression or function of RORγ suppresses the differentiation and activation of Th17 cells and the production of IL-17 (Non-patent Document 4).

In patients with autoimmune diseases (multiple sclerosis, psoriasis, systemic lupus erythematosus etc.) and patients with allergic diseases (eg allergic dermatitis), the amount of RORγ expression in peripheral blood mononuclear cells or skin tissue is compared with that in healthy people It has been reported to show high values (non-patent documents 5 to 7). In RORγ knockout mice, suppression of the pathological condition of mouse experimental autoimmune encephalomyelitis model, which is an animal model of multiple sclerosis, and symptoms of autoimmune diseases such as colitis and allergic diseases such as asthma It has been reported that the symptoms of are suppressed (Non-patent Documents 3, 8 and 9).

Furthermore, it has been suggested that in order for RORγ to function as a transcription factor, it is necessary to bind RORγ to a coactivator (Non-patent Document 10). Therefore, RORγ antagonists, which are compounds that inhibit the binding of RORγ to coactivators, are expected to be useful as therapeutic or prophylactic agents for autoimmune diseases.

On the other hand, as RORγ antagonists, N- (5- (N- (4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) phenyl) sulfamoyl) has hitherto been described. -4-methylthiazol-2-yl) acetamide (non-patent document 11), 6- (2-chloro-4-methylphenyl) -3- (4-cyclopropyl-5- (3-neopentylcyclobutyl) Substituted azole derivatives such as isoxazol-3-yl) -5-oxohexanoic acid (Patent Document 1), N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl Sulfonylbenzene derivatives such as -4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide have been reported (Patent Document 2), but 1-substituted piperidine - has not been disclosed to have a cyclic amine structure, such as a carboxamide.

Moreover, as a compound having a cyclic amine structure such as 1-substituted piperidine-2-carboxamide, (S) -1-propionyl-N- (4 '-(2-((S ) -Propionyl pyrrolidin-2-yl) -1H-imidazol-4-yl)-[1,1'-biphenyl] -4-yl) pyrrolidine-2-carboxamide etc. (Patent Document 3), and 2- ((4-((4-Aminophenyl) thio) -3-((7-isopropylpyrido [2,3-d] pyrimidin-4-yl) amino) phenyl) carbamoyl) pyrrolidine-1-carboxylic acid (S Although -benzyl and the like have been reported (Patent Document 4), the action of these compounds on RORγ is neither disclosed nor suggested.

JP 2012-236822 A International Publication No. 2013/029338 International Publication No. 2011/031934 WO 2010/075376

However, for actual treatment of autoimmune diseases and allergic diseases, steroids or immunosuppressants acting on the entire immune system are used as internal medicines, and it is sufficient because of serious side effects such as infections. At present, there are a large number of cases in which the administration must be discontinued before any therapeutic effect is observed. For this reason, development of new medicines targeting molecules that play an important role in the onset and development mechanism of autoimmune diseases and allergic diseases is desired.

Therefore, the present invention has RORγ antagonist activity and has a therapeutic effect on autoimmune diseases such as multiple sclerosis or psoriasis or allergic diseases such as contact dermatitis or allergic dermatitis such as atopic dermatitis or It aims at providing a novel compound which exerts a preventive effect.

As a result of intensive studies to solve the above problems, the present inventors have found novel cyclic amine derivatives having RORγ antagonist activity, and have completed the present invention.

That is, the present invention provides a cyclic amine derivative represented by the following general formula (I), a stereoisomer or a hydrate thereof, or a pharmacologically acceptable salt thereof.

[Wherein, A represents a group represented by the following general formula (II-1), (II-2), (II-3), (II-4) or (II-5)

(Wherein, R ¹ is a hydrogen atom, cyano group, hydroxymethyl group, —C (= O) —OR ³ , an alkylsulfonyl group having a carbon number of 1 to 3) having 1 to 3 optional hydrogen atoms; An alkyl group having 1 to 3 carbon atoms (in the alkyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom) and an alkyloxy group having 1 to 3 carbon atoms (the alkyloxy group And the group is an aryl group or a heteroaryl group which may be substituted with a group selected from the group consisting of 1 to 3 arbitrary hydrogen atoms which may be substituted with a halogen atom); R ² represents a halogen atom, R ³ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and a double line of a solid line and a dotted line represents a single bond or a double bond, and a wavy line represents Represents a bonding point with the general formula (I))
X represents a group represented by —C (= O) — (CH ₂ ) _n —R ⁴ or —S (= O) ₂ —R ⁵ ; n represents an integer of 0 to 5; R ⁴ represents a cyano group, a hydroxy group, -N (R ⁶ ) R ⁷ , -NH-C (= Y) -NHR ⁶ , -NH-S (= O) ₂ -NHR ⁶ , -C (= O) -OR ⁶ , -C (= O) -NHR ⁶ , a cyclic ether group having 4 to 6 ring atoms, an alkyl group having 1 to 3 carbon atoms (the alkyl group is an optional hydrogen atom of 1 to 3) And R.sup.5 may be substituted with a halogen atom) or a heteroaryl group in which one or two of the optional hydrogen atoms may be substituted with an alkyl group of 1 to 3 carbon atoms, R ⁵ R represents an alkyl group having 1 to 3 carbon atoms, R ⁶ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (wherein the alkyl group is any of 1 to 3 carbon atoms) Hydrogen atom may be substituted with a halogen atom), and R ⁷ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an acyl group having 2 to 4 carbon atoms or an alkyl having 1 to 3 carbon atoms Represents a sulfonyl group, and Y represents an oxygen atom, a sulfur atom or = N-CN. ]

In the cyclic amine derivative represented by the above general formula (I), one or two optional hydrogen atoms of R ¹ are a fluorine atom, a chlorine atom, a cyano group, a hydroxymethyl group, -C (= O) -OR ³ , an alkylsulfonyl group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms (in the alkyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom And an alkyloxy group having 1 to 3 carbon atoms (in the alkyloxy group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom), and R ² is a fluorine atom or a chlorine atom, R ³ is an alkyl group having 1 to 3 carbon atoms, which is a phenyl group, a pyridyl group or a pyrimidinyl group which may be substituted by a selected group , N is an integer from 0 to 4 There, ^{R 4} is cyano group, hydroxy ^{^{^{group, -N (R 6) R 7}}} , -NH-C (= Y) -NHR 6, -NH-S (= O) 2 -NHR 6, -C (= O) -OR ⁶ , -C (= O) -NHR ⁶ , oxetan-3-yl group, alkyl group having 1 to 3 carbon atoms (in the alkyl group, one to three arbitrary hydrogen atoms are fluorine atoms Or a heteroaryl group which may be substituted with a chlorine atom), or one or two optional hydrogen atoms may be substituted with a methyl group, and R ⁶ is a hydrogen atom or carbon It is preferable that it is an alkyl group of several to three (in the alkyl group, one to three arbitrary hydrogen atoms may be substituted by a fluorine atom or a chlorine atom).

In this case, higher RORγ antagonist activity can be expected.

In the cyclic amine derivative represented by the above general formula (I), one or two optional hydrogen atoms of R ¹ are a fluorine atom, a chlorine atom, a cyano group, an isopropyl group, 1 to 3 A group selected from the group consisting of a methyl group which may be substituted with a fluorine atom, and a methoxy group which may be substituted with one to three arbitrary hydrogen atoms. R ² is a chlorine atom, n is an integer of 0 to 3, and R ⁴ is a methyl group, a cyano group, -N (R ⁶ ) R ⁷ , ^{-NH-C (= Y) -NHR} 6, -NH-S (= O) 2 -NHR 6, oxetane-3-yl group, or, one or two arbitrary hydrogen atoms are substituted with a methyl group Imidazolyl group, pyrazolyl group, triazolyl group, which may be 1,3,4-oxadiazolyl group, tetrazolyl group or pyridyl group, R ⁵ is a methyl group, R ⁶ is a hydrogen atom or a methyl group, R ⁷ is a hydrogen atom, a methyl group, acetyl It is more preferable that it is a group or a methylsulfonyl group.

In this case, higher RORγ antagonist activity can be expected, and further, excellent therapeutic effects or preventive effects can be expected in autoimmune diseases such as multiple sclerosis or psoriasis or allergic diseases such as allergic dermatitis.

In the cyclic amine derivative represented by the above general formula (I), one or two optional hydrogen atoms of R ¹ are a fluorine atom, a chlorine atom, a methyl group, an isopropyl group, a trifluoromethyl group, R ² is a chlorine atom which may be substituted by a group selected from the group consisting of difluoromethoxy and trifluoromethoxy, R ² is a chlorine atom, n is an integer of 0 to 2, R ⁴ is a methyl group, a cyano ^{^{^{group, -N (R 6) R 7}}} , -NH-C (= Y) -NHR 6, -NH-S (= O) 2 -NHR 6, or 1 or 2 A hydrogen atom of any one of which may be substituted with a methyl group, a triazolyl group, a 1,3,4-oxadiazolyl group or a tetrazolyl group, R ⁵ is a methyl group, and R ⁶ is a hydrogen atom or Methyl, R ⁷ Is a hydrogen atom, a methyl group, an acetyl group or a methylsulfonyl group, and Y is more preferably an oxygen atom or NN—CN.

Also, the present invention is a medicament comprising, as an active ingredient, the cyclic amine derivative represented by the above general formula (I), a stereoisomer thereof or a hydrate thereof, or a pharmacologically acceptable salt thereof And RORγ antagonists.

The above-mentioned medicament is preferably a therapeutic agent or a preventive agent for an autoimmune disease or an allergic disease, and a therapeutic agent or a preventive agent for the above-mentioned autoimmune disease is a therapeutic agent or a preventive agent for multiple sclerosis or psoriasis It is more preferable that the therapeutic agent or preventive agent for allergic disease described above is a therapeutic agent or preventive agent for allergic dermatitis, and it is more preferable that the therapeutic agent or preventive agent for allergic dermatitis. More preferably, the agent is a therapeutic agent or a preventive agent for contact dermatitis or atopic dermatitis.

Since the cyclic amine derivative of the present invention, its stereoisomer or hydrate thereof, or pharmacologically acceptable salts thereof have RORγ antagonist activity, they can effectively suppress the function of RORγ, and can self It can be used as a therapeutic agent or prophylactic agent for immune diseases or allergic diseases.

Fig. 15 shows the inhibitory effect of the compound of Example 46 on the increase in ear thickness in the imiquimod-induced mouse psoriasis model. Fig. 24 shows the inhibitory effect of the compound of Example 74 on the increase in ear thickness in the imiquimod-induced mouse psoriasis model. Fig. 15 shows the inhibitory effect of the compound of Example 109 on the increase in ear thickness in the imiquimod-induced mouse psoriasis model. Fig. 15 shows the inhibitory effect of the compound of Example 117 on the increase in ear thickness in the imiquimod-induced mouse psoriasis model. Fig. 25 shows the inhibitory effect of the compound of Example 74 on the increase of neurological symptom score in a mouse experimental autoimmune encephalomyelitis model. Fig. 15 shows the inhibitory effect of the compound of Example 46 on the increase in ear swelling rate in a dinitrofluorobenzene-induced mouse allergic dermatitis model. Fig. 24 shows the inhibitory effect of the compound of Example 74 on the increase in auricle swelling rate in a dinitrofluorobenzene-induced mouse allergic dermatitis model. FIG. 16 shows the inhibitory effect of the compound of Example 109 on the increase in ear swelling rate in a dinitrofluorobenzene-induced mouse allergic dermatitis model. Fig. 15 shows the inhibitory effect of the compound of Example 117 on the increase in ear swelling rate in a dinitrofluorobenzene-induced mouse allergic dermatitis model. Fig. 15 shows the inhibitory effect of the compound of Example 46 on the increase in ear thickness in an oxazolone-induced mouse atopic dermatitis model. Fig. 7 shows the inhibitory effect of the compound of Example 74 on the increase in ear thickness in a oxazolone-induced mouse atopic dermatitis model. It is a figure which shows the inhibitory effect of the compound of Example 109 with respect to the increase in the auricle thickness in a oxazolone-induced mouse atopic dermatitis model. Fig. 16 shows the inhibitory effect of the compound of Example 117 on the increase in ear thickness in an oxazolone-induced mouse atopic dermatitis model.

The cyclic amine derivative of the present invention is characterized by being represented by the following general formula (I).

The following terms used herein are as defined below unless otherwise indicated.

The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The "C1-C3 alkyl group" means a methyl group, an ethyl group, a propyl group or an isopropyl group.

The “alkyl group having 1 to 3 carbon atoms (in this alkyl group, any hydrogen atom of 1 to 3 may be substituted with a halogen atom)” means the above-mentioned alkyl having 1 to 3 carbon atoms 1 to 3 arbitrary hydrogen atoms of the group each independently represent a group which may be substituted by the above-mentioned halogen atom, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group and a fluoro group. Examples thereof include a methyl group, a difluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a trifluoroethyl group, a trichloromethyl group and a trichloroethyl group.

The "C1-C3 alkyl group (in the alkyl group, one to three arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom)" means the above-mentioned C1-C3 alkyl group. It means a group in which one to three arbitrary hydrogen atoms of three alkyl groups may be each independently substituted with a fluorine atom or a chlorine atom, and examples thereof include a methyl group, an ethyl group and a propyl group, And isopropyl group, fluoromethyl group, difluoromethyl group, trifluoromethyl group, 2-fluoroethyl group, trifluoroethyl group, trichloromethyl group or trichloroethyl group.

The "C1-C3 alkyloxy group" means a methoxy group, an ethoxy group, a propyloxy group or an isopropyloxy group.

The "C1-C3 alkyloxy group (in the alkyloxy group, one to three arbitrary hydrogen atoms may be substituted with a halogen atom)" means that the above-mentioned C1-C3 alkyl 1 to 3 optional hydrogen atoms of the alkyloxy group each independently represent an optionally substituted group of the above-mentioned halogen atoms, and examples thereof include a methoxy group, an ethoxy group and a propyloxy group, And isopropyloxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy, trifluoroethoxy, trichloromethoxy or trichloroethoxy.

The phrase "an alkyloxy group having 1 to 3 carbon atoms (in the alkyloxy group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom)" means the above-mentioned carbon number It means a group in which 1 to 3 optional hydrogen atoms of 1 to 3 alkyloxy groups may be each independently substituted with a fluorine atom or a chlorine atom, and examples thereof include a methoxy group and an ethoxy group, A propyloxy group, an isopropyloxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group, a 2-fluoroethoxy group, a trifluoroethoxy group, a trichloromethoxy group or a trichloroethoxy group can be mentioned.

The “C1-C3 alkylsulfonyl group” means a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group or an isopropylsulfonyl group.

The “C4 to C4 acyl group” means an acetyl group, a propionyl group, a butanoyl group or a 2-methylpropanoyl group.

“Cyclic ether group having 4 to 6 ring atoms” includes oxetan-2-yl group, oxetan-3-yl group, tetrahydrofuran-2-yl group, tetrahydrofuran-3-yl group, tetrahydro-2H-pyran-2 -Yl, tetrahydro-2H-pyran-3-yl or tetrahydro-2H-pyran-4-yl is meant.

The "aryl group" means an aromatic hydrocarbon group, and examples thereof include a phenyl group, a 1-naphthyl group or a 2-naphthyl group.

“Heteroaryl group” means a heteroaromatic group containing 1 to 4 hetero atoms each independently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, each independently selected from, for example, , Thienyl group, pyrrolyl group, furyl group, thiazolyl group, imidazolyl group, oxazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, triazolyl group, oxadiazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group or triazinyl Groups are mentioned.

“1 to 3 arbitrary hydrogen atoms are a halogen atom, a cyano group, a hydroxymethyl group, —C (= O) —OR ³ , an alkylsulfonyl group having 1 to 3 carbon atoms, an alkyl having 1 to 3 carbon atoms Group (in the alkyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom) and an alkyloxy group having 1 to 3 carbon atoms (the alkyloxy group is 1 to 3) And “optionally substituted hydrogen atom” may be substituted with a group selected from the group consisting of halogen atoms, and “aryl group” means one or more of the above aryl groups And each hydrogen atom is independently a halogen atom, a cyano group, a hydroxymethyl group, -C (= O) -OR ³ , an alkylsulfonyl group having 1 to 3 carbon atoms as described above, 1 carbon atom as described above To 3 alkyl groups (wherein the alkyl group is 1 to And 3 optional hydrogen atoms may be substituted with a halogen atom) and the above-mentioned alkyloxy group having 1 to 3 carbon atoms (in the alkyloxy group, 1 to 3 optional hydrogen atoms are a halogen) A group optionally substituted with a group selected from the group consisting of atoms, for example, phenyl group, 1-naphthyl group, 2-naphthyl group, fluorophenyl group, Difluorophenyl group, Chlorophenyl group, dichlorophenyl group, chlorofluorophenyl group, bromophenyl group, iodophenyl group, tolyl group, dimethylphenyl group, ethylphenyl group, propylphenyl group, isopropylphenyl group, fluoromethylphenyl group, chloromethylphenyl group Group, (fluoromethyl) phenyl group, (difluoromethyl) phenyl group, (trifluoromethane) ) Phenyl group, (2-fluoroethyl) phenyl group, (trifluoroethyl) phenyl group, (trichloromethyl) phenyl group, (trichloroethyl) phenyl group, fluoro (trifluoromethyl) phenyl group, chloro (trifluoromethyl) ) Phenyl group, methyl (trifluoromethyl) phenyl group, methoxyphenyl group, ethoxyphenyl group, propyloxyphenyl group, isopropyloxyphenyl group, (fluoromethoxy) phenyl group, (difluoromethoxy) phenyl group, (trifluoromethoxy) Phenyl group, (2-fluoroethoxy) phenyl group, (trifluoroethoxy) phenyl group, (trichloromethoxy) phenyl group, (trichloroethoxy) phenyl group, fluoromethoxyphenyl group, chloromethoxyphenyl group, Xymethylphenyl group, methoxy (trifluoromethyl) phenyl group, fluoro (trifluoromethoxy) phenyl group, chloro (trifluoromethoxy) phenyl group, methyl (trifluoromethoxy) phenyl group, methoxy (trifluoromethoxy) phenyl group, (Methylsulfonyl) phenyl group, (ethylsulfonyl) phenyl group, (propylsulfonyl) phenyl group, (isopropylsulfonyl) phenyl group, cyanophenyl group, cyanofluorophenyl group, chlorocyanophenyl group, cyanomethylphenyl group, cyano Fluoromethyl) phenyl group, cyano (trifluoromethoxy) phenyl group, (hydroxymethyl) phenyl group, (hydroxycarbonyl) phenyl group, (methoxycarbonyl) phenyl group, (ethoxycarbonyl) And R) phenyl group, (propyloxycarbonyl) phenyl group or (isopropyloxycarbonyl) phenyl group.

“1 to 3 arbitrary hydrogen atoms are a halogen atom, a cyano group, a hydroxymethyl group, —C (= O) —OR ³ , an alkylsulfonyl group having 1 to 3 carbon atoms, an alkyl having 1 to 3 carbon atoms Group (in the alkyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom) and an alkyloxy group having 1 to 3 carbon atoms (the alkyloxy group is 1 to 3) And “optionally hydrogen atom may be substituted with a halogen atom.)”, A heteroaryl group which may be substituted with a group selected from the group consisting of one of the above-mentioned heteroaryl groups -3 optional hydrogen atoms are each independently a halogen atom, a cyano group, a hydroxymethyl group, -C (= O) -OR ³ , an alkylsulfonyl group having 1 to 3 carbon atoms as described above, the above carbons Several alkyl groups (the alkyl And 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom), and the above-mentioned alkyl having 1 to 3 carbon atoms (the alkyloxy group is 1 to 3). A hydrogen atom optionally substituted with a halogen atom)) means a group optionally substituted with a group selected from the group consisting of: thienyl group, pyrrolyl group, furyl group, thiazolyl group , Oxazolyl group, isothiazolyl group, isoxazolyl group, oxadiazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, fluorothienyl group, chlorothienyl group, methylthienyl group, dimethylthienyl group, ethylthienyl group, (trifluoromethyl) Thienyl group, methoxythienyl group, fluoropyrrolyl group, chloropyrrolyl group, methylpyrrolyl group, Ryl group, ethyl pyrrolyl group, (trifluoromethyl) pyrrolyl group, methoxy pyrrolyl group, fluorofuryl group, chlorofuryl group, methylfuryl group, methylfuryl group, dimethylfuryl group, ethylfuryl group, (trifluoromethyl) furyl group, methoxyfuryl group Fluorothiazolyl group, chlorothiazolyl group, methylthiazolyl group, dimethylthiazolyl group, ethylthiazolyl group, (trifluoromethyl) thiazolyl group, methoxythiazolyl group, fluorooxazolyl group, chlorooxazolyl group, methyloxaxyl group Zoryl group, dimethyl oxazolyl group, ethyl oxazolyl group, (trifluoromethyl) oxazolyl group, methoxy oxazolyl group, fluoroisothiazolyl group, chloroisothiazolyl group, methylisothiazolyl group, dimethylisothiol group Azolyl group, ethyl isothi Zoryl group, (trifluoromethyl) isothiazolyl group, fluoroisoxazolyl group, chloroisoxazolyl group, methylisoxazolyl group, dimethylisoxazolyl group, ethylisoxazolyl group, (trifluoromethyl ) Isoxazolyl group, methoxy isoxazolyl group, fluoro oxadiazolyl group, chloro oxadiazolyl group, methyl oxadiazolyl group, ethyl oxadiazolyl group, (trifluoromethyl) oxadiazolyl group, methoxy oxadiazolyl group, fluoro A pyridyl group, a difluoro pyridyl group, a chloro pyridyl group, a dichloro pyridyl group, a chloro fluoro pyridyl group, a methyl pyridyl group, a dimethyl pyridyl group, an ethyl pyridyl group, a fluoro methyl pyridyl group, a chloro methyl pyridyl group, (trifluoromethyl) Lysyl group, fluoro (trifluoromethyl) pyridyl group, chloro (trifluoromethyl) pyridyl group, methyl (trifluoromethyl) pyridyl group, methoxy pyridyl group, fluoro methoxy pyridyl group, chloro methoxy pyridyl group, methoxy methyl pyridyl group ( (Trifluoromethoxy) pyridyl group, fluoro (trifluoromethoxy) pyridyl group, chloro (trifluoromethoxy) pyridyl group, methyl (trifluoromethoxy) pyridyl group, fluoropyridazinyl group, chloropyridazinyl group, methylpyri Dazinyl group, dimethylpyridazinyl group, ethyl pyridazinyl group, (trifluoromethyl) pyridazinyl group, methoxypyridazinyl group, (trifluoromethoxy) pyridazinyl group, fluoropyrimidinyl group, difluoropyrimidinyl group, Black Pyrimidinyl, dichloropyrimidinyl, chlorofluoropyrimidinyl, methyl pyrimidinyl, dimethyl pyrimidinyl, ethyl pyrimidinyl, fluoromethyl pyrimidinyl, chloromethyl pyrimidinyl, (trifluoromethyl) pyrimidinyl, fluoro (trifluoromethyl) pyrimidinyl , Chloro (trifluoromethyl) pyrimidinyl group, methyl (trifluoromethyl) pyrimidinyl group, methoxy pyrimidinyl group, fluoromethoxy pyrimidinyl group, chloromethoxy pyrimidinyl group, methoxymethyl pyrimidinyl group, (trifluoromethoxy) pyrimidinyl group, fluoro (trifluoro) (Methoxy) pyrimidinyl group, chloro (trifluoromethoxy) pyrimidinyl group, methyl (trifluoromethoxy) pyrimidinyl group, Ruoropirajiniru group, Kuroropirajiniru group, Mechirupirajiniru group, dimethyl pyrazinyl group, Echirupirajiniru group, (trifluoromethyl) pyrazinyl group or a methoxy pyrazinyl group, and a (trifluoromethoxy) pyrazinyl groups.

“One or two optional hydrogen atoms are fluorine, chlorine, cyano, hydroxymethyl, —C (、 O) —OR ³ , alkylsulfonyl having 1 to 3 carbon atoms, 1 to 3 carbon atoms An alkyl group of 3 (in the alkyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom) and an alkyloxy group having 1 to 3 carbon atoms (the alkyloxy group Is optionally substituted with a group selected from the group consisting of 1 to 3 arbitrary hydrogen atoms which may be substituted with a fluorine atom or a chlorine atom), a phenyl group, a pyridyl group or The “pyrimidinyl group” means that one or two optional hydrogen atoms of a phenyl group, a pyridyl group or a pyrimidinyl group are each independently a fluorine atom, a chlorine atom, a cyano group, a hydroxymethyl group, —C (= O ) -O ^3, the above alkylsulfonyl group having 1 to 3 carbon atoms, alkyl group (the alkyl group having a carbon number of 1 to 3 above, one to three arbitrary hydrogen atoms are substituted with fluorine atom or chlorine atom And the above-mentioned alkyloxy group having 1 to 3 carbon atoms (in the alkyloxy group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom), Means a group optionally substituted with a group selected from the group consisting of: phenyl group, fluorophenyl group, difluorophenyl group, chlorophenyl group, dichlorophenyl group, chlorofluorophenyl group, tolyl group, dimethylphenyl group , Ethylphenyl group, propylphenyl group, isopropylphenyl group, fluoromethylphenyl group, chloromethylphenyl group, (fluoromethyl group Phenyl group, (difluoromethyl) phenyl group, (trifluoromethyl) phenyl group, (2-fluoroethyl) phenyl group, (trifluoroethyl) phenyl group, (trichloromethyl) phenyl group, (trichloroethyl) phenyl group, fluoro (Trifluoromethyl) phenyl group, chloro (trifluoromethyl) phenyl group, methyl (trifluoromethyl) phenyl group, methoxyphenyl group, ethoxyphenyl group, propyloxyphenyl group, isopropyloxyphenyl group, (fluoromethoxy) phenyl group , (Difluoromethoxy) phenyl group, (trifluoromethoxy) phenyl group, (2-fluoroethoxy) phenyl group, (trifluoroethoxy) phenyl group, (trichloromethoxy) phenyl group, (trichloroethoxy) phenyl group Group, fluoromethoxyphenyl group, chloromethoxyphenyl group, methoxymethylphenyl group, methoxy (trifluoromethyl) phenyl group, fluoro (trifluoromethoxy) phenyl group, chloro (trifluoromethoxy) phenyl group, methyl (trifluoromethoxy) Phenyl group, methoxy (trifluoromethoxy) phenyl group, (methylsulfonyl) phenyl group, (ethylsulfonyl) phenyl group, (propylsulfonyl) phenyl group, (isopropylsulfonyl) phenyl group, cyanophenyl group, cyanofluorophenyl group, chloro Cyanophenyl group, cyanomethylphenyl group, cyano (trifluoromethyl) phenyl group, cyano (trifluoromethoxy) phenyl group, (hydroxymethyl) phenyl group, (hydroxycarbonyl) phenyl Group, (methoxycarbonyl) phenyl group, (ethoxycarbonyl) phenyl group, (propyloxycarbonyl) phenyl group, (isopropyloxycarbonyl) phenyl group, fluoropyridyl group, difluoropyridyl group, chloropyridyl group, dichloropyridyl group, chloro Fluoropyridyl group, methyl pyridyl group, dimethyl pyridyl group, ethyl pyridyl group, fluoro methyl pyridyl group, chloromethyl pyridyl group, (trifluoromethyl) pyridyl group, fluoro (trifluoromethyl) pyridyl group, chloro (trifluoromethyl) pyridyl Group, methyl (trifluoromethyl) pyridyl group, methoxy pyridyl group, fluoromethoxy pyridyl group, chloromethoxy pyridyl group, methoxymethyl pyridyl group, (trifluoromethoxy) pyridyl group, Luoro (trifluoromethoxy) pyridyl group, chloro (trifluoromethoxy) pyridyl group, methyl (trifluoromethoxy) pyridyl group, fluoropyrimidinyl group, difluoropyrimidinyl group, chloropyrimidinyl group, dichloropyrimidinyl group, chlorofluoropyrimidinyl group, methyl pyrimidinyl group Group, dimethyl pyrimidinyl group, ethyl pyrimidinyl group, fluoromethyl pyrimidinyl group, chloromethyl pyrimidinyl group, (trifluoromethyl) pyrimidinyl group, fluoro (trifluoromethyl) pyrimidinyl group, chloro (trifluoromethyl) pyrimidinyl group, methyl (trifluoro) Methyl) pyrimidinyl group, methoxy pyrimidinyl group, fluoromethoxy pyrimidinyl group, chloromethoxy pyrimidinyl group, methoxymethyl pyrimidinyl group (Trifluoromethoxy) pyrimidinyl group, fluoro (trifluoromethoxy) pyrimidinyl group, chloro (trifluoromethoxy) pyrimidinyl group or a methyl (trifluoromethoxy) include pyrimidinyl group.

The “methyl group in which one to three arbitrary hydrogen atoms may be substituted with a fluorine atom” means a methyl group, a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group.

The “methoxy group in which one to three optional hydrogen atoms may be substituted with a fluorine atom” means a methoxy group, a fluoromethoxy group, a difluoromethoxy group or a trifluoromethoxy group.

“One or two optional hydrogen atoms are a fluorine atom, a chlorine atom, a cyano group, an isopropyl group, a methyl group in which one to three optional hydrogen atoms may be substituted with a fluorine atom, and one The term “phenyl group optionally substituted by a group selected from the group consisting of methoxy group optionally substituted with a hydrogen atom of up to 3 hydrogen atoms” means one or two phenyl groups And each of the hydrogen atoms is independently a fluorine atom, a chlorine atom, a cyano group, an isopropyl group, a methyl group in which any one of the aforementioned 1 to 3 hydrogen atoms may be substituted with a fluorine atom, and Or a group optionally substituted with a group selected from the group consisting of a methoxy group in which one to three arbitrary hydrogen atoms may be substituted with a fluorine atom; Phenyl group, diful Lophenyl group, chlorophenyl group, dichlorophenyl group, chlorofluorophenyl group, tolyl group, dimethylphenyl group, isopropylphenyl group, fluoromethylphenyl group, chloromethylphenyl group, (fluoromethyl) phenyl group, (difluoromethyl) phenyl group, ( Trifluoromethyl) phenyl group, (trichloromethyl) phenyl group, fluoro (trifluoromethyl) phenyl group, chloro (trifluoromethyl) phenyl group, methyl (trifluoromethyl) phenyl group, methoxyphenyl group, (fluoromethoxy) phenyl Group, (difluoromethoxy) phenyl group, (trifluoromethoxy) phenyl group, (trichloromethoxy) phenyl group, fluoromethoxyphenyl group, chloromethoxyphenyl group, methoxymethylphenyl , Methoxy (trifluoromethyl) phenyl group, fluoro (trifluoromethoxy) phenyl group, chloro (trifluoromethoxy) phenyl group, methyl (trifluoromethoxy) phenyl group, methoxy (trifluoromethoxy) phenyl group, cyanophenyl group, Examples thereof include cyanofluorophenyl group, chlorocyanophenyl group, cyanomethylphenyl group, cyano (trifluoromethyl) phenyl group or cyano (trifluoromethoxy) phenyl group.

“One or two optional hydrogen atoms are substituted with a group selected from the group consisting of fluorine atom, chlorine atom, methyl group, isopropyl group, trifluoromethyl group, difluoromethoxy group and trifluoromethoxy group The “optionally substituted phenyl group” means that one or two optional hydrogen atoms of the phenyl group are each independently a fluorine atom, a chlorine atom, a methyl group, an isopropyl group, a trifluoromethyl group, a difluoromethoxy group And a group optionally substituted with a group selected from the group consisting of and trifluoromethoxy, such as phenyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, chlorofluorophenyl, Tolyl, dimethylphenyl, isopropylphenyl, fluoromethylphenyl, Lomethylphenyl group, (trifluoromethyl) phenyl group, fluoro (trifluoromethyl) phenyl group, chloro (trifluoromethyl) phenyl group, methyl (trifluoromethyl) phenyl group, (difluoromethoxy) phenyl group, (trifluoro Mention may be made of methoxy) phenyl, fluoro (trifluoromethoxy) phenyl, chloro (trifluoromethoxy) phenyl or methyl (trifluoromethoxy) phenyl.

The “heteroaryl group in which one or two optional hydrogen atoms may be substituted with an alkyl group having 1 to 3 carbon atoms” means one or two optional hydrogen atoms of the above-mentioned heteroaryl group. And each independently represent the group which may be substituted with the above-mentioned alkyl group having 1 to 3 carbon atoms, and examples thereof include thienyl group, pyrrolyl group, furyl group, thiazolyl group, imidazolyl group, oxazolyl group and pyrazolyl group. Group, isothiazolyl group, isoxazolyl group, triazolyl group, oxadiazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, methylthienyl group, dimethylthienyl group, dimethylthienyl group, ethylthienyl group, methylpyrrolyl group, dimethylpyrrolyl group Group, ethyl pyrrolyl group, methyl furyl group, dimethyl furyl group, ethyl Group, methyl thiazolyl group, dimethyl thiazolyl group, ethyl thiazolyl group, methyl imidazolyl group, dimethyl imidazolyl group, ethyl imidazolyl group, methyl oxazolyl group, dimethyl oxazolyl group, ethyl oxazolyl group, methyl pyrazolyl group, dimethyl Pyrazolyl group, ethyl pyrazolyl group, methylisothiazolyl group, dimethylisothiazolyl group, ethylisothiazolyl group, methylisoxazolyl group, dimethylisoxazolyl group, ethylisoxazolyl group, methyltriazolyl group Group, dimethyl triazolyl group, ethyl triazolyl group, methyl oxadiazolyl group, ethyl oxadiazolyl group, methyl tetrazolyl group, ethyl tetrazolyl group, methyl pyridyl group, dimethyl pyridyl group, ethyl pyridyl group, Methyl pyridazinyl group, di Ethyl pyridazinyl group, ethyl pyridazinyl group, methyl pyrimidinyl group, dimethyl pyrimidinyl group, ethyl pyrimidinyl group, methyl pyrazinyl group, methyl pyrazinyl group, dimethyl pyrazinyl group, ethyl pyrazinyl group, ethyl pyrazinyl group, methyl triazinyl group, dimethyl triazinyl group or ethyl triazinyl Groups are mentioned.

The “heteroaryl group in which one or two arbitrary hydrogen atoms may be substituted with a methyl group” means that one or two arbitrary hydrogen atoms in the above heteroaryl group are substituted with a methyl group. Means an optionally substituted group such as thienyl group, pyrrolyl group, furyl group, thiazolyl group, imidazolyl group, oxazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, triazolyl group, oxadiazolyl group, tetrazolyl group, pyridyl group, Pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazinyl group, methylthienyl group, dimethylthienyl group, methylpyrrolyl group, dimethylpyrrolyl group, methylpyrrolyl group, methylfuryl group, dimethylfuryl group, methylthiazolyl group, dimethylthiazolyl group, methylimidazolyl group, dimethyl Imidazolyl group, methyl oxazo Group, dimethyloxazolyl group, methylpyrazolyl group, dimethylpyrazolyl group, methylisothiazolyl group, dimethylisothiazolyl group, methylisoxazolyl group, dimethylisoxazolyl group, methyltriazolyl group, dimethyl Triazolyl group, methyl oxadiazolyl group, methyl tetrazolyl group, methyl pyridyl group, dimethyl pyridyl group, methyl pyridazinyl group, dimethyl pyridazinyl group, methyl pyrimidinyl group, dimethyl pyrimidinyl group, methyl pyrazinyl group, Dimethyl pyrazinyl group, methyl triazinyl group or dimethyl triazinyl group is mentioned.

The “imidazolyl group, pyrazolyl group, triazolyl group, 1,3,4-oxadiazolyl group, tetrazolyl group or pyridyl group” in which “one or two arbitrary hydrogen atoms may be substituted with a methyl group” means imidazolyl A group in which one or two arbitrary hydrogen atoms of a group, pyrazolyl group, triazolyl group, 1,3,4-oxadiazolyl group, tetrazolyl group or pyridyl group may be substituted with a methyl group, for example, Imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, 1,3,4-oxadiazolyl group, pyridyl group, methyl imidazolyl group, dimethyl imidazolyl group, methyl pyrazolyl group, dimethyl pyrazolyl group, methyl triazolyl group, dimethyl triazolyl group Group, methyl-1,3,4-oxadiazolyl group, methyl teto Zoriru groups include methylpyridyl or dimethylpyridyl group.

“A triazolyl group, a 1,3,4-oxadiazolyl group or a tetrazolyl group in which one or two optional hydrogen atoms may be substituted with a methyl group” means a triazolyl group or a 1,3,4-oxadiazolyl group It means a group in which one or two arbitrary hydrogen atoms of a group or tetrazolyl group may be substituted with a methyl group, and examples thereof include triazolyl group, 1,3,4-oxadiazolyl group, tetrazolyl group, methyl triazolyl group Groups, dimethyl triazolyl group, methyl-1,3,4-oxadiazolyl group or methyl tetrazolyl group.

The “cyclic amine derivative represented by the general formula (I), its stereoisomer or hydrate thereof, or the pharmacologically acceptable salt thereof” is a cyclic amine represented by the general formula (I) Derivative, stereoisomer of cyclic amine derivative represented by the general formula (I), hydrate of cyclic amine derivative represented by the general formula (I), stereoisomer of cyclic amine derivative represented by the general formula (I) Hydrate, pharmacologically acceptable salt of cyclic amine derivative represented by the general formula (I), pharmacologically acceptable salt of stereoisomer of cyclic amine derivative represented by the general formula (I), Pharmacologically acceptable salt of the hydrate of the cyclic amine derivative represented by the general formula (I) or pharmacologically acceptable of the hydrate of the stereoisomer of the cyclic amine derivative represented by the general formula (I) Mean salt.

In the above-mentioned cyclic amine derivative, in the general formula (I), one or two arbitrary hydrogen atoms in R ¹ are a fluorine atom, a chlorine atom, a cyano group, a hydroxymethyl group, -C (= O)- OR ³ , an alkylsulfonyl group having 1 to 3 carbon atoms, an alkyl group having 1 to 3 carbon atoms (in the alkyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom And an alkyloxy group having 1 to 3 carbon atoms (wherein any hydrogen atom of 1 to 3 may be substituted with a fluorine atom or a chlorine atom), and the alkyloxy group having 1 to 3 carbon atoms is selected from It is preferable that it is a phenyl group, a pyridyl group or a pyrimidinyl group which may be substituted by the above-mentioned group, and one or two optional hydrogen atoms are a fluorine atom, a chlorine atom, a cyano group, an isopropyl group, 1 to 3 Arbitrary hydrogen atom is substituted by a group selected from the group consisting of a methyl group which may be substituted by a fluorine atom and one to three arbitrary hydrogen atoms which may be substituted by a fluorine atom More preferably, it is a phenyl group which may be substituted, and one or two optional hydrogen atoms are a fluorine atom, a chlorine atom, a methyl group, an isopropyl group, a trifluoromethyl group, a difluoromethoxy group and a trifluoromethoxy group. More preferably, it is a phenyl group which may be substituted by a group selected from the group consisting of:

R ² is preferably a fluorine atom or a chlorine atom, and more preferably a chlorine atom.

R ³ is preferably an alkyl group having 1 to 3 carbon atoms.

N is preferably an integer of 0 to 4, more preferably an integer of 0 to 3, and still more preferably an integer of 0 to 2.

R ⁴ represents a cyano group, a hydroxy group, -N (R ⁶ ) R ⁷ , -NH-C (= Y) -NHR ⁶ , -NH-S (= O) ₂ -NHR ⁶ , -C (= O) -OR ⁶ , -C (= O) -NHR ⁶ , oxetan-3-yl group, alkyl group having 1 to 3 carbon atoms (in the alkyl group, one to three arbitrary hydrogen atoms are a fluorine atom or chlorine Preferably, it is a heteroaryl group which may be substituted by an atom, or one or two arbitrary hydrogen atoms may be substituted by a methyl group, a methyl group, a cyano group,- N (R ⁶ ) R ⁷ , —NH—C (= Y) —NHR ⁶ , —NH—S (= O) ₂ —NHR ⁶ , an oxetan-3-yl group, or one or two arbitrary Imidazolyl group, pyrazolyl group, triazo wherein the hydrogen atom may be substituted by a methyl group Ryl, 1,3,4-oxadiazolyl, tetrazolyl or pyridyl is more preferred, and methyl, cyano, -N (R ⁶ ) R ⁷ , -NH-C (= Y) -NHR ⁶ , -NH-S (= O) ₂ -NHR ⁶ or a triazolyl group, a 1,3,4-oxadiazolyl group or a 1 or 2 optional hydrogen atom may be substituted with a methyl group More preferably, it is a tetrazolyl group.

R ⁵ is preferably a methyl group.

R ⁶ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (in the alkyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom) Preferably, it is a hydrogen atom or a methyl group.

R ⁷ is preferably a hydrogen atom, a methyl group, an acetyl group or a methylsulfonyl group.

Y is preferably an oxygen atom or NN-CN.

The cyclic amine derivative represented by the above general formula (I) preferably has a configuration represented by the following general formula (Ia). That is, in the cyclic amine derivative represented by the above general formula (I), in the above general formula (I), the configuration of the carbon atom at the 2-position of the piperidinyl group is preferably R configuration.

A has the following general formula (II-1), (II-2-a), (II-3-a), (II-4), (II-5-a) or (II-5-b) It is preferably a group represented by That is, in the above general formula (II-2), the group represented by the above general formula (II-2) is preferably a group in which the configuration of the carbon atom at the 3-position of the piperidinyl group is S configuration, The group represented by the general formula (II-3) is preferably a group in which the configuration of the carbon atom at the 3-position of the pyrrolidinyl group in the above general formula (II-3) is S configuration.

In the cyclic amine derivative represented by the above general formula (I), the preferable R ¹ , the preferable R ² , the preferable R ³ , the preferable R ⁴ , the preferable R ⁵ , and the preferable R ^{6 as} described above. The above-mentioned preferable R ⁷ , the above-mentioned preferred n, the above-mentioned preferred Y, the above-mentioned preferred general formula (I) and the above-mentioned preferred A can be selected and combined in any manner. For example, the following combinations may be mentioned, but are not limited thereto.

In the cyclic amine derivative represented by the above general formula (I), R ¹ is a hydrogen atom, a cyano group, a hydroxymethyl group, -C (= O) -OR ^{3 in which} 1 to 3 optional hydrogen atoms are contained. And an alkylsulfonyl group having 1 to 3 carbon atoms and an alkyl group having 1 to 3 carbon atoms (in the alkyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with halogen atoms) and the carbon number 1 to 3 alkyloxy groups (wherein each of 1 to 3 optional hydrogen atoms may be substituted with a halogen atom), which is substituted with a group selected from the group consisting of R ² is a halogen atom, R ³ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and a double line of a solid line and a dotted line is preferably an aryl group or a heteroaryl group; A single bond or a double bond, the wavy line is A point of attachment to the general formula (I-a), X _{is, -C (= O) - (} CH 2) n -R 4 or -S _{(= O)} is 2 -R ^5, n is 0 R ⁴ is a cyano group, a hydroxy group, -N (R ⁶ ) R ⁷ , -NH-C (= Y) -NHR ⁶ , -NH-S (= O) ₂ -NHR ⁶ , -C (= O) -OR ⁶ , -C (= O) -NHR ⁶ , cyclic ether group having 4 to 6 ring atoms, alkyl group having 1 to 3 carbon atoms (the alkyl group is 1 to 3 optional hydrogen atoms may be substituted with a halogen atom) or heteroaryl having 1 or 2 optional hydrogen atoms optionally substituted with an alkyl group of 1 to 3 carbon atoms group is,, R ⁵ is an alkyl group having 1 to 3 carbon atoms, R ⁶ is a hydrogen atom or an alkyl group (the alkyl group having a carbon number of 1 to 3, 1 1-3 arbitrary hydrogen atom may be substituted with a halogen atom.), And, R ⁷ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an acyl group or a carbon number of 2 to 4 carbon atoms 1 to 3 alkylsulfonyl group, Y is an oxygen atom, a sulfur atom or = N-CN, general formula (I) is a general formula (I-a) below, and A is A group represented by general formula (II-1), (II-2-a), (II-3-a), (II-4), (II-5-a) or (II-5-b) Is preferred.

In another embodiment, in the cyclic amine derivative represented by the above general formula (I), one or two optional hydrogen atoms of R ¹ may be fluorine atom, chlorine atom, methyl group, isopropyl group, trifluoro A phenyl group which may be substituted by a group selected from the group consisting of a methyl group, a difluoromethoxy group and a trifluoromethoxy group, R ² is a chlorine atom, and n is an integer of 0 to 2 And R ⁴ is a methyl group, a cyano group, -N (R ⁶ ) R ⁷ , -NH-C (= Y) -NHR ⁶ , -NH-S (= O) ₂ -NHR ⁶ or 1 Or two optional hydrogen atoms may be substituted with a methyl group, a triazolyl group, a 1,3,4-oxadiazolyl group or a tetrazolyl group, R ⁵ is a methyl group, and R ⁶ is Hydrogen or methyl Ri, ^{R 7} is a hydrogen atom, a methyl group, an acetyl group or a methylsulfonyl group, Y is an oxygen atom or = N-CN, general formula (I), the above general formula (I-a) And A is a group represented by the general formula (II-1), (II-2-a), (II-3-a), (II-4), (II-5-a) or (II-5) described above. It is more preferable that it is a group represented by -b).

Specific examples of preferable compounds of the cyclic amine derivative represented by the above general formula (I) are shown in Tables 1-1 to 1-5, but the present invention is not limited thereto.

The compounds described in Tables 1-1 to 1-5 also include their stereoisomers and their hydrates, and their pharmacologically acceptable salts, and their mixtures.

The cyclic amine derivatives represented by the above general formula (I) may exist as stereoisomers, but include not only single isomers but also mixtures such as racemates and mixtures of diastereomers.

"Stereoisomer" refers to a compound having the same chemical structure but different arrangement in three-dimensional space, such as, for example, conformer, rotamer, tautomer, optical isomer, diastereomer Etc.

The cyclic amine derivative represented by the above general formula (I) may be labeled with one or more isotopes, and the isotopes to be labeled include, for example, ² H, ³ H, ¹³ C, ¹⁴ C , ¹⁵ N, ¹⁵ O, ¹⁸ O and / or ¹²⁵ I.

Examples of the “pharmacologically acceptable salt” of the cyclic amine derivative represented by the above general formula (I) include salts with inorganic bases, salts with organic bases, salts with inorganic acids or organic acids Salt of Examples of salts with inorganic bases include alkali metal salts such as sodium salts or potassium salts, alkaline earth metal salts such as calcium salts or magnesium salts, ammonium salts, aluminum salts or zinc salts, and salts with organic bases Examples of the salt include salts with organic amines such as triethylamine, ethanolamine, morpholine, piperidine or dicyclohexylamine, and salts with basic amino acids such as arginine or lysine. Examples of salts with inorganic acids include hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides or phosphates, and salts with organic acids include, for example, oxalic acid. Salt, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, ascorbic acid Salt, glutarate, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, aspartate, glutamate or cinnamate An acid salt etc. are mentioned. In addition, “pharmaceutically acceptable salts” of stereoisomers of cyclic amine derivatives represented by the above general formula (I), “hydrates of hydrates of cyclic amine derivatives represented by the above general formula (I) The same applies to "pharmacologically acceptable salts" and "pharmaceutically acceptable salts" of hydrates of stereoisomers of cyclic amine derivatives represented by the above general formula (I).

The cyclic amine derivative represented by the above general formula (I) or a stereoisomer thereof, or a pharmacologically acceptable salt thereof may be an anhydride or a solvate such as a hydrate May be formed. Here, as a solvate, a pharmacologically acceptable solvate is preferable. The pharmacologically acceptable solvate may be either hydrate or non-hydrate, but hydrate is preferred. Examples of the solvent constituting the solvate include alcohol solvents such as methanol, ethanol or n-propanol, N, N-dimethylformamide (hereinafter, DMF), dimethyl sulfoxide (hereinafter, DMSO) or water.

The cyclic amine derivative represented by the above general formula (I) (hereinafter, cyclic amine derivative (I)) can be produced by an appropriate method based on the characteristics derived from the basic skeleton and the type of substituent. Starting materials and reagents used for producing these compounds can be generally purchased or can be produced by known methods.

The cyclic amine derivative (I) and the intermediates and starting materials used for its preparation can be isolated and purified by known means. Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.

When the cyclic amine derivative (I) contains a stereoisomer, each optical isomer or diastereomer can be obtained as a single optically active substance by a known method. Known methods include, for example, crystallization, enzymatic resolution or chiral chromatography.

The crystallization can be carried out according to a known method (for example, Brittain, H. G., "Polymorphism in Pharmaceutical Solids, Second Edition", CRC Press) or a method analogous thereto.

As a solvent used for crystallization of cyclic amine derivative (I), its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof, for example, tetrahydrofuran (hereinafter THF), 1, 1 Ether solvents such as 4-dioxane, diethyl ether, tert-butyl methyl ether or anisole, methanol, ethanol, 2-methoxyethanol, 2-ethoxyethanol, n-propanol, 2-propanol, 2-methyl-1-propanol, Alcohol solvents such as n-butanol, 2-butanol, 3-methyl-1-butanol, n-pentanol or ethylene glycol, aromatic hydrocarbon solvents such as toluene, xylene, cumene or tetralin DMF, N, N -Dimethylacetamide, formamide, N Aprotic polar solvents such as methyl pyrrolidone, DMSO or sulfolane, nitrile solvents such as acetonitrile or propionitrile, ester solvents such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, butyl acetate, isobutyl acetate or ethyl formate Ketone solvents such as acetone, methyl ethyl ketone, methyl butyl ketone or methyl isobutyl ketone, halogen solvents such as dichloromethane, chloroform, 1,2-dichloroethene, 1,1,2-trichloroethene or chlorobenzene, hexane, pentane, heptane Hydrocarbon solvents such as cyclohexane or methylcyclohexane, nitro solvents such as nitromethane, pyridine solvents such as pyridine, carboxylic acid solvents such as acetic acid or formic acid, water A mixed solvent thereof, or a mixed solvent of these solvents and cyclic amine derivative (I) and a solvent containing a base or acid to form the pharmacologically acceptable salts thereof.

In each reaction of the production method described below, when the raw material compound has an amino group or a carboxyl group, a protective group may be introduced to these groups, and after the reaction, the protective group is optionally deprotected. Thus, the target compound can be obtained.

As a protecting group of an amino group, for example, an alkylcarbonyl group having 2 to 6 carbon atoms (eg, acetyl group), benzoyl group, an alkyloxycarbonyl group having 2 to 8 carbon atoms (eg, tert-butoxycarbonyl group or benzyloxy) And a carbonyl group), an aralkyl group having 7 to 10 carbon atoms (eg, benzyl group) or a phthaloyl group.

Examples of the protecting group for the carboxyl group include, for example, an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group or tert-butyl group) or an aralkyl group having 7 to 10 carbon atoms (eg, benzyl group).

The deprotection of the protective group varies depending on the type of protective group, but is carried out according to known methods (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method according thereto. be able to.

The cyclic amine derivative (I) is, for example, as shown in Scheme 1, a condensation reaction (step 1) of an aniline derivative (III) with a pipecolic acid derivative (IV) in the presence of a condensing agent and a base (step 1), followed by an acid Deprotection reaction of tert-butoxycarbonyl group of N-tert-butoxycarbonylpipecolic acid amide derivative (V) obtained in the first step in the presence (step 2), followed by the second step in the presence of a base A condensation reaction of the pipecolic acid amide derivative (VI) obtained in the above and the organic acid chloride derivative (VII) can be obtained (the third step). In addition, cyclic amine derivative (I) can also be obtained by condensation reaction of pipecolic acid amide derivative (VI) with organic acid anhydride derivative (VIII). The cyclic amine derivative (I) can also be obtained by the condensation reaction of the pipecolic acid amide derivative (VI) and the organic acid derivative (IX) in the presence of a condensing agent and a base. Moreover, cyclic amine derivative (I) can also be obtained by condensation reaction of pipecolic acid amide derivative (VI) with trimethylsilyl isocyanate in the presence of a base. The optically active form of cyclic amine derivative (I) can be obtained, for example, by using the optically active form of pipecolic acid derivative (IV).

In the above cyclic amine derivative (I), for example, when it contains an amino group, the amino group is converted to an amide group, a sulfonamide group, etc. or an N-alkyl compound by condensation reaction or reductive amination reaction, etc It may be converted. When an ester group is contained, the ester group may be converted to a carboxyl group by a hydrolysis reaction. In addition, when a double bond is contained, the double bond may be converted to a single bond by a reduction reaction.

[Wherein, A and X are as defined above. ]

(Step 1)
The amount of pipecolic acid derivative (IV) used for the condensation reaction is preferably 0.1 to 10 equivalents, and more preferably 0.5 to 3 equivalents with respect to aniline derivative (III).

Examples of the condensing agent used for the condensation reaction include N, N'-dicyclohexylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide hydrochloride (hereinafter referred to as EDC.HCl), N, N'-carbodiimidazole {{[(1-cyano-2-ethoxy-2-oxoethylidene) amino] oxy} -4-morpholinomethylene} dimethyl ammonium hexafluorophosphate (hereinafter COMU), O- (7-azabenzotriazole- 1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (hereinafter HATU) or O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyl Although uronium hexafluorophosphate (following, HBTU) is mentioned, HATU or HBTU is preferred

The amount of the condensing agent used for the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents with respect to the aniline derivative (III).

Examples of the base used for the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogencarbonate or potassium carbonate, sodium hydride, hydrogenated metal compounds such as potassium hydride or calcium hydride, methyl lithium Or an alkyllithium such as butyllithium, a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof, but an organic base such as triethylamine or diisopropylethylamine is preferred.

The amount of the base used for the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents based on the aniline derivative (III).

The aniline derivative (III) used for the condensation reaction may be a free form or a salt such as hydrochloride.

The reaction solvent used for the condensation reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxymethane Ether solvents such as ethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, or nitrile solvents such as acetonitrile or propionitrile Halogenated solvents such as chloroform or 1,2-dichloroethane or aprotic polar solvents such as DMF or DMSO are preferred.

The reaction temperature of the condensation reaction is preferably 0 to 200 ° C., and more preferably 20 to 100 ° C.

The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.

The concentration at the start of the reaction of the aniline derivative (III) used for the condensation reaction is preferably 1 mmol / L to 1 mol / L.

The aniline derivative (III) and the pipecolic acid derivative (IV) used for the condensation reaction can be purchased or can be produced by a known method or a method analogous thereto.

(Step 2)
Examples of the acid used for the deprotection reaction include acids such as hydrochloric acid, trifluoroacetic acid or hydrofluoric acid, with hydrochloric acid or trifluoroacetic acid being preferred.

The amount of the acid used for the deprotection reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents with respect to the N-tert-butoxycarbonylpipecolic acid amide derivative (V).

The reaction solvent for the deprotection reaction is appropriately selected depending on the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include diethyl ether, THF, dimethoxyethane or 1,4-dioxane Etc., ester solvents such as ethyl acetate or propyl acetate, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, alcohol solvents such as methanol or ethanol, or mixed solvents thereof. Ester solvents such as ethyl acetate or propyl acetate or chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane are preferred.

The reaction temperature of the deprotection reaction is preferably −78 ° C. to 200 ° C., and more preferably −20 ° C. to 100 ° C.

The reaction time of the deprotection reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 50 hours.

The concentration of the N-tert-butoxycarbonylpipecolic acid amide derivative (V) used for the deprotection reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

(Third step)
The amount of the organic acid chloride derivative (VII), the organic acid anhydride derivative (VIII), the organic acid derivative (IX) or trimethylsilyl isocyanate used for the condensation reaction is 0.5 to 10 with respect to the pipecolic acid amide derivative (VI) An equivalent is preferred, and 1 to 3 equivalents are more preferred.

As a condensing agent used for a condensation reaction, although EDC * HCl, COMU, HATU or HBTU is mentioned, for example, HATU or HBTU is preferable.

The amount of the base used for the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents based on the pipecolic acid amide derivative (VI).

The pipecolic acid amide derivative (VI) used for the condensation reaction may be a free form or a salt such as hydrochloride.

The reaction solvent used for the condensation reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxymethane Ether solvents such as ethane, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, or nitrile solvents such as acetonitrile or propionitrile Halogenated solvents such as chloroform or 1,2-dichloroethane or aprotic polar solvents such as DMF or DMSO are preferred.

The reaction temperature of the condensation reaction is preferably -78 ° C to 200 ° C, and more preferably -20 ° C to 100 ° C.

The reaction time of the condensation reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 0.5 to 30 hours.

The concentration of the pipecolic acid amide derivative (VI) used for the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

Organic acid chloride derivative (VII), organic acid anhydride derivative (VIII), organic acid derivative (IX) and trimethylsilyl isocyanate which are used for condensation reaction can be purchased or manufactured by a known method or a method according thereto it can.

Of the aniline derivatives (III) shown in Scheme 1, aniline derivatives (III-a) wherein A is a group represented by the above general formula (II-1), (II-2) or (II-3) For example, as shown in Scheme 2, a nucleophilic substitution reaction (step 1) for a fluorophenyl derivative (XI) of alcohol derivative (X) in the presence of a base, followed by an acid, is obtained in the first step Reaction of the tert-butoxycarbonyl group of the phenyl ether derivative (XII) (step 2), followed by the aliphatic amine derivative obtained in the step 2 in the presence of a metal catalyst, a ligand and a base XIII) Coupling reaction of halogenated aryl derivative (XIV) (step 3), followed by reduction reaction of nitrophenyl derivative (XV) obtained in step 3 in the presence of metal and acid (4th work) It can be obtained by). The optically active substance of aniline derivative (III-a) can be obtained, for example, by using the optically active substance of alcohol derivative (X).

[Wherein, V represents a group represented by the following general formula (XVI-1), (XVI-2) or (XVI-3),

W represents a group represented by the following general formula (XVII-1), (XVII-2) or (XVII-3),

A represents a group represented by the above general formula (II-1), (II-2) or (II-3), Q represents a halogen atom, R ¹ and R ² are the same as the above definition is there. ]

(Step 1)
The amount of fluorophenyl derivative (XI) used for the nucleophilic substitution reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to alcohol derivative (X).

Examples of the base used in the nucleophilic substitution reaction include organic bases such as triethylamine and diisopropylethylamine, inorganic bases such as sodium carbonate and potassium carbonate, hydrogenated metal compounds such as sodium hydride, potassium hydride and calcium hydride, lithium Lithium amide such as hexamethyl disilazide or lithium diisopropylamide, metal alkoxide such as tert-butyl oxy sodium or tert- butyl oxy potassium, or a mixture thereof may be mentioned, and sodium hydride, potassium hydride or calcium hydride etc. Hydrogenated metal compounds are preferred.

The amount of the base used for the nucleophilic substitution reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents with respect to the alcohol derivative (X).

The reaction solvent used for the nucleophilic substitution reaction is appropriately selected according to the type of the reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, for example, THF, 1,4-dioxane, ethylene glycol dimethyl ether Or an ether solvent such as dimethoxyethane, a nitrile solvent such as acetonitrile or propionitrile, an aromatic hydrocarbon solvent such as benzene or toluene, an aprotic polar solvent such as DMF or DMSO, water or a mixed solvent thereof Although non-polar polar solvents such as DMF or DMSO are preferred.

The reaction temperature of the nucleophilic substitution reaction is preferably −78 ° C. to 200 ° C., and more preferably −20 ° C. to 100 ° C.

The reaction time of the nucleophilic substitution reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.

The concentration of the alcohol derivative (X) at the start of the reaction used for the nucleophilic substitution reaction is preferably 1 mmol / L to 1 mol / L.

The alcohol derivative (X) and the fluorophenyl derivative (XI) used for the nucleophilic substitution reaction can be purchased or can be produced by a known method or an analogous method.

The amount of the acid used for the deprotection reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents with respect to the phenyl ether derivative (XII).

The reaction time of the deprotection reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.

The concentration at the start of the reaction of the phenyl ether derivative (XII) used for the deprotection reaction is preferably 1 mmol / L to 1 mol / L.

(Third step)
The amount of the halogenated aryl derivative (XIV) used for the coupling reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the aliphatic amine derivative (XIII).

Examples of the metal catalyst used for the coupling reaction include 1,1′-bis (diphenylphosphino) ferrocenedichloropalladium (II) dichloromethane adduct, palladium (II) chloride, palladium (II) acetate, tris (dibenzylideneacetone) A) palladium (0), tetrakistriphenylphosphine palladium (0) or dichlorobis triphenylphosphine palladium (0), with preference given to palladium (II) acetate.

The amount of the metal catalyst used for the coupling reaction is preferably 0.01 to 5 equivalents, more preferably 0.05 to 0.5 equivalents, with respect to the aliphatic amine derivative (XIII).

Examples of the ligand used for the coupling reaction include tri-tert-butylphosphine or 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, but tri-tert-butylphosphine is preferable.

The amount of the ligand used for the coupling reaction is preferably 0.01 to 5 equivalents, more preferably 0.05 to 0.5 equivalents, with respect to the aliphatic amine derivative (XIII).

As a base used for the coupling reaction, for example, organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium carbonate or potassium carbonate, lithium amides such as lithium hexamethyl disilazide or lithium diisopropylamide, tert-butyloxy sodium Or a metal alkoxide such as tert-butyloxy potassium or a mixture thereof, preferably a metal alkoxide such as tert-butyloxy sodium or tert-butyloxy potassium.

The amount of the base used for the coupling reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents with respect to the aliphatic amine derivative (XIII).

The aliphatic amine derivative (XIII) used for the coupling reaction may be a free form or a salt such as hydrochloride.

The reaction solvent used for the coupling reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF, 1,4-dioxane, ethylene glycol dimethyl ether or Ether solvents such as dimethoxyethane, nitrile solvents such as acetonitrile or propionitrile, aromatic hydrocarbon solvents such as benzene or toluene, aprotic polar solvents such as DMF or DMSO, water or mixed solvents thereof However, aromatic hydrocarbon solvents such as benzene or toluene are preferred.

The reaction temperature of the coupling reaction is preferably 0 to 200 ° C., and more preferably 50 to 150 ° C.

The reaction time of the coupling reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 60 hours.

The concentration at the start of the reaction of the aliphatic amine derivative (XIII) used for the coupling reaction is preferably 1 mmol / L to 1 mol / L.

The halogenated aryl derivative (XIV) used for the coupling reaction can be purchased or can be produced by a known method or a method analogous thereto.

(Step 4)
Examples of the metal used for the reduction reaction include iron powder and tin (II) chloride, with iron powder being preferred.

The amount of metal used for the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, to the nitrophenyl derivative (XV).

Examples of the acid used for the reduction reaction include acetic acid, hydrochloric acid or an aqueous solution of ammonium chloride, and an aqueous solution of ammonium chloride is preferable.

The amount of the acid used for the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, to the nitrophenyl derivative (XV).

The reaction solvent used for the reduction reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, for example, alcohol solvents such as methanol or ethanol, diethyl ether, THF Examples thereof include ether solvents such as dimethoxyethane and 1,4-dioxane, water, and mixed solvents thereof, but a mixed solvent of water and an alcohol solvent such as methanol or ethanol is preferable.

The reaction temperature of the reduction reaction is preferably 0 to 200 ° C., and more preferably 50 to 150 ° C.

The reaction time of the reduction reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.

The concentration of the nitrophenyl derivative (XV) used for the reduction reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

Among the aniline derivatives (III) shown in Scheme 1, an aniline derivative (III-b) in which A is a group represented by the above general formula (II-4) or (II-5) is, for example, As shown in the following, in the presence of a metal catalyst, a ligand and a base, the coupling reaction of a secondary amine derivative (XVIII) with an aryl halide derivative (XIV) (first step), followed by an acid in the presence of Deprotection of the cyclic acetal group of the tertiary amine derivative (XIX) obtained in one step (step 2), followed by the nucleophilic addition of ethynyl magnesium bromide to the ketone derivative (XX) obtained in the second step Reaction (Step 3), followed by nucleophilic substitution reaction (Step 4) on fluorophenyl derivative (XI) of tertiary alcohol derivative (XXI) obtained in Step 3 in the presence of a base Reduction reaction of the nitrophenyl derivative (XXII) obtained in the fourth step in the presence of a genus and an acid (step 5), followed by cyclization reaction of the aniline derivative (XXIII) obtained in the fifth step (step 6) Can be obtained by

[Wherein, m represents an integer of 1 to 2; A represents a group represented by the above general formula (II-4) or (II-5); R ¹ , R ² and Q each represent It is the same as the definition. ]

(Step 1)
The amount of the halogenated aryl derivative (XIV) used for the coupling reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the secondary amine derivative (XVIII).

Examples of the metal catalyst used for the coupling reaction include 1,1′-bis (diphenylphosphino) ferrocenedichloropalladium (II) dichloromethane adduct, palladium (II) chloride, palladium (II) acetate, tris (dibenzylideneacetone) A) Dipalladium (0), tetrakistriphenylphosphine palladium (0) or dichlorobistriphenylphosphine palladium (0), preferably tris (dibenzylideneacetone) dipalladium (0).

The amount of the metal catalyst used for the coupling reaction is preferably 0.01 to 5 equivalents, more preferably 0.05 to 0.5 equivalents, with respect to the secondary amine derivative (XVIII).

Examples of the ligand used for the coupling reaction include tri-tert-butylphosphine or 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl, and the 2,2′-bis ( Diphenylphosphino) -1,1'-binaphthyl is preferred.

The amount of the ligand used for the coupling reaction is preferably 0.01 to 5 equivalents, more preferably 0.05 to 0.5 equivalents, with respect to the secondary amine derivative (XVIII).

The amount of the base used for the coupling reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents, relative to the secondary amine derivative (XVIII).

The secondary amine derivative (XVIII) used for the coupling reaction may be a free form or a salt such as hydrochloride.

The concentration at the start of the reaction of the secondary amine derivative (XVIII) used for the coupling reaction is preferably 1 mmol / L to 1 mol / L.

The secondary amine derivative (XVIII) and the halogenated aryl derivative (XIV) used for the coupling reaction can be purchased or can be produced by a known method or a method analogous thereto.

(Step 2)
Examples of the acid used for the deprotection reaction include acids such as hydrochloric acid, acetic acid, trifluoroacetic acid or hydrofluoric acid, with preference given to acetic acid.

The amount of the acid used for the deprotection reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents with respect to the tertiary amine derivative (XIX).

The reaction solvent for the deprotection reaction is appropriately selected depending on the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include diethyl ether, THF, dimethoxyethane or 1,4-dioxane And ether solvents such as ethyl acetate or propyl acetate, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, water, and mixed solvents thereof, but diethyl ether, THF, dimethoxyethane Alternatively, a mixed solvent of an ether solvent such as 1,4-dioxane and water is preferable.

The reaction temperature for the deprotection reaction is preferably 0 to 200 ° C., more preferably 50 to 150 ° C.

The concentration at the start of the reaction of the tertiary amine derivative (XIX) used for the deprotection reaction is preferably 1 mmol / L to 1 mol / L.

(Third step)
The amount of ethynyl magnesium bromide used in the nucleophilic addition reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, to the ketone derivative (XX).

The reaction solvent for the nucleophilic addition reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and, for example, ether solvents such as diethyl ether, THF or dimethoxyethane And hydrocarbon solvents such as hexane and pentane; aromatic hydrocarbon solvents such as benzene and toluene; and mixed solvents thereof, with preference given to ether solvents such as diethyl ether, THF or dimethoxyethane.

The reaction temperature of the nucleophilic addition reaction is preferably -78 ° C to 100 ° C, more preferably -20 ° C to 100 ° C.

The reaction time of the nucleophilic addition reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.

The concentration at the start of the reaction of the ketone derivative (XX) used for the nucleophilic addition reaction is preferably 1 mmol / L to 1 mol / L.

(Step 4)
The amount of the fluorophenyl derivative (XI) used for the nucleophilic substitution reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, relative to the tertiary alcohol derivative (XXI).

The amount of the base used for the nucleophilic substitution reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents with respect to the tertiary alcohol derivative (XXI).

The concentration at the start of the reaction of the tertiary alcohol derivative (XXI) used for the nucleophilic substitution reaction is preferably 1 mmol / L to 1 mol / L.

The fluorophenyl derivative (XI) used for the nucleophilic substitution reaction can be purchased or can be produced by a known method or a method analogous thereto.

(Step 5)
Examples of the metal used for the reduction reaction include iron powder and tin (II) chloride, with iron powder being preferred.

The amount of metal used for the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, to the nitrophenyl derivative (XXII).

The amount of the acid used for the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, to the nitrophenyl derivative (XXII).

The concentration at the start of the reaction of the nitrophenyl derivative (XXII) used for the reduction reaction is preferably 1 mmol / L to 1 mol / L.

(Step 6)
The reaction solvent used for the cyclization reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, for example, aromatic hydrocarbon such as benzene, toluene or xylene A solvent is mentioned.

The reaction temperature of the cyclization reaction is preferably 50 to 250 ° C., and more preferably 100 to 200 ° C.

The reaction time of the cyclization reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.

The concentration of the aniline derivative (XXIII) used for the cyclization reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.

With respect to the optically active form of cyclic amine derivative (I) wherein A is a group represented by the above general formula (II-5), the racemate of the compound is obtained, for example, by a known method (eg, chiral chromatography) By separating the body or other mixture, each optical isomer or diastereomer can be obtained as a single optically active substance. Also, for example, derivatization with a homochiral acid and then separation of diastereomeric derivatives by known methods (eg, crystallization or chromatography), each optical isomer or diastereomer as a single optically active substance It can also be obtained as

The medicament of the present invention, RORγ antagonists, and therapeutic or prophylactic agents for autoimmune diseases or allergic diseases are cyclic amine derivatives (I), stereoisomers thereof or hydrates thereof, or pharmacologically thereof It is characterized in that it contains an acceptable salt as an active ingredient. The above-mentioned autoimmune disease is preferably multiple sclerosis or psoriasis, and the above-mentioned allergic disease is preferably allergic dermatitis, more preferably contact dermatitis or atopic dermatitis is there.

The “RORγ antagonist” means a compound having the function of suppressing the function of RORγ to abolish or attenuate its activity.

"Autoimmune disease" is a general term for diseases in which excessive immune reaction causes symptoms by attacking normal cells and tissues of the patient, and includes, for example, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus Inflammatory bowel disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica, scleroderma, vasculitis, pemphigus, pemphigus or dermatomyositis. The autoimmune diseases of the present invention also include acne, vitiligo or alopecia areata.

"Allergic disease" is a disease derived from the occurrence of excessive immune reaction against a specific antigen, such as allergic dermatitis, contact dermatitis, atopic dermatitis, allergic rhinitis (pollen Disease, allergic conjunctivitis, allergic gastroenteritis, bronchial asthma, childhood asthma or food allergy.

"Multiple sclerosis" is a disease characterized by demyelination in which a myelin sheath covering nerve fibers such as the brain, spinal cord and optic nerve is destroyed, and the disorder progresses while repeating relapse and remission. The symptoms vary depending on the lesion site and show various neurological symptoms such as visual impairment, paralysis of limbs, sensory impairment and gait disorder. Multiple sclerosis includes, for example, relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis or secondary progressive multiple sclerosis.

"Psoriasis" is an inflammatory disease of the skin associated with infiltration and activation of immune cells and concomitant epidermal hyperplasia. Typically, white scales adhere thickly on a red rash in various places throughout the body, causing symptoms of scaling that may fall off. Psoriasis includes, for example, psoriasis vulgaris, pustular psoriasis, arthritic psoriasis, psoriatic psoriasis, psoriatic erythroderma.

"Allergic dermatitis" is a generic term for skin diseases predisposed to allergic reactions, characterized by chronic itching and rashes on the face, neck, elbow and / or knees. Examples of allergic dermatitis include contact dermatitis, atopic dermatitis and the like.

"Contact dermatitis" is an eczematous inflammatory disease that develops when foreign antigens come in contact with the skin, and for example, allergic contact dermatitis, photocontact dermatitis, systemic contact dermatitis or Contact urticaria can be mentioned. In addition, examples of the antigen include metal allergens (cobalt, nickel etc.), plant allergens (urushi, primrose etc.) or food allergens (mango, ginnan etc.).

"Atopic dermatitis" is a skin disease in which many patients have an atopic tendency. It is characterized by symmetrical systemic eczema which aggravates and repeats remission, for example, diffuse neurodermatitis, atopic eczema, atopic neurodermatitis, Benie's eczema, acute infantile eczema, flexion eczema, childhood eczema, Pediatric atopic eczema, childhood dry eczema, pediatric eczema, adult atopic dermatitis, intrinsic eczema, infant dermatitis, or chronic infant eczema.

The cyclic amine derivative (I), its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof inhibits the function of RORγ by inhibiting the binding of RORγ to a coactivator. It is characterized by suppressing. It is known that RORγ is involved in various diseases, and that suppression of its function is expected to improve the pathological condition or ameliorate the symptoms, so cyclic amine derivatives (I), their stereoisomers or their hydrates Or a pharmacologically acceptable salt thereof is a medicament for a disease which can be expected to improve the condition or ameliorate the symptoms by suppressing the function of RORγ, in particular, a therapeutic agent for an autoimmune disease or an allergic disease Or it can be used as a preventive agent. The therapeutic agent or prophylactic agent for the above-mentioned autoimmune diseases is preferably multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica Can be used as a therapeutic or prophylactic agent for atrophy, scleroderma, vasculitis, pemphigus, pemphigus, dermatomyositis, acne, vitiligo or alopecia areata, more preferably multiple sclerosis or psoriasis It can be used as a therapeutic or prophylactic agent. The therapeutic agent or preventive agent for the above allergic diseases is preferably allergic dermatitis, atopic dermatitis, allergic rhinitis (hay fever), allergic conjunctivitis, allergic gastroenteritis, bronchial asthma, childhood asthma or food It can be used as an agent for treating or preventing allergy, and more preferably, as an agent for treating or preventing contact dermatitis or atopic dermatitis.

The cyclic amine derivative (I), a stereoisomer thereof or a hydrate of these or a pharmacologically acceptable salt thereof has RORγ antagonist activity which inhibits the binding of RORγ to a coactivator, It can be evaluated using in vitro tests. As an in vitro test, for example, a method of evaluating the binding of RORγ to an agonist (eg, cholesterol) (WO 2012/158784, WO 2013/018695), a ligand binding domain of RORγ and a coacti Methods for assessing binding to beta can be mentioned (WO 2012/064744, WO 2013/018695). In addition, the transcriptional activity inhibitory action of RORγ can be evaluated using various reporter gene assays (WO 2012/158784, WO 2012/064744, WO 2013/018695).

The cyclic amine derivative (I), its stereoisomer or hydrate thereof, or pharmacologically acceptable salt thereof suppressing the function of RORγ is derived from various organs such as spleen or peripheral blood Lymphocytes can be used to evaluate IL-17 production or Th17 cell differentiation as an indicator. As a method using IL-17 production as an index, for example, a method of measuring IL-17 production by IL-23 stimulation using mouse splenocytes can be mentioned (The Journal of Biological Chemistry, 2003, 278) , No. 3, p. 1910-1914). As a method using Th17 cell differentiation as an index, for example, various cytokines (eg, IL-1β, IL-6, IL-23 and / or TGF are used, using CD4 positive naive T cells derived from mouse splenocytes or human PBMC). Stimulate with -β) and various antibodies (eg, anti-CD3 antibody, anti-CD28 antibody, anti-IL-4 antibody, anti-IFN-γ antibody and / or anti-IL-2 antibody) to differentiate to Th17 and produce IL-17 The method includes measuring the amount or the proportion of IL-17 positive cells etc. (WO 2012/158784, WO 2013/018695).

The effectiveness of the cyclic amine derivative (I), its stereoisomer or hydrates thereof, or their pharmacologically acceptable salts for the treatment or prevention of autoimmune diseases can be determined using a pathological model It can be evaluated. As a pathological model, for example, experimental autoimmune encephalomyelitis model (Journal of Neuroscience Research, 2006, 84, pages 1225-1234), imiquimod-induced psoriasis model (Journal of Immunology, 2009, 182) , P. 5836-5845), collagen arthritis model (Annual Review of Immunology, 1984, Volume 2, 199-218), spontaneous lupus erythematosus model (Nature, volume 404, p. 2000). .995-999), TNBS-induced colitis model (European Journal of Pharmacology, 2001, 431, p. 103-110), ankylosing spondylitis Dell (Arthritis Research & Therapy, 2012, 14, p. 253-265), experimental autoimmune uveitis model (Journal of Immunology, 2006, 36, p. 3071-3081), strong Dermatosis model (Journal of Investigative Dermatology, 1999, 112, p. 456-462), vasculitis model (The Journal of Clinical Investigation, 2002, 110, p. 955-963), pemphigus model (The Journal of Clinical Investigation, 2000, 105, p. 625-631), pemphigoid model (Expe imental Dermatology, 2012, Vol. 21, p. 901-905), Dermatomyositis model (American Journal of Pathology, 1985, Vol. 120, p. 323-325), spontaneous onset model of acne (European Journal of Europe) Dermatology, 2005, vol. 15, p. 459-464, vitiligo model (Pigment Cell & Melanoma Research, 2014, vol. 27, p. 1075-1085), or alopecia areata model (Journal of Investigative Dermatology, Vol. 2015, Volume 135, pp. 2530-2532). The experimental autoimmune encephalomyelitis model is common as a model of multiple sclerosis. In addition, the imiquimod-induced psoriasis model is common as a model of psoriasis.

In addition, that the cyclic amine derivative (I), its stereoisomer or hydrate thereof, or pharmacologically acceptable salts thereof is effective for treatment or prevention of allergic diseases is a pathological model. It can be evaluated using. As a pathological model, for example, dinitrofluorobenzene (hereinafter, DNFB) -induced allergic dermatitis model (Pharmacological Reports, 2013, 65, p. 1237-1246), oxazolone-induced atopic dermatitis model (Journal of Investigative) Dermatology, 2014, vol. 134, p. 2122-2130), ovalbumin-induced allergic rhinitis model (Journal of Animal Science, 2010, vol. 81, p. 699-705), IgE-induced allergic conjunctivitis model (vol. British Journal of Ophthalmology, 2012, Vol. 96, p. 1332-1336), allergic gastroenteritis Dell (Gastroenterology, 1997, 113, p. 1560-1569), ovalbumin-induced asthma model (American Journal of Respiratory and Critical Care Medicine, 1997, 156, p. 766-775), or egg white An albumin-induced food allergy model (Clinical & Experimental Allergy, 2005, 35, 461-466) can be mentioned. The DNFB-induced allergic dermatitis model is common as a model of allergic dermatitis, in particular as a contact dermatitis model. In addition, the oxazolone-induced atopic dermatitis model is common as a model of atopic dermatitis.

The efficacy of the cyclic amine derivative (I), a stereoisomer thereof or a hydrate of these or a pharmacologically acceptable salt thereof for the treatment or prevention of autoimmune diseases or allergic diseases is For example, a decrease in the amount of binding between the ligand binding domain of RORγ and the coactivator, or a decrease in the amount of IL-17 production, which is an indicator of the function of RORγ, can be evaluated using in vitro tests. In addition, the efficacy for treatment or prevention of multiple sclerosis can be evaluated using, for example, a decrease in neurological symptom score, which is a characteristic index of multiple sclerosis, using the above-mentioned experimental autoimmune encephalomyelitis model. It can be evaluated. In addition, the efficacy for treatment or prevention of psoriasis may be evaluated using, for example, the reduction in thickness of skin such as auricle or the like, which increases with the progression of symptoms of the psoriasis model, using the imiquimod-induced psoriasis model described above as an indicator. it can. Moreover, the efficacy for treatment or prevention of allergic dermatitis, particularly contact dermatitis, is increased using, for example, the above-mentioned DNFB-induced allergic dermatitis model, such as the auricle, etc., along with the progress of skin inflammation. The decrease in skin thickness can be evaluated as an index. Moreover, the efficacy for the treatment or prevention of atopic dermatitis is, for example, using the above-mentioned oxazolone-induced atopic dermatitis model to decrease the thickness of the skin such as the auricle that increases with the progress of skin inflammation. It can be evaluated on indicators.

The cyclic amine derivative (I), its stereoisomer or a hydrate thereof, or a pharmacologically acceptable salt thereof is a mammal (eg, mouse, rat, hamster, rabbit, dog, cat, monkey, etc.) Can be used as useful medicaments (especially, therapeutic or prophylactic agents for autoimmune diseases or allergic diseases) when administered to cattle, sheep or humans), particularly humans. When the cyclic amine derivative (I), its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof is used clinically as a medicament, the cyclic amine derivative (I), its steric structure The isomers or their hydrates, or their pharmacologically acceptable salts can be administered orally or parenterally, as they are or in combination with pharmacologically acceptable carriers. . The above-mentioned medicines, if necessary, binders, excipients, lubricants, disintegrants, sweeteners, stabilizers, flavoring agents, flavors, coloring agents, fluidizers, preservatives, buffers, solution aids Additives such as an agent, an emulsifying agent, a surfactant, a suspending agent, a diluent or an isotonic agent may be appropriately mixed. Pharmaceutically acceptable carriers include these additives. Also, the above-mentioned medicament can be manufactured by a usual method using appropriately these pharmaceutical carriers. The dosage form of the above-mentioned medicine includes, for example, oral preparations such as tablets, capsules, granules, powders or syrups, parenteral preparations such as inhalants, injections, suppositories or solutions, or topical administration. An ointment, a cream or a patch may be mentioned. Also, it may be a known sustained release preparation.

Binders include, for example, syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride or tragacanth.

Excipients include, for example, sugar, lactose, corn starch, calcium phosphate, sorbitol or glycine.

As the lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, talc or silica can be mentioned.

Disintegrants include, for example, starch or calcium carbonate.

Sweetening agents include, for example, glucose, fructose, invert sugar, sorbitol, xylitol, glycerin or simple syrup.

The above-mentioned medicament preferably contains 0.00001 to 90% by weight of cyclic amine derivative (I), its stereoisomer or hydrate thereof, or pharmacologically acceptable salt thereof, and 0 More preferably, the content is from 0.1 to 70% by weight. The dose is appropriately selected according to the patient's condition, age and body weight, and administration method, but as an active ingredient amount for adults, 0.1 μg to 1 g per day for injections and 1 for oral preparations The amount is preferably 1 μg to 10 g per day, and in the case of a patch, 1 μg to 10 g per day, each of which can be administered once or several times.

The above-mentioned medicines may be used together with other medicines in appropriate amounts or in combination for complementation or enhancement of their therapeutic or preventive effects or reduction of dosage.

The present invention will be described in more detail by the following reference examples and examples, but the present invention is not limited thereto.

The compounds used for the synthesis of the compounds of Reference Examples and Examples were commercially available compounds that were not described in the synthesis method. The “room temperature” in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C. % Indicates mol / mol% for yield, volume% for solvents used in column chromatography and high performance liquid chromatography, and weight% unless otherwise specified. The solvent name shown in the NMR data indicates the solvent used for the measurement. In addition, the 400 MHz NMR spectrum was measured using a JNM-AL400 nuclear magnetic resonance apparatus (Nippon Denshi Co., Ltd.) or a JNM-ECS400 nuclear magnetic resonance apparatus (Nippon Denshi Co., Ltd.). Chemical shifts are expressed in δ (unit: ppm) relative to tetramethylsilane, and signals are s (singlet), d (doublet), t (triplet), q (quadruple), quint respectively (Quaternion), sept (seven), m (multiple), br (wide), dd (double double), dt (double triple), ddd (double double) , Dq (double quadruple), td (triple doublet), tt (triple triple). When protons such as a hydroxyl group and an amino group are very mild peaks, they are not described. The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (Agilent Technologies). Silica gel used silica gel 60 (Merck), amine silica gel used amine silica gel DM 1020 (Fuji Silysia Chemical Ltd.), and chromatography used YFLC W-prep 2 XY (Yamazen Co.).

Reference Example 1 Synthesis of benzyl 4- (2-chloro-4-nitrophenoxy) piperidine-1-carboxylate:

Benzyl 4-hydroxypiperidine-1-carboxylate (0.804 g, 3.42 mmol) and 2-chloro-1-fluoro-4-nitrobenzene (0.500 g, 2.85 mmol) with N, N-dimethylacetamide (2. It was dissolved in 85 mL) and cesium carbonate (1.86 g, 5.70 mmol) was added at room temperature. After stirring at 150 ° C. for 3 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, distilled water and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90 / 10-75 / 25) to give the title compound (hereinafter referred to as the compound of Reference Example 1) (0.757 g, 1.94 mmol, 68) %) As a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.92-1.94 (m, 4 H), 3.66-3. 68 (m, 4 H), 4.74-4. 78 (m, 1 H) , 5.15 (s, 2 H), 6.99 (d, J = 9.5 Hz, 1 H), 7.31-7.38 (m, 5 H), 8. 14 (dd, J = 9.5, 2.7 Hz, 1 H), 8.31 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 413 (M + Na) ⁺ .

Reference Example 2 Synthesis of benzyl 4- (4-amino-2-chlorophenoxy) piperidine-1-carboxylate:

The compound of Reference Example 1 (0.750 g, 1.92 mmol) was dissolved in ethanol (3.84 mL) and distilled water (1.92 mL), iron powder (0.536 g, 9.60 mmol) and ammonium chloride (0. 513 g, 9.60 mmol) were added at room temperature. After stirring at 80 ° C. for 1 hour, the reaction solution was filtered, distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 50/50) to give the title compound (hereinafter referred to as the compound of Reference Example 2) (0.528 g, 1.46 mmol, 76) %) As a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.81-1.84 (m, 4 H), 3. 45 (ddd, J = 13.4, 6.8, 4.1 Hz, 2 H), 3. 52 (brs, 2H), 3.78 (ddd, J = 13.4, 8.2, 4.1 Hz, 2H), 4.27-4.32 (m, 1H), 5.14 (s, 2H) ), 6.51 (dd, J = 8.6, 2.7 Hz, 1 H), 6.73 (d, J = 2.7 Hz, 1 H), 6. 80 (d, J = 8.6 Hz, 1 H) , 7.31-7.37 (m, 5H).
ESI-MS: m / z = 361 (M + H) ⁺ .

Reference Example 3 Synthesis of benzyl 4- (4- (1-acetylpiperidine-2-carboxamido) -2-chlorophenoxy) piperidine-1-carboxylate:

The compound of Reference Example 2 (0.150 g, 0.416 mmol) and 1-acetylpiperidine-2-carboxylic acid (0.0854 g, 0.499 mmol) are dissolved in DMF (2.08 mL), and HATU (0.205 g, 0.540 mmol) and diisopropylethylamine (0.109 mL, 0.624 mmol) were added at room temperature. After stirring at the same temperature for 14 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 60/40 to 5/95), and the title compound (hereinafter, the compound of Reference Example 3) (0.175 g, 0.340 mmol, 82) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49 to 1.55 (m, 2 H), 1.71 to 1.78 (m, 2 H), 1.85 to 1. 97 (m, 5 H) , 2.20 (s, 3 H), 2.25-2. 28 (m, 1 H), 3.11-3. 19 (m, 1 H), 3.50-3.56 (m, 2 H), 3 .68-3.78 (m, 3 H), 4.45-4. 50 (m, 1 H), 5. 14 (s, 2 H), 5. 24 (d, J = 5.4 Hz, 1 H), 6 .88 (d, J = 9.1 Hz, 1 H), 7.29-7.37 (m, 6 H), 7.63 (d, J = 2.7 Hz, 1 H), 8.32 (s, 1 H) .
ESI-MS: m / z = 536 (M + Na) ⁺ .

Reference Example 4 Synthesis of 1-acetyl-N- (3-chloro-4- (piperidin-4-yloxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 3 (0.170 g, 0.331 mmol) was dissolved in dichloromethane (1.65 mL), and iodotrimethylsilane (0.135 mL, 0.992 mmol) was added at 0 ° C. After stirring at room temperature for 5 hours, methanol and distilled water were added to the reaction solution, and the aqueous layer was washed with chloroform, then a saturated aqueous sodium hydrogen carbonate solution was added to the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (hereinafter referred to as the compound of Reference Example 4) (0.112 g, 0.295 mmol, 89%) Obtained as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.60 (m, 2 H), 1.70 to 2.01 (m, 7 H), 2.20 (s, 3 H), 2.25 -2.29 (m, 1 H), 2.70-2.76 (m, 2 H), 3.14-3. 20 (m, 3 H), 3.74-3. 78 (m, 1 H), 4 .32-4.38 (m, 1 H), 5.25 (d, J = 5.4 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 1 H), 7.29 (dd, J = 8.6, 2.7 Hz, 1 H), 7.63 (d, J = 2.7 Hz, 1 H), 8.34 (s, 1 H).
ESI-MS: m / z = 380 (M + H) ⁺ .

Example 1 Synthesis of 1-Acetyl-N- (3-chloro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 4 (0.0400 g, 0.105 mmol) is dissolved in toluene (1.05 mL), iodobenzene (0.0176 mL, 0.158 mmol), palladium (II) acetate (0.00473 g, 0.0211 mmol) ), Tri-tert-butylphosphino tetrafluoroborate (0.00611 g, 0.0211 mmol) and tert-butyloxy sodium (0.0304 g, 0.316 mmol) were added at room temperature. After stirring for 1 hour at 120 ° C., the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 60/40 to 10/90) to give the title compound (compound of Example 1 below) (0.00852 g, 0.0189 mmol, 18) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.56 (m, 2H), 1.71-1.78 (m, 2H), 1.90-2.02 (m, 3H) , 2.04-2.11 (m, 2H), 2.21 (s, 3H), 2.26-2.29 (m, 1H), 3.10-3.20 (m, 3H), 3 .48-3.54 (m, 2 H), 3.74-3. 78 (m, 1 H), 4.42-4. 47 (m, 1 H), 5.25 (d, J = 5.0 Hz, 1H), 6.83-6.87 (m, 1H), 6.92-6.98 (m, 3H), 7.24-7.29 (m, 2H), 7.31 (dd, J = 9.1, 2.7 Hz, 1 H), 7.63 (d, J = 2.7 Hz, 1 H), 8.32 (s, 1 H).
ESI-MS: m / z = 456 (M + H) ⁺ .

Reference Example 5 Synthesis of tert-butyl 4- (2-chloro-4-nitrophenoxy) piperidine-1-carboxylate:

4-hydroxypiperidine-1-carboxylic acid tert-butyl (2.43 g, 12.1 mmol) and sodium hydride (55 wt% mineral oil dispersion, 0.552 g, 12.7 mmol) are suspended in DMF (11.5 mL) After becoming cloudy and stirring at 0 ° C. for 1 hour, 2-chloro-1-fluoro-4-nitrobenzene (2.02 g, 11.5 mmol) dissolved in DMF (11.5 mL) was added at the same temperature. After stirring for 2 hours at the same temperature, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 75/25), and the title compound (hereinafter, the compound of Reference Example 5) (3.65 g, 10.2 mmol, 89) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (s, 9 H), 1.84-1.98 (m, 4 H), 3.51-3. 65 (m, 4 H), 4.71 -4.76 (m, 1 H), 7.00 (d, J = 9.5 Hz, 1 H), 8. 14 (dd, J = 9.5, 2.7 Hz, 1 H), 8.31 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 301 (M-tBu + H) ⁺ .

Reference Example 6 Synthesis of 4- (2-chloro-4-nitrophenoxy) piperidine hydrochloride:

The compound of Reference Example 5 (3.65 g, 10.2 mmol) was dissolved in ethyl acetate (10.2 mL), and hydrogen chloride-ethyl acetate solution (4.0 M, 38.4 mL, 153 mmol) was added at room temperature. After stirring for 1 hour at the same temperature, the reaction solution is filtered, and the solid collected by filtration is washed with ethyl acetate and then dried, and the title compound (hereinafter, the compound of Reference Example 6) (2.94 g, 10.0 mmol, 98%) ) As a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 1.89-1.97 (m, 2 H), 2.13-2.20 (m, 2 H), 3.08-3.14 (m, 2) 2H), 3.17-3.23 (m, 2H), 4.98-5.03 (m, 1H), 7.51 (d, J = 9.3 Hz, 1H), 8.23 (dd, J = 9.3, 3.2 Hz, 1 H, 8. 35 (d, J = 3.2 Hz, 1 H), 8.97 (brs, 2 H).
ESI-MS: m / z = 257 (M + H) ⁺ .

Reference Example 7 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (2-fluorophenyl) piperidine:

Compound of Reference Example 6 (0. 100 g, 0.342 mmol), palladium (II) acetate (0.0154 g, 0.0682 mmol), tri-tert-butylphosphino tetrafluoroborate (0.0199 g, 0.0682 mmol), and Sodium tert-butyloxy (0.115 g, 1.20 mmol) was suspended in toluene (1.71 mL) and 1-fluoro-2-iodobenzene (0.0590 mL, 0.513 mmol) was added at room temperature. After stirring for 2 hours at 110 ° C., the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 85/15) to give the title compound (hereinafter referred to as the compound of Reference Example 7) (0.0524 g, 0.149 mmol, 44) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.07-2.24 (m, 4 H), 3.08-3.14 (m, 2 H), 3.30-3.36 (m, 2 H) , 4.72-4.77 (m, 1 H), 6.93-7. 10 (m, 5 H), 8. 15 (dd, J = 9.1, 2.9 Hz, 1 H), 8.32 (m. d, J = 2.9 Hz, 1 H).
ESI-MS: m / z = 351 (M + H) ⁺ .

Reference Example 8 Synthesis of 3-chloro-4-((1- (2-fluorophenyl) piperidin-4-yl) oxy) aniline:

The compound of Reference Example 7 (0.0500 g, 0.143 mmol) was suspended in ethanol (1.00 mL) and distilled water (0.500 mL), iron powder (0.0398 g, 0.713 mmol) and ammonium chloride (0. 0381 g, 0.713 mmol) was added at room temperature. After stirring at 80 ° C. for 3 hours, the reaction solution was filtered, distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 50/50) to give the title compound (hereinafter referred to as the compound of Reference Example 8) (0.0470 g, 0.147 mmol) ) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.04-2.09 (m, 4 H), 2.93-2.99 (m, 2 H), 3.35-3. 41 (m, 2 H) , 3.52 (s, 2H), 4.27-4.30 (m, 1H), 6.53 (dd, J = 8.8, 2.7 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1 H), 6.85 (d, J = 8.8 Hz, 1 H), 6.92-7.08 (m, 4 H).
ESI-MS: m / z = 321 (M + H) ⁺ .

Example 2 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (2-fluorophenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 8 (0.0250 g, 0.0779 mmol) and 1-acetylpiperidine-2-carboxylic acid (0.0160 g, 0.0935 mmol) were dissolved in DMF (1.00 mL), and HATU (0.0356 g, 0.0935 mmol) and diisopropylethylamine (0.0204 mL, 0.117 mmol) were added at room temperature. After stirring at the same temperature for 16 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/50 to 5/95), and the title compound (compound of Example 2 below) (0.0206 g, 0.0435 mmol, 56) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 to 1.60 (m, 2H), 1.71 to 1.78 (m, 2H), 1.89 to 1.98 (m, 1H) , 2.00-2.15 (m, 4 H), 2.21 (s, 3 H), 2.26-2.29 (m, 1 H), 2.98-3. 04 (m, 2 H), 3 .12-3.20 (m, 1 H), 3.32-3.38 (m, 2 H), 3.75-3. 78 (m, 1 H), 4.44-4. 49 (m, 1 H) , 5.25-5.26 (m, 1H), 6.92-6.94 (m, 2H), 6.97-7.08 (m, 3H), 7.30 (dd, J = 8. 8, 2.4 Hz, 1 H), 7.64 (d, J = 2.4 Hz, 1 H), 8.32 (s, 1 H).
ESI-MS: m / z = 474 (M + H) ⁺ .

Reference Example 9 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (3-fluorophenyl) piperidine:

The title compound (hereinafter referred to as the compound of Reference Example 9) (0.0863 g) was prepared according to the same procedure as in Reference Example 7 except for using 1-bromo-3-fluorobenzene instead of 1-fluoro-2-iodobenzene. , 0.246 mmol, 72%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.00-2.17 (m, 4 H), 3.24-3.30 (m, 2 H), 3.45-3.51 (m, 2 H) , 4.72-4.77 (m, 1H), 6.52-6.57 (m, 1H), 6.61-6.65 (m, 1H), 6.75-6.73 (m, 1H), 7.02 (d, J = 9.1 Hz, 1H), 7.18-7.23 (m, 1H), 8.16 (dd, J = 9.1, 2.8 Hz, 1H), 8.32 (d, J = 2.8 Hz, 1 H).
ESI-MS: m / z = 351 (M + H) ⁺ .

Reference Example 10 Synthesis of 3-chloro-4-((1- (3-fluorophenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 9 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 10) (0.0783 g, 0.244 mmol, quantitation ) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90 to 2.07 (m, 4 H), 3.08 to 3.14 (m, 2 H), 3.52 to 3.58 (m, 4 H) , 4.27-4.32 (m, 1 H), 6.48-6.54 (m, 2 H), 6.59-6. 63 (m, 1 H), 6.68-6. 71 (m, 1 H) 1H), 6.74 (d, J = 2.9 Hz, 1 H), 6.84 (d, J = 8.8 Hz, 1 H), 7.15-7.21 (m, 1 H).
ESI-MS: m / z = 321 (M + H) ⁺ .

EXAMPLE 3 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (3-fluorophenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 10 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 3 below) (0.0211 g, 0.0445 mmol, 57) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 to 1.60 (m, 2H), 1.71 to 1.78 (m, 2H), 1.90 to 2.08 (m, 5H) , 2.21 (s, 3 H), 2. 26-2. 29 (m, 1 H), 3.1 2-3. 19 (m, 3 H), 3.48-3. 54 (m, 2 H), 3 .75-3.78 (m, 1 H), 4.44-4. 49 (m, 1 H), 5.24-5. 26 (m, 1 H), 6.48-6.53 (m, 1 H) , 6.59-6.64 (m, 1 H), 6. 68-6. 71 (m, 1 H), 6. 92 (d, J = 9.0 Hz, 1 H), 7.15-7.21 (m. m, 1 H), 7.31 (dd, J = 9.0, 2.7 Hz, 1 H), 7.63 (d, J = 2.7 Hz, 1 H), 8.32 (s, 1 H).
ESI-MS: m / z = 474 (M + H) ⁺ .

Reference Example 11 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (4-fluorophenyl) piperidine:

The title compound (hereinafter, the compound of Reference Example 11) (0.113 g) was prepared according to the same procedure as in Reference Example 7 except for using 1-fluoro-4-iodobenzene instead of 1-fluoro-2-iodobenzene. , 0.322 mmol, 94%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.03-2.20 (m, 4 H), 3.12-3.18 (m, 2 H), 3.34-3. 40 (m, 2 H) , 4.75 to 4.75 (m, 1 H), 6.91 to 4. 04 (m, 5 H), 8. 15 (dd, J = 9.1, 2.8 Hz, 1 H), 8.32 (m. d, J = 2.8 Hz, 1 H).
ESI-MS: m / z = 351 (M + H) ⁺ .

Reference Example 12 Synthesis of 3-chloro-4-((1- (4-fluorophenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 11 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 12) (0.0987 g, 0.308 mmol, 98) %) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.93-2.10 (m, 4 H), 2.96-3. 02 (m, 2 H), 3.40-3.46 (m, 2 H) , 3.52 (brs, 2 H), 4.23-4.29 (m, 1 H), 6.53 (dd, J = 8.5, 2.9 Hz, 1 H), 6.74 (d, J = 2.9 Hz, 1 H), 6.84 (d, J = 8.5 Hz, 1 H), 6.89-6.98 (m, 4 H).
ESI-MS: m / z = 321 (M + H) ⁺ .

EXAMPLE 4 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (4-fluorophenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 12 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 4 below) (0.0259 g, 0.0546 mmol, 70) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.90-2.11 (m, 5H) , 2.21 (s, 3 H), 2.26-2.29 (m, 1 H), 3.01-3.07 (m, 2 H), 3.12-3. 19 (m, 1 H), 3 .37-3.43 (m, 2H), 3.74-3.78 (m, 1H), 4.41-4.46 (m, 1H), 5.24-5.26 (m, 1H) , 6.89-6.98 (m, 5H), 7.30 (dd, J = 8.9, 2.7 Hz, 1 H), 7.63 (d, J = 2.7 Hz, 1 H), 8. 32 (s, 1 H).
ESI-MS: m / z = 474 (M + H) ⁺ .

Reference Example 13 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (2-chlorophenyl) piperidine:

The title compound (hereinafter, the compound of Reference Example 13) (0.0475 g) was prepared according to the same procedure as in Reference Example 7 using 1-chloro-2-iodobenzene instead of 1-fluoro-2-iodobenzene , 0.129 mmol, 38%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.07-2.15 (m, 2H), 2.18-2.25 (m, 2H), 3.03-3.08 (m, 2H) , 3.26-3.32 (m, 2H), 4.73-4.78 (m, 1H), 6.97-7.01 (m, 1H), 7.04 (d, J = 9). 1 Hz, 1 H), 7.09 (dd, J = 8.2, 1.4 Hz, 1 H), 7.22-7.26 (m, 1 H), 7.38 (dd, J = 7.9, 1 6 Hz, 1 H), 8. 16 (dd, J = 9.1, 2.7 Hz, 1 H), 8.32 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 367 (M + H) ⁺ .

Reference Example 14 Synthesis of 3-chloro-4-((1- (2-chlorophenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 13 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 14) (0.0380 g, 0.113 mmol, 92) %) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.99-2.11 (m, 4H), 2.89-2.94 (m, 2H), 3.30-3.36 (m, 2H) , 3.52 (brs, 2 H), 4.27-4. 33 (m, 1 H), 6.53 (dd, J = 8.8, 2.9 Hz, 1 H), 6.75 (d, J = 2.9 Hz, 1 H), 6.86 (d, J = 8.8 Hz, 1 H), 6.94-6. 98 (m, 1 H), 7.06-7.09 (m, 1 H), 7. 19-7.23 (m, 1 H), 7.35-7. 37 (m, 1 H).
ESI-MS: m / z = 338 (M + H) ⁺ .

EXAMPLE 5 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (2-chlorophenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 14 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 5 below) (0.0233 g, 0.0475 mmol, 80) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49 to 1.60 (m, 2 H), 1.71 to 1. 78 (m, 2 H), 1.90 to 1. 98 (m, 1 H) , 2.01-2.16 (m, 4 H), 2.21 (s, 3 H), 2.26-2.29 (m, 1 H), 2.93-2.99 (m, 2 H), 3 .12-3.20 (m, 1 H), 3.27-3. 33 (m, 2 H), 3.75-3. 78 (m, 1 H), 4.45-4. 50 (m, 1 H) , 5.25-5.26 (m, 1 H), 6.94 (d, J = 8.8 Hz, 1 H), 6.94-6. 98 (m, 1 H), 7.08 (dd, J = 8.2, 1.4 Hz, 1 H), 7.20-7. 24 (m, 1 H), 7. 30 (dd, J = 8.8, 2.5 Hz, 1 H), 7.36 (dd, J = 7.7, 1.4 Hz, 1 H), .64 (d, J = 2.5Hz, 1H), 8.31 (s, 1H).
ESI-MS: m / z = 490 (M + H) ⁺ .

Reference Example 15 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (3-chlorophenyl) piperidine:

The title compound (hereinafter, the compound of Reference Example 15) (0.110 g) was prepared according to the same procedure as in Reference Example 7 except for using 1-chloro-3-iodobenzene instead of 1-fluoro-2-iodobenzene. , 0.300 mmol, 88%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.00-2.08 (m, 2H), 2.10-2.17 (m, 2H), 3.24-3.30 (m, 2H) , 3.44-3.51 (m, 2 H), 4.72-4. 77 (m, 1 H), 6.81-6.84 (m, 2 H), 6.92-6. 93 (m, 2) 1H), 7.02 (d, J = 9.1 Hz, 1H), 7.16-7.20 (m, 1H), 8.16 (dd, J = 9.1, 2.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 367 (M + H) ⁺ .

Reference Example 16 Synthesis of 3-chloro-4-((1- (3-chlorophenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 15 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 16) (0.0220 g, 0.0652 mmol, 21 %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90-1.98 (m, 2H), 2.00-2.08 (m, 2H), 3.08-3.14 (m, 2H) , 3.50-3.57 (m, 2 H), 3.54 (brs, 2 H), 4.27-4. 32 (m, 1 H), 6.53 (dd, J = 8.6, 2. 7 Hz, 1 H), 6.74 (d, J = 2.7 Hz, 1 H), 6.78-6.84 (m, 2 H), 6.84 (d, J = 8.6 Hz, 1 H), 6. 90-6.92 (m, 1 H), 7.14-7. 18 (m, 1 H).
ESI-MS: m / z = 338 (M + H) ⁺ .

EXAMPLE 6 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (3-chlorophenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 16 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 6 below) (0.0245 g, 0.0500 mmol, 84) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.61 (m, 2H), 1.72-1.78 (m, 2H), 1.91-2.07 (m, 5H) , 2.21 (s, 3 H), 2. 26-2. 29 (m, 1 H), 3. 12-3. 19 (m, 3 H), 3. 47-3. 53 (m, 2 H), 3 .75-3.78 (m, 1 H), 4.44-4. 49 (m, 1 H), 5.24-5. 26 (m, 1 H), 6.78-6.83 (m, 2 H) , 6.96-6.91 (m, 1 H), 6.92 (d, J = 8.8 Hz, 1 H), 7.16 (dd, J = 8.2, 8.2 Hz, 1 H), 7. 31 (dd, J = 8.8, 2.5 Hz, 1 H), 7.63 (d, J = 2.5 Hz, 1 H), 8.32 (s, 1 H).
ESI-MS: m / z = 490 (M + H) ⁺ .

Reference Example 17 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (4-chlorophenyl) piperidine:

The title compound (hereinafter referred to as the compound of Reference Example 17) (0.118 g) was prepared according to the same procedure as in Reference Example 7 except for using 1-chloro-4-iodobenzene instead of 1-fluoro-2-iodobenzene. , 0.321 mmol, 94%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.01-2.09 (m, 2 H), 2.11-2. 18 (m, 2 H), 3.19-3. 25 (m, 2 H) , 3.40 to 3.46 (m, 2 H), 4.71 to 4. 76 (m, 1 H), 6.89 (d, J = 9.1 Hz, 2 H), 7.02 (d, J = 9.1 Hz, 1 H), 7.22 (d, J = 9.1 Hz, 2 H), 8. 15 (dd, J = 9.1, 2.7 Hz, 1 H), 8.32 (d, J = 2) .7 Hz, 1 H).
ESI-MS: m / z = 367 (M + H) ⁺ .

Reference Example 18 Synthesis of 3-chloro-4-((1- (4-chlorophenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 17 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 18) (0.108 g, 0.320 mmol, quantitation ) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.91 to 1.99 (m, 2 H), 2.01 to 2. 08 (m, 2 H), 3.02 to 3.09 (m, 2 H) , 3.46 to 3.52 (m, 2 H), 3.52 (brs, 2 H), 4.25 to 4.31 (m, 1 H), 6.53 (dd, J = 8.6, 2. 7 Hz, 1 H), 6.74 (d, J = 2.7 Hz, 1 H), 6. 84 (d, J = 8.6 Hz, 1 H), 6.87 (d, J = 9.1 Hz, 2 H), 7.19 (d, J = 9.1 Hz, 2 H).
ESI-MS: m / z = 338 (M + H) ⁺ .

Example 7 Synthesis of 1-Acetyl-N- (3-chloro-4-((1- (4-chlorophenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 18 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 7 below) (0.0234 g, 0.0477 mmol, 80) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49 to 1.60 (m, 2 H), 1.71 to 1.78 (m, 2 H), 1.89 to 2.09 (m, 5 H) , 2.21 (s, 3 H), 2.25-2.29 (m, 1 H), 3.08-3. 19 (m, 3 H), 3.43-3. 48 (m, 2 H), 3 .74-3.78 (m, 1 H), 4.43-4. 48 (m, 1 H), 5.24-5.25 (m, 1 H), 6.87 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 9.1 Hz, 1 H), 7.20 (d, J = 8.6 Hz, 2 H), 7.30 (dd, J = 9.1, 2.7 Hz, 1 H) ), 7.63 (d, J = 2.7 Hz, 1 H), 8.32 (s, 1 H).
ESI-MS: m / z = 490 (M + H) ⁺ .

Reference Example 19 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (2-methoxyphenyl) piperidine:

The title compound (hereinafter, the compound of Reference Example 19) (0.105 g) was prepared according to the same procedure as in Reference Example 7 except for using 1-iodo-2-methoxybenzene instead of 1-fluoro-2-iodobenzene. , 0.289 mmol, 56%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.07-2.14 (m, 2H), 2.18-2.26 (m, 2H), 3.03-3.09 (m, 2H) , 3.28-3.34 (m, 2 H), 3.89 (s, 3 H), 4.75-4. 75 (m, 1 H), 6.88-6. 90 (m, 1 H), 6 .92-6.96 (m, 1 H), 6.99-7.05 (m, 3 H), 8. 15 (dd, J = 9.5, 2.7 Hz, 1 H), 8.32 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 363 (M + H) ⁺ .

Reference Example 20 Synthesis of 3-chloro-4-((1- (2-methoxyphenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 19 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 20) (0.0834 g, 0.251 mmol, 91 %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.99-2.15 (m, 4 H), 2.86-2.92 (m, 2 H), 3.34-3. 39 (m, 2 H) , 3.51 (brs, 2H), 3.88 (s, 3H), 4.24-4.29 (m, 1H), 6.53 (dd, J = 8.7, 2.8 Hz, 1H) , 6.74 (d, J = 2.8 Hz, 1 H), 6.85-6.87 (m, 2 H), 6.90-6.94 (m, 1 H), 6.98-7.02 ( m, 2H).
ESI-MS: m / z = 333 (M + H) ⁺ .

Example 8 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (2-methoxyphenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 20 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except the above, the title compound (the compound of Example 8 below) (0.0518 g, 0.107 mmol, 89) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1 to 59 (m, 2 H), 1.71 to 1. 78 (m, 2 H), 1.90 to 1. 98 (m, 1 H) , 2.00-2.16 (m, 4 H), 2.21 (s, 3 H), 2.26-2.29 (m, 1 H), 2.92-2.97 (m, 2 H), 3 .12-3.20 (m, 1 H), 3.30-3.36 (m, 2 H), 3.74-3. 78 (m, 1 H), 3.88 (s, 3 H), 4.42 -4.47 (m, 1 H), 5.25-5. 26 (m, 1 H), 6.86-7.02 (m, 4 H), 6. 94 (d, J = 8.9 Hz, 1 H) , 7.30 (dd, J = 8.9, 2.6 Hz, 1 H), 7.63 (d, J = 2.6 Hz, 1 H), 8.30 (brs, 1 H).
ESI-MS: m / z = 486 (M + H) ^<+> .

Reference Example 21 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (3-methoxyphenyl) piperidine:

The title compound (hereinafter, the compound of Reference Example 21) (0.144 g) was prepared according to the same procedure as in Reference Example 7 except for using 1-bromo-3-methoxybenzene instead of 1-fluoro-2-iodobenzene. , 0.397 mmol, 77%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.00-2.18 (m, 4 H), 3.21-3.27 (m, 2 H), 3.45-3.51 (m, 2 H) , 3.80 (s, 3 H), 4.704 to 4.76 (m, 1 H), 6.42-6. 45 (m, 1 H), 6.51 (dd, J = 2.3, 2. 3 Hz, 1 H), 6.57-6.60 (m, 1 H), 7.03 (d, J = 9.1 Hz, 1 H), 7.19 (dd, J = 8.2, 8.2 Hz, 1 H ), 8.15 (dd, J = 9.1, 2.7 Hz, 1 H), 8.32 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 363 (M + H) ⁺ .

Reference Example 22 Synthesis of 3-chloro-4-((1- (3-methoxyphenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 21 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for the above, the title compound (hereinafter, the compound of Reference Example 22) (0.126 g, 0.376 mmol, 91) %) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90-2.09 (m, 4 H), 3.04-3.10 (m, 2 H), 3.52-3. 58 (m, 2 H) , 3.52 (brs, 2H), 3.79 (s, 3H), 4.24-4.30 (m, 1H), 6.39-6.42 (m, 1H), 6.49-6 .59 (m, 3 H), 6.74 (d, J = 2.5 Hz, 1 H), 6. 84 (d, J = 8.0 Hz, 1 H), 7.15 to 7.19 (m, 1 H) .
ESI-MS: m / z = 333 (M + H) ⁺ .

Example 9 Synthesis of 1-Acetyl-N- (3-chloro-4-((1- (3-methoxyphenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 22 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 9 below) (0.0448 g, 0.0922 mmol, 77) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.60 (m, 2H), 1.70-1.78 (m, 2H), 1.89-2.09 (m, 5H) , 2.21 (s, 3 H), 2. 26-2.29 (m, 1 H), 3. 10-3. 19 (m, 3 H), 3. 48-3. 54 (m, 2 H), 3 .74-3.78 (m, 1 H), 3.79 (s, 3 H), 4.42-4.47 (m, 1 H), 5.24-5.26 (m, 1 H), 6.41 (Dd, J = 8.0, 2.2 Hz, 1 H), 6.49 (dd, J = 2.2, 2.2 Hz, 1 H), 6.57 (dd, J = 8.3, 2.2 Hz , 1 H), 6.92 (d, J = 8.8 Hz, 1 H), 7.17 (dd, J = 8.3, 8.0 Hz, 1 H), 7.30 (dd, J = 8.8, 2.6 Hz, 1 H), 7.63 ( , J = 2.6Hz, 1H), 8.31 (s, 1H).
ESI-MS: m / z = 486 (M + H) ^<+> .

Reference Example 23 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (4-methoxyphenyl) piperidine:

The title compound (hereinafter, the compound of Reference Example 23) (0.163 g) was prepared by the same procedure as in Reference Example 7 using 1-bromo-4-methoxybenzene instead of 1-fluoro-2-iodobenzene , 0.449 mmol, 88%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.03-2.21 (m, 4 H), 3.07-3. 13 (m, 2 H), 3.32-3. 38 (m, 2 H) , 3.78 (s, 3 H), 4. 68-4. 73 (m, 1 H), 6. 85 (d, J = 9.1 Hz, 2 H), 6.95 (d, J = 9.1 Hz, 2H), 7.03 (d, J = 9.1 Hz, 1 H), 8.15 (dd, J = 9.1, 2.7 Hz, 1 H), 8.31 (d, J = 2.7 Hz, 1 H) ).
ESI-MS: m / z = 363 (M + H) ⁺ .

Reference Example 24 Synthesis of 3-chloro-4-((1- (4-methoxyphenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 23 instead of the compound of Reference Example 7, and following the same procedure as in Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 24) (0.152 g, 0.457 mmol, quantitation ) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.94-2.11 (m, 4 H), 2.9 1-2. 97 (m, 2 H), 3. 38-3. 43 (m, 2 H) , 3.51 (brs, 2H), 3.77 (s, 3H), 4.21-4.27 (m, 1H), 6.53 (dd, J = 8.5, 2.7 Hz, 1H) , 6.74 (d, J = 2.7 Hz, 1 H), 6.82-6. 85 (m, 3 H), 6.94 (d, J = 9.3 Hz, 2 H).
ESI-MS: m / z = 333 (M + H) ⁺ .

Example 10 Synthesis of 1-Acetyl-N- (3-chloro-4-((1- (4-methoxyphenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 24 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 10 below) (0.0385 g, 0.0792 mmol, 66) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.89-2.12 (m, 5H) , 2.21 (s, 3 H), 2. 26-2. 29 (m, 1 H), 2.96-3. 02 (m, 2 H), 3. 12-3. 19 (m, 1 H), 3 .34-3.40 (m, 2H), 3.74-3.77 (m, 1H), 3.77 (s, 3H), 4.39-4.44 (m, 1H), 5.24 −5.26 (m, 1 H), 6.84 (d, J = 9.0 Hz, 2 H), 6.93 (d, J = 8.8 Hz, 1 H), 6.94 (d, J = 9. 0 Hz, 2 H), 7.30 (dd, J = 8.8, 2.7 Hz, 1 H), 7.63 (d, J = 2.7 Hz, 1 H), 8.31 (s, 1 H).
ESI-MS: m / z = 486 (M + H) ^<+> .

Reference Example 25 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (o-tolyl) piperidine:

The title compound (hereinafter, the compound of Reference Example 25) (0.162 g) was prepared according to the same procedure as in Reference Example 7 except for using 1-bromo-2-methylbenzene instead of 1-fluoro-2-iodobenzene. , 0.467 mmol, 92%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.04-2.11 (m, 2H), 2.15-2.22 (m, 2H), 2.33 (s, 3H), 2.85 -2.91 (m, 2 H), 3.16-3.22 (m, 2 H), 4.67-4. 73 (m, 1 H), 6.98-7.07 (m, 3 H), 7 .16-7.23 (m, 2H), 8.15 (dd, J = 9.1, 2.7 Hz, 1 H), 8.32 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 347 (M + H) +.

Reference Example 26 Synthesis of 3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 25 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 26) (0.137 g, 0.432 mmol, 91) %) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.94-2.03 (m, 2H), 2.05-2.12 (m, 2H), 2.32 (s, 3H), 2.73 -2.79 (m, 2 H), 3.15-3. 21 (m, 2 H), 3.51 (s, 2 H), 4.21-4. 27 (m, 1 H), 6.53 (dd) , J = 8.6, 2.7 Hz, 1 H), 6. 75 (d, J = 2.7 Hz, 1 H), 6.86 (d, J = 8.6 Hz, 1 H), 6.95-6. 99 (m, 1 H), 7.03-7. 05 (m, 1 H), 7.14-7. 19 (m, 2 H).
ESI-MS: m / z = 317 (M + H) ⁺ .

EXAMPLE 11 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 26 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 11 below) (0.0360 g, 0.0766 mmol, 97) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.60 (m, 2 H), 1.71-1. 78 (m, 2 H), 1.89-2.04 (m, 3 H) , 2.06-2.13 (m, 2H), 2.21 (s, 3H), 2.26-2.29 (m, 1H), 2.32 (s, 3H), 2.76-2 .82 (m, 2 H), 3.12-3. 20 (m, 3 H), 3.75-3. 78 (m, 1 H), 4.40-4. 43 (m, 1 H), 5.25 -5.26 (m, 1 H), 6.93-6.99 (m, 2 H), 7.04-7.06 (m, 1 H), 7.14-7. 19 (m, 2 H), 7 30 (dd, J = 9.1, 2.7 Hz, 1 H), 7.64 (d, J = 2.7 Hz, 1 H), 8.31 (s, 1 H).
ESI-MS: m / z = 470 (M + H) ⁺ .

Reference Example 27 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (m-tolyl) piperidine:

The title compound (hereinafter, the compound of Reference Example 27) (0.129 g) was prepared according to the same procedure as in Reference Example 7 except for using 1-bromo-3-methylbenzene instead of 1-fluoro-2-iodobenzene. , 0.372 mmol, 73%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.01 to 2.09 (m, 2 H), 2.12 to 2. 19 (m, 2 H), 2.32 (s, 3 H), 3.19 -3.25 (m, 2 H), 3.44-3. 50 (m, 2 H), 4.75-4. 75 (m, 1 H), 6.60-6.72 (m, 1 H), 6 .78-6.80 (m, 2H), 7.03 (d, J = 9.1 Hz, 1 H), 7.15-7.19 (m, 1 H), 8.15 (dd, J = 9). 1, 2.7 Hz, 1 H), 8.31 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 347 (M + H) ⁺ .

Reference Example 28 Synthesis of 3-chloro-4-((1- (m-tolyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 27 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 28) (0.0857 g, 0.270 mmol, 76 %) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.91 to 1.99 (m, 2 H), 2.03-2.10 (m, 2 H), 2. 32 (s, 3 H), 3.02 -3.08 (m, 2H), 3.51-3.57 (m, 2H), 3.51 (s, 2H), 4.24-4.29 (m, 1H), 6.53 (dd) , J = 8.8, 2.9 Hz, 1 H), 6.67 (d, J = 7.7 Hz, 1 H), 6.74 (d, J = 2.9 Hz, 1 H), 6.76-6. 78 (m, 2H), 6.84 (d, J = 8.8 Hz, 1 H), 7.15 (dd, J = 7.7, 7.7 Hz, 1 H).
ESI-MS: m / z = 317 (M + H) ⁺ .

EXAMPLE 12 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (m-tolyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The title compound (the compound of Example 12 below) (0.0330 g, 0.0702 mmol, 89) was prepared according to the procedure as Example 2, except that the compound of Reference Example 28 was used instead of the compound of Reference Example 8. %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.60 (m, 2 H), 1.71-1. 78 (m, 2 H), 1.89-2.01 (m, 3 H) , 2.03-2.10 (m, 2H), 2.21 (s, 3H), 2.26-2.29 (m, 1H), 2.32 (s, 3H), 3.08-3 .19 (m, 3H), 3.47-3.53 (m, 2H), 3.74-3.78 (m, 1H), 4.41-4. 47 (m, 1H), 5.25 -5.26 (m, 1 H), 6.68 (d, J = 7.2 Hz, 1 H), 6.76-6.78 (m, 2 H), 6.93 (d, J = 9.1 Hz, 1H), 7.13-7.17 (m, 1H), 7.30 (dd, J = 9.1, 2.7 Hz, 1 H), 7.63 (d, J = 2.7 Hz, 1 H), 8.31 (s, 1 H).
ESI-MS: m / z = 470 (M + H) ⁺ .

Reference Example 29 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (p-tolyl) piperidine:

The title compound (hereinafter, the compound of Reference Example 29) (0.167 g) was prepared according to the procedure as in Reference Example 7 except for using 1-bromo-4-methylbenzene instead of 1-fluoro-2-iodobenzene. , 0.482 mmol, 94%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.02-2.09 (m, 2 H), 2.14-2.18 (m, 2 H), 2.28 (s, 3 H), 3.14 -3.20 (m, 2H), 3.40-3.46 (m, 2H), 4.69-4.74 (m, 1H), 6.89 (d, J = 8.6 Hz, 2H) , 7.02 (d, J = 9.1 Hz, 1 H), 7.09 (d, J = 8.6 Hz, 2 H), 8. 15 (dd, J = 9.1, 2.7 Hz, 1 H), 8.31 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 347 (M + H) ⁺ .

Reference Example 30 Synthesis of 3-chloro-4-((1- (p-tolyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 29 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 30) (0.140 g, 0.442 mmol, 93) %) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.92-2.00 (m, 2 H), 2.03-2.10 (m, 2 H), 2.27 (s, 3 H), 2.97 -3.03 (m, 2 H), 3.46-3.51 (m, 2 H), 3.51 (s, 2 H), 4.22-4.28 (m, 1 H), 6.53 (dd) , J = 8.6, 2.7 Hz, 1 H), 6. 74 (d, J = 2.7 Hz, 1 H), 6. 84 (d, J = 8.6 Hz, 1 H), 6.88 (d, J = 8.2 Hz, 2 H), 7.07 (d, J = 8.2 Hz, 2 H).
ESI-MS: m / z = 317 (M + H) ⁺ .

EXAMPLE 13 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (p-tolyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 30 instead of the compound of Reference Example 8 and using the procedure of Example 2 except for the above, the title compound (the compound of Example 13 below) (0.0325 g, 0.0691 mmol, 88) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.60 (m, 2 H), 1.71 to 1.77 (m, 2 H), 1.89 to 2.02 (m, 3 H) , 2.04-2.11 (m, 2H), 2.21 (s, 3H), 2.26-2.28 (m, 1H), 2.27 (s, 3H), 3.03-3 .09 (m, 2 H), 3.12-3. 19 (m, 1 H), 3.42-3. 48 (m, 2 H), 3.74-3. 78 (m, 1 H), 4.40 -4.45 (m, 1H), 5.24-5.26 (m, 1H), 6.88 (d, J = 8.6 Hz, 2 H), 6.92 (d, J = 9.1 Hz, 1H), 7.07 (d, J = 8.6 Hz, 2 H), 7. 30 (dd, J = 9.1, 2.7 Hz, 1 H), 7.63 (d, J = 2.7 Hz, 1 H) ), 8.31 (s, 1 H).
ESI-MS: m / z = 470 (M + H) ⁺ .

Reference Example 31 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (2- (trifluoromethyl) phenyl) piperidine:

Title compound (following, compound of Reference Example 31) in the same manner as in Reference Example 7 except for using 1-iodo-2- (trifluoromethyl) benzene instead of 1-fluoro-2-iodobenzene (0.0195 g, 0.0487 mmol, 10%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.04-2.11 (m, 2H), 2.13-2.20 (m, 2H), 2.86-2.92 (m, 2H) , 3.18-3.24 (m, 2 H), 4.72-4. 77 (m, 1 H), 7.03 (d, J = 9.5 Hz, 1 H), 7.23-7. m, 1 H), 7.41 (dd, J = 7.7, 0.9 Hz, 1 H), 7.52-7.56 (m, 1 H), 7.64 (dd, J = 7.7, 1 .4 Hz, 1 H), 8. 16 (dd, J = 9.5, 2.7 Hz, 1 H), 8.33 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 401 (M + H) ⁺ .

Reference Example 32 Synthesis of 3-chloro-4-((1- (2- (trifluoromethyl) phenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 31 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 32) (0.0193 g, 0.0521 mmol, quantitation ) As a brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.96-2.09 (m, 4 H), 2.77-2.83 (m, 2 H), 3.17-3. 23 (m, 2 H) , 3.51 (brs, 2H), 4.28-4.31 (m, 1H), 6.54 (dd, J = 8.6, 2.7 Hz, 1H), 6.75 (d, J = 2.7 Hz, 1 H), 6.85 (d, J = 8.6 Hz, 1 H), 7.19-7.23 (m, 1 H), 7.39 (d, J = 7.7 Hz, 1 H), 7.49-7.53 (m, 1 H), 7.62 (d, J = 7.7 Hz, 1 H).
ESI-MS: m / z = 371 (M + H) ⁺ .

Example 14 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (2- (trifluoromethyl) phenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide

Using the compound of Reference Example 32 instead of the compound of Reference Example 8, and using the procedure of Example 2 except the above, the title compound (the compound of Example 14 below) (0.0118 g, 0.0225 mmol, 52) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.90-2.10 (m, 5H) , 2.21 (s, 3 H), 2.26-2.29 (m, 1 H), 2.79-2. 84 (m, 2 H), 3.12-3.23 (m, 3 H), 3 .74-3.78 (m, 1 H), 4.45-4. 50 (m, 1 H), 5.25-5.26 (m, 1 H), 6.93 (d, J = 8.6 Hz, 1H), 7.21 (dd, J = 7.5, 7.5 Hz, 1 H), 7.30 (dd, J = 8.6, 2.7 Hz, 1 H), 7.40 (d, J = 8 .2 Hz, 1 H), 7.50-7.53 (m, 1 H), 7.61-7. 63 (m, 1 H), 7.65 (d, J = 2.7 Hz, 1 H), 8.30 (S, 1 H).
ESI-MS: m / z = 524 (M + H) ⁺ .

Reference Example 33 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (4- (trifluoromethyl) phenyl) piperidine:

Title compound (hereinafter, the compound of Reference Example 33) in the same manner as in Reference Example 7 except for using 1-bromo-4- (trifluoromethyl) benzene instead of 1-fluoro-2-iodobenzene (0.118 g, 0.294 mmol, 58%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.01-2.08 (m, 2 H), 2.10-2.17 (m, 2 H), 3.36-3. 42 (m, 2 H) , 3.53-3.60 (m, 2H), 4.76-4.81 (m, 1H), 6.97 (d, J = 9.1 Hz, 2H), 7.03 (d, J = 9.1 Hz, 1 H), 7. 50 (d, J = 9.1 Hz, 2 H), 8. 16 (dd, J = 9.1, 2.7 Hz, 1 H), 8.32 (d, J = 2) .7 Hz, 1 H).
ESI-MS: m / z = 401 (M + H) ⁺ .

Reference Example 34 Synthesis of 3-chloro-4-((1- (4- (trifluoromethyl) phenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 33 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 34) (0.113 g, 0.305 mmol, quantitation ) As a brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90-1.98 (m, 2 H), 2.00-2.07 (m, 2 H), 3.19-3. 25 (m, 2 H) , 3.53 (brs, 2H), 3.60-3.66 (m, 2H), 4.30-4.36 (m, 1H), 6.53 (dd, J = 8.6, 2. 7 Hz, 1 H), 6.74 (d, J = 2.7 Hz, 1 H), 6. 84 (d, J = 8.6 Hz, 1 H), 6.94 (d, J = 9.1 Hz, 2 H), 7.47 (d, J = 9.1 Hz, 2 H).
ESI-MS: m / z = 371 (M + H) ⁺ .

Example 15 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (4- (trifluoromethyl) phenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 34 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 15 below) (0.0195 g, 0.0372 mmol, 69) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.62 (m, 2 H), 1.71-1. 78 (m, 2 H), 1.91-2.08 (m, 5 H) , 2.21 (s, 3 H), 2. 26-2. 29 (m, 1 H), 3. 12-3. 19 (m, 1 H), 3. 25-3. 31 (m, 2 H), 3 .56-3.63 (m, 2H), 3.75-3.78 (m, 1H), 4.48-4.53 (m, 1H), 5.24-5.26 (m, 1H) , 6.92 (d, J = 8.8 Hz, 1 H), 6.95 (d, J = 8.6 Hz, 2 H), 7.31 (dd, J = 8.8, 2.7 Hz, 1 H), 7.48 (d, J = 8.6 Hz, 2 H), 7.64 (d, J = 2.7 Hz, 1 H), 8.33 (s, 1 H).
ESI-MS: m / z = 524 (M + H) ⁺ .

EXAMPLE 16 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (2-cyanophenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 4 (0.100 g, 0.263 mmol) and 2-fluorobenzonitrile (0.0638 g, 0.526 mmol) were dissolved in N, N-dimethylacetamide (1.76 mL), and cesium carbonate (0. 257 g, 0.790 mmol) were added at room temperature. After stirring at 150 ° C. for 3 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 60/40 to 5/95), and the title compound (hereinafter, the compound of Example 16) (0.0219 g, 0.0455 mmol, 17) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.61 (m, 2 H), 1.71 to 1. 78 (m, 2 H), 1.90 to 2.02 (m, 1 H) , 2.05-2.18 (m, 4H), 2.21 (s, 3H), 2.26-2.29 (m, 1H), 3.12-3.22 (m, 3H), 3 .41-3.47 (m, 2H), 3.75-3.78 (m, 1 H), 4.52-4.57 (m, 1 H), 5.25-5.26 (m, 1 H) , 6.93 (d, J = 9.1 Hz, 1 H), 6.98-7.02 (m, 1 H), 7.06 (d, J = 8.2 Hz, 1 H), 7.30 (dd, J = 9.1, 2.7 Hz, 1 H), 7.46-7.50 (m, 1 H), 7.56 (dd, J = 7.5, 1.6 Hz, 1 H), 7.65 (d , J = 2.7 Hz, 1 H), 8. 2 (s, 1H).
ESI-MS: m / z = 503 (M + Na) ⁺ .

Reference Example 35 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (3-cyanophenyl) piperidine:

Using 3-iodobenzonitrile instead of 1-fluoro-2-iodobenzene, and using the same procedure as in Reference Example 7 except the above, the title compound (hereinafter, the compound of Reference Example 35) (0.0199 g, 0. 0556 mmol, 14%) was obtained as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.03-2.18 (m, 4 H), 3.29-3. 35 (m, 2 H), 3.46-3. 52 (m, 2 H) , 4.76-4.80 (m, 1 H), 7.03 (d, J = 9.1 Hz, 1 H), 7.10-7.13 (m, 1 H), 7.14-7. m, 2H), 7.32-7.36 (m, 1H), 8.16 (dd, J = 9.1, 2.7 Hz, 1 H), 8.33 (d, J = 2.7 Hz, 1 H) ).
ESI-MS: m / z = 358 (M + H) ^<+> .

Reference Example 36 Synthesis of 3-chloro-4-((1- (3-cyanophenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 35 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 36) (0.0204 g, 0.0622 mmol, quantitation ) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.92 to 2.07 (m, 4 H), 3.13 to 3.19 (m, 2 H), 3.53 to 3.59 (m, 2 H) , 3.56 (brs, 2 H), 4.40-4. 35 (m, 1 H), 6.54 (dd, J = 8.7, 2.8 Hz, 1 H), 6.74 (d, J = 2.8 Hz, 1 H), 6.84 (d, J = 8.7 Hz, 1 H), 7.06-7.08 (m, 1 H), 7.12-7.14 (m, 2 H), 7. 29-7.33 (m, 1 H).
ESI-MS: m / z = 328 (M + H) ⁺ .

Example 17 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (3-cyanophenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 36 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 17 below) (0.0207 g, 0.0430 mmol, 86) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.61 (m, 2 H), 1.71 to 1. 78 (m, 2 H), 1.89 to 2.08 (m, 5 H) , 2.21 (s, 3 H), 2. 26-2.29 (m, 1 H), 3. 13-3. 25 (m, 3 H), 3. 4-9. 55 (m, 2 H), 3 .75-3.78 (m, 1 H), 4.47-4. 52 (m, 1 H), 5.24-5. 26 (m, 1 H), 6.92 (d, J = 8.6 Hz, 1H), 7.07-7.09 (m, 1H), 7.12-7.15 (m, 2H), 7.29-7.33 (m, 2H), 7.64 (d, J = 2.7 Hz, 1 H), 8. 35 (s, 1 H).
ESI-MS: m / z = 503 (M + H) ⁺ .

EXAMPLE 18 Synthesis of 1-Acetyl-N- (3-chloro-4-((1- (4-cyanophenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide

The title compound (hereinafter, the compound of Example 18) (0.0299 g, 0.0622 mmol, 24) was prepared by the same procedure as Example 16 except for using 4-fluorobenzonitrile instead of 2-fluorobenzonitrile %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.61 (m, 2 H), 1.71 to 1. 78 (m, 2 H), 1.89 to 2.55 (m, 5 H) , 2.21 (s, 3 H), 2.25-2.29 (m, 1 H), 3. 13-3. 20 (m, 1 H), 3.33-3. 39 (m, 2 H), 3 .60-3.66 (m, 2 H), 3.75-3. 78 (m, 1 H), 4.51-4. 56 (m, 1 H), 5.24-5. 26 (m, 1 H) , 6.88 (d, J = 9.1 Hz, 2 H), 6.91 (d, J = 9.1 Hz, 1 H), 7.31 (dd, J = 9.1, 2.7 Hz, 1 H), 7.49 (d, J = 9.1 Hz, 2 H), 7.64 (d, J = 2.7 Hz, 1 H), 8.36 (s, 1 H).
ESI-MS: m / z = 481 (M + H) ⁺ .

Reference Example 37 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (4- (trifluoromethoxy) phenyl) piperidine:

Title compound (hereinafter, the compound of Reference Example 37) in the same manner as in Reference Example 7 except for using 1-iodo-4- (trifluoromethoxy) benzene instead of 1-fluoro-2-iodobenzene (0.140 g, 0.336 mmol, 98%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.02-2.19 (m, 4 H), 3.21-3.27 (m, 2 H), 3.41-3. 48 (m, 2 H) , 4.72-4.77 (m, 1 H), 6.94 (d, J = 9.1 Hz, 2 H), 7.03 (d, J = 9.1 Hz, 1 H), 7.13 (d, J J = 9.1 Hz, 2 H), 8. 16 (dd, J = 9.1, 2.7 Hz, 1 H), 8.32 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 417 (M + H) ⁺ .

Reference Example 38 Synthesis of 3-chloro-4-((1- (4- (trifluoromethoxy) phenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 37 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 38) (0.125 g, 0.323 mmol, 96 %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.92 to 2.09 (m, 4 H), 3.05 to 3.11 (m, 2 H), 3.48 to 3. 54 (m, 2 H) , 3.51 (brs, 2H), 4.26-4.31 (m, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1 H), 6.74 (d, J = 2.7 Hz, 1 H), 6. 84 (d, J = 8.6 Hz, 1 H), 6. 91 (d, J = 9.1 Hz, 2 H), 7. 10 (d, J = 9.1 Hz, 2 H ).
ESI-MS: m / z = 387 (M + H) ⁺ .

EXAMPLE 19 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (4- (trifluoromethoxy) phenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide

Using the compound of Reference Example 38 instead of the compound of Reference Example 8, and using the procedure of Example 2 except the above, the title compound (the compound of Example 19 below) (0.0302 g, 0.0559 mmol, 87) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.89-2.10 (m, 5H) , 2.21 (s, 3 H), 2.26-2.29 (m, 1 H), 3.10-3.20 (m, 3 H), 3.44-3. 50 (m, 2 H), 3 .75-3.78 (m, 1 H), 4.44-4. 49 (m, 1 H), 5.24-5. 26 (m, 1 H), 6.90-6.93 (m, 3 H) , 7.10 (d, J = 8.6 Hz, 2 H), 7.31 (dd, J = 8.6, 2.7 Hz, 1 H), 7.63 (d, J = 2.7 Hz, 1 H), 8.32 (s, 1 H).
ESI-MS: m / z = 540 (M + H) ⁺ .

Reference Example 39 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (4- (difluoromethoxy) phenyl) piperidine:

Using 1-bromo-4- (difluoromethoxy) benzene instead of 1-fluoro-2-iodobenzene, and using the same procedure as in Reference Example 7 except for the above, to give the title compound (hereinafter, the compound of Reference Example 39) 0.128 g (0.321 mmol, 69%) was obtained as a brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.03-2.10 (m, 2H), 2.12-2.19 (m, 2H), 3.18-3.24 (m, 2H) , 3.39-3.45 (m, 2 H), 4.71-4. 76 (m, 1 H), 6.43 (t, J = 74.3 Hz, 1 H), 6.94 (d, J = 9.1 Hz, 2H), 7.03 (d, J = 9.1 Hz, 1 H), 7.06 (d, J = 9.1 Hz, 2 H), 8.16 (dd, J = 9.1, 2 .7 Hz, 1 H), 8.32 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 399 (M + H) ^<+> .

Reference Example 40 Synthesis of 3-chloro-4-((1- (4- (difluoromethoxy) phenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 39 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 40) (0.114 g, 0.309 mmol, quantification ) As a brown solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.92-2.00 (m, 2H), 2.02-2.09 (m, 2H), 3.01-3.07 (m, 2H) , 3.45 to 3.51 (m, 2 H), 3.52 (brs, 2 H), 4.25 to 4. 31 (m, 1 H), 6.41 (t, J = 74.3 Hz, 1 H) , 6.53 (dd, J = 8.6, 2.7 Hz, 1 H), 6.74 (d, J = 2.7 Hz, 1 H), 6.84 (d, J = 8.6 Hz, 1 H), 6.92 (d, J = 9.1 Hz, 2 H), 7.03 (d, J = 9.1 Hz, 2 H).
ESI-MS: m / z = 369 (M + H) ⁺ .

EXAMPLE 20 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (4- (difluoromethoxy) phenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide

Using the compound of Reference Example 40 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except the above, the title compound (the compound of Example 20 below) (0.0204 g, 0.0391 mmol, 72) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.59 (m, 2H), 1.71-1.78 (m, 2H), 1.89-2.10 (m, 5H) , 2.21 (s, 3 H), 2.25-2.29 (m, 1 H), 3.07-3. 20 (m, 3 H), 3.42-3. 48 (m, 2 H), 3 .75-3.78 (m, 1 H), 4.43-4. 48 (m, 1 H), 5.24-5. 26 (m, 1 H), 6.42 (t, J = 74.5 Hz, 1H), 6.91-6.93 (m, 3H), 7.04 (d, J = 9.1 Hz, 2H), 7.31 (dd, J = 8.6, 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1 H), 8.33 (s, 1 H).
ESI-MS: m / z = 522 (M + H) ⁺ .

Reference Example 41 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (4- (methylsulfonyl) phenyl) piperidine:

The compound of Reference Example 6 (0.100 g, 0.341 mmol) and 1-fluoro-4- (methylsulfonyl) benzene (0.119 g, 0.682 mmol) were suspended in N, N-dimethylacetamide (1.71 mL). , Cesium carbonate (0.333 g, 1.02 mmol) was added at room temperature. After stirring at 150 ° C. for 6 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, distilled water and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 70/30 to 40/60), and the title compound (hereinafter, the compound of Reference Example 41) (0.0700 g, 0.170 mmol, 50) %) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.01-2.16 (m, 4 H), 3.03 (s, 3 H), 3.48-3. 54 (m, 2 H), 3.60 -3.67 (m, 2H), 4.84-4.85 (m, 1H), 6.98 (d, J = 9.1 Hz, 2 H), 7.03 (d, J = 9.5 Hz, 1H), 7.79 (d, J = 9.1 Hz, 2 H), 8. 16 (dd, J = 9.5, 2.7 Hz, 1 H), 8.33 (d, J = 2.7 Hz, 1 H) ).
ESI-MS: m / z = 411 (M + H) ⁺ .

Reference Example 42 Synthesis of 3-chloro-4-((1- (4- (methylsulfonyl) phenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 41 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 42) (0.0602 g, 0.158 mmol, 99 %) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90-2.05 (m, 4 H), 3.02 (s, 3 H), 3.32-3. 38 (m, 2 H), 3.54 (S, 2 H), 3.67-3. 74 (m, 2 H), 4. 35-4. 40 (m, 1 H), 6.54 (dd, J = 8.6, 2.7 Hz, 1 H) , 6.75 (d, J = 2.7 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 1 H), 6.95 (d, J = 9.1 Hz, 2 H), 7.76 ( d, J = 9.1 Hz, 2 H).
ESI-MS: m / z = 381 (M + H) ⁺

EXAMPLE 21 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (4- (methylsulfonyl) phenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide

Using the compound of Reference Example 42 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except the above, the title compound (the compound of Example 21 below) (0.0405 g, 0.0758 mmol, 96) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.61 (m, 2 H), 1.71-1. 78 (m, 2 H), 1.90-2.04 (m, 5 H) , 2.21 (s, 3 H), 2. 26-2. 29 (m, 1 H), 3.02 (s, 3 H), 3. 12-3. 19 (m, 1 H), 3. 37-3 .43 (m, 2 H), 3.63-3. 70 (m, 2 H), 3.75-3. 79 (m, 1 H), 4.52-4. 57 (m, 1 H), 5.24 −5.26 (m, 1 H), 6.92 (d, J = 9.1 Hz, 1 H), 6.95 (d, J = 9.1 Hz, 2 H), 7.32 (dd, J = 9. 1, 2.7 Hz, 1 H), 7. 65 (d, J = 2.7 Hz, 1 H), 7. 76 (d, J = 9.1 Hz, 2 H), 8. 35 (s, 1 H).
ESI-MS: m / z = 556 (M + Na) ⁺ .

Reference Example 43 Synthesis of ethyl 4- (4- (2-chloro-4-nitrophenoxy) piperidin-1-yl) benzoate:

Using a similar procedure to Reference Example 41 except that ethyl 4-fluorobenzoate was used instead of 1-fluoro-4- (methylsulfonyl) benzene, the title compound (hereinafter, the compound of Reference Example 43) (0. 1) was prepared. 0619 g (0.153 mmol, 30%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.37 (t, J = 7.2 Hz, 3 H), 2.00-2.07 (m, 2 H), 2.09-2.16 (m, 2H), 3.41-3.47 (m, 2H), 3.58-3.64 (m, 2H), 4.34 (q, J = 7.2 Hz, 2H), 4.76-4. 81 (m, 1 H), 6.91 (d, J = 9.1 Hz, 2 H), 7.03 (d, J = 9.1 Hz, 1 H), 7.94 (d, J = 9.1 Hz, 2 H ), 8.16 (dd, J = 9.1, 2.7 Hz, 1 H), 8.32 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 405 (M + H) ⁺ .

Reference Example 44 Synthesis of ethyl 4- (4- (4-amino-2-chlorophenoxy) piperidin-1-yl) benzoate:

Using the compound of Reference Example 43 instead of the compound of Reference Example 7, and following the same procedure as in Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 44) (0.0600 g, 0.160 mmol, quantitation ) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.37 (t, J = 7.0 Hz, 3 H), 1.89-1.97 (m, 2 H), 1.99-2.06 (m, 2H), 3.25-3.31 (m, 2H), 3.53 (brs, 2H), 3.66-6.72 (m, 2H), 4.33 (q, J = 7.0 Hz, 2H), 6.53 (dd, J = 8.6, 2.7 Hz, 1 H), 6.74 (d, J = 2.7 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 1 H) ), 6.88 (d, J = 9.1 Hz, 2 H), 7.92 (d, J = 9.1 Hz, 2 H).
ESI-MS: m / z = 375 (M + H) ⁺ .

Example 22 Synthesis of Ethyl 4- (4- (4- (1-Acetylpiperidine-2-carboxamido) -2-chlorophenoxy) piperidin-1-yl) benzoate:

Using the compound of Reference Example 44 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 22 below) (0.0483 g, 0.0915 mmol, 62) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.37 (t, J = 7.2 Hz, 3 H), 1.47-1.61 (m, 2 H), 1.71-1.78 (m, 2H), 1.90 to 2.07 (m, 5 H), 2.21 (s, 3 H), 2.26 to 2.29 (m, 1 H), 3.12 to 3. 19 (m, 1 H) , 3.31-3.37 (m, 2H), 3.62-3.68 (m, 2H), 3.75-3. 78 (m, 1H), 4.33 (q, J = 7). 2 Hz, 2 H), 4.48-4.53 (m, 1 H), 5.24-5. 26 (m, 1 H), 6.89 (d, J = 9.1 Hz, 2 H), 6.92 ( d, J = 8.6 Hz, 1 H), 7.31 (dd, J = 8.6, 2.7 Hz, 1 H), 7.64 (d, J = 2.7 Hz, 1 H), 7. 92 (d , J = 9.1 Hz, 2 H), 8 33 (s, 1H).
ESI-MS: m / z = 528 (M + H) ⁺ .

Reference Example 45 Synthesis of (4- (4- (2-chloro-4-nitrophenoxy) piperidin-1-yl) phenyl) methanol:

The compound of Reference Example 43 (0.0500 g, 0.124 mmol) is dissolved in dichloromethane (1.24 mL), and diisobutylaluminum hydride-toluene solution (1.0 M, 0.247 mL, 0.247 mmol) is added at -78.degree. The After stirring for 2 hours at 0 ° C., an aqueous potassium sodium tartrate solution was added to the reaction solution. After stirring at room temperature for 1 hour, the aqueous layer was extracted with chloroform. The organic layer was washed with distilled water and saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 70/30 to 40/60), and the title compound (hereinafter, the compound of Reference Example 45) (0.0305 g, 0.0841 mmol, 68) %) As a pale yellow solid.
Obtained.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.51 (t, J = 5.9 Hz, 1 H), 2.02-2.09 (m, 2 H), 2.12-2.19 (m, 2H), 3.22-3.28 (m, 2H), 3.45-3.51 (m, 2H), 4.61 (d, J = 5.9 Hz, 2H), 4.71-4. 76 (m, 1 H), 6.97 (d, J = 8.6 Hz, 2 H), 7.03 (d, J = 9.1 Hz, 1 H), 7. 29 (d, J = 8.6 Hz, 2 H ), 8.15 (dd, J = 9.1, 2.7 Hz, 1 H), 8.32 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 363 (M + H) ⁺ .

Reference Example 46 Synthesis of (4- (4- (4-amino-2-chlorophenoxy) piperidin-1-yl) phenyl) methanol:

Using the compound of Reference Example 45 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 46) (0.0533 g, 0.160 mmol, 83) %) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (brs, 1 H), 1.92-2.00 (m, 2 H), 2.03-2.09 (m, 2 H), 3.05 -3.11 (m, 2 H), 3.52-3. 58 (m, 2 H), 3.53 (brs, 2 H), 4.25-4. 31 (m, 1 H), 4.60 (s) , 2H), 6.53 (dd, J = 8.6, 2.7 Hz, 1 H), 6.74 (d, J = 2.7 Hz, 1 H), 6.84 (d, J = 8.6 Hz, 1 H), 6.95 (d, J = 8.6 Hz, 2 H), 7. 27 (d, J = 8.6 Hz, 2 H).
ESI-MS: m / z = 333 (M + H) ⁺ .

EXAMPLE 23 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (4- (hydroxymethyl) phenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide

Using the compound of Reference Example 46 instead of the compound of Reference Example 8, and using the procedure of Example 2 except for the above, the title compound (the compound of Example 23 below) (0.0155 g, 0.0319 mmol, 43) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1 to 1. 60 (m, 3 H), 1. 70 1. 78 (m, 2 H), 1. 9 to 2. 10 (m, 5 H) , 2.21 (s, 3 H), 2.25-2.29 (m, 1 H), 3.11-3. 20 (m, 3 H), 3.48-3. 54 (m, 2 H), 3 .74-3.78 (m, 1 H), 4.43-4. 48 (m, 1 H), 4.60 (d, J = 5.0 Hz, 2 H), 5.24-5. 26 (m, 1 H) 1H), 6.91-6.96 (m, 3H), 7.26-7.28 (m, 2H), 7.31 (dd, J = 9.1, 2.7 Hz, 1H), 7. 63 (d, J = 2.7 Hz, 1 H), 8.31 (s, 1 H).
ESI-MS: m / z = 486 (M + H) ^<+> .

Reference Example 47 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (2,4-dimethylphenyl) piperidine:

The title compound (hereinafter, the compound of Reference Example 47) was prepared according to the same procedure as in Reference Example 7 except for using 1-bromo-2,4-dimethylbenzene instead of 1-fluoro-2-iodobenzene. .0692 g, 0.192 mmol, 56%) were obtained as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.03-2.10 (m, 2H), 2.14-2.20 (m, 2H), 2.28 (s, 3H), 2.29 (S, 3H), 2.81-2.87 (m, 2H), 3.12-3.18 (m, 2H), 4.66-4.71 (m, 1H), 6.95-7 .05 (m, 4 H), 8. 15 (dd, J = 9.1, 2.7 Hz, 1 H), 8.32 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 361 (M + H) +.

Reference Example 48 Synthesis of 3-chloro-4-((1- (2,4-dimethylphenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 47 instead of the compound of Reference Example 7, and using the same procedure as in Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 48) (0.0647 g, 0.196 mmol, quantitation (D) as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.93-2.01 (m, 2H), 2.05-2.11 (m, 2H), 2.27 (s, 3H), 2.28 (S, 3 H), 2. 70-2. 75 (m, 2 H), 3.11-3. 17 (m, 2 H), 3.5 1 (s, 2 H), 4. 20-4. 25 (m , 1 H), 6.53 (dd, J = 8.6, 2.9 Hz, 1 H), 6.74 (d, J = 2.9 Hz, 1 H), 6.86 (d, J = 8.6 Hz, 1 H), 6.93-7.00 (m, 3 H).
ESI-MS: m / z = 331 (M + H) ⁺ .

Example 24 Synthesis of 1-Acetyl-N- (3-chloro-4-((1- (2,4-dimethylphenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 48 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except the above, the title compound (the compound of Example 24 below) (0.0285 g, 0.0589 mmol, 68) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49 to 1.60 (m, 2 H), 1.71 to 1.78 (m, 2 H), 1.91 to 2. 03 (m, 3 H) , 2.06-2.12 (m, 2H), 2.21 (s, 3H), 2.26-2.27 (m, 1H), 2.27 (s, 3H), 2.28 (s) , 3H), 2.72-2.78 (m, 2H), 3.11-3.20 (m, 3H), 3.74-3.78 (m, 1H), 4.37-4.43 (M, 1 H), 5.25-5. 26 (m, 1 H), 6. 94 (d, J = 9.1 Hz, 1 H), 6.96-7.00 (m, 3 H), 7.30 (Dd, J = 9.1, 2.7 Hz, 1 H), 7.64 (d, J = 2.7 Hz, 1 H), 8.31 (s, 1 H).
ESI-MS: m / z = 484 (M + H) ⁺ .

Reference Example 49 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1- (2-fluoro-4-methylphenyl) piperidine:

Title compound (following, compound of Reference Example 49) in the same manner as in Reference Example 7 except for using 1-bromo-2-fluoro-4-methylbenzene instead of 1-fluoro-2-iodobenzene (0.0515 g, 0.141 mmol, 41%) was obtained as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.05-2.13 (m, 2H), 2.16-2.23 (m, 2H), 2.29 (s, 3H), 3.03 -3.08 (m, 2H), 3.26-3.32 (m, 2H), 4.75-4.75 (m, 1H), 6.85-6. 93 (m, 3H), 7 .03 (d, J = 9.1 Hz, 1 H), 8. 15 (dd, J = 9.1, 2.7 Hz, 1 H), 8.32 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 365 (M + H) +.

Reference Example 50 Synthesis of 3-chloro-4-((1- (2-fluoro-4-methylphenyl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 49 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 50) (0.0453 g, 0.135 mmol, 99 %) As a brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.97 to 2.12 (m, 4 H), 2.28 (s, 3 H), 2.88 to 2.94 (m, 2 H), 3.30 -3.36 (m, 2H), 3.50 (brs, 2H), 4.24-4.30 (m, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H) , 6.74 (d, J = 2.7 Hz, 1 H), 6.83-6.91 (m, 4 H).
ESI-MS: m / z = 335 (M + H) ⁺ .

Example 25 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (2-fluoro-4-methylphenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 50 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 25 below) (0.0235 g, 0.0482 mmol, 72) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.89-2.14 (m, 5H) , 2.21 (s, 3 H), 2. 26-2.28 (m, 1 H), 2. 28 (s, 3 H), 2.93-2 2. 98 (m, 2 H), 3. 12-3. .20 (m, 1 H), 3.27-3. 33 (m, 2 H), 3.74-3. 78 (m, 1 H), 4.42-4. 47 (m, 1 H), 5.25 -5.26 (m, 1 H), 6.84-6. 90 (m, 3 H), 6.93 (d, J = 9.1 Hz, 1 H), 7.30 (dd, J = 9.1, 2.3 Hz, 1 H), 7.63 (d, J = 2.3 Hz, 1 H), 8.31 (s, 1 H).
ESI-MS: m / z = 488 (M + H) ⁺ .

Example 26 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (pyridin-2-yl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 4 (0.100 g, 0.263 mmol) is dissolved in 1,4-dioxane (1.32 mL), and 2-bromopyridine (0.0385 mL, 0.395 mmol), [1,3-bis ( 2,6-Diisopropylphenyl) imidazol-2-ylidene] (3-chloropyridyl) palladium (II) dichloride (0.0179 g, 0.0263 mmol) and tert-butyloxy potassium (0.0886 g, 0.790 mmol) at room temperature Added. After stirring at 80 ° C. for 16 hours, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 to 97/3) to give the title compound (hereinafter, the compound of Example 26) (0.0178 g, 0.0390 mmol, 15%) Was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.59 (m, 2 H), 1.71 to 1. 78 (m, 2 H), 1.86 to 2.05 (m, 5 H) , 2.21 (s, 3 H), 2. 26-2.29 (m, 1 H), 3. 13-3. 20 (m, 1 H), 3. 48-3. 54 (m, 2 H), 3 .75-3.78 (m, 1 H), 3.85-3. 91 (m, 2 H), 4.48-4.54 (m, 1 H), 5.25-5.26 (m, 1 H) , 6.59-6.61 (m, 1 H), 6.69 (d, J = 8.6 Hz, 1 H), 6.93 (d, J = 8.6 Hz, 1 H), 7.31 (dd, J = 8.6, 2.3 Hz, 1 H), 7.45-7.49 (m, 1 H), 7.64 (d, J = 2.3 Hz, 1 H), 8.18-8.20 (m , 1H), 8.33 (s, 1H)
ESI-MS: m / z = 457 (M + H) ^<+> .

EXAMPLE 27 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (5-chloropyridin-2-yl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 27) (0.0033 g, 0.0067 mmol) was prepared according to the same procedure as Example 16 except that 2,5-dichloropyridine was used instead of 2-fluorobenzonitrile. 6%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.86-2.02 (m, 5H) , 2.21 (s, 3 H), 2. 26-2. 29 (m, 1 H), 3.1 2-3. 20 (m, 1 H), 3.48-3. 54 (m, 2 H), 3 .75-3.85 (m, 3 H), 4.49-4.54 (m, 1 H), 5.25-5.26 (m, 1 H), 6.62 (d, J = 9.1 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 7.31 (dd, J = 8.8, 2.7 Hz, 1H), 7.41 (dd, J = 9.1, 2) .7 Hz, 1 H), 7.64 (d, J = 2.7 Hz, 1 H), 8. 10 (d, J = 2.7 Hz, 1 H), 8.33 (s, 1 H).
ESI-MS: m / z = 491 (M + H) ⁺ .

Reference Example 51 Synthesis of 5-chloro-2- (4- (2-chloro-4-nitrophenoxy) piperidin-1-yl) -3-fluoropyridine:

The title compound (the compound of Reference Example 51) was prepared by the same procedure as Reference Example 41 except for using 5-chloro-2,3-difluoropyridine instead of 1-fluoro-4- (methylsulfonyl) benzene ) (0.119 g, 0.308 mmol, 90%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.97-2.05 (m, 2 H), 2.09-2.16 (m, 2 H), 3.50 to 3.56 (m, 2 H) , 3.70 to 3.76 (m, 2H), 4.76 to 4.81 (m, 1 H), 7.03 (d, J = 9.1 Hz, 1 H), 7.28 (dd, J = 12.2, 2.3 Hz, 1 H), 7.98 (d, J = 2.3 Hz, 1 H), 8. 16 (dd, J = 9.1, 2.7 Hz, 1 H), 8.32 (d , J = 2.7 Hz, 1 H).
ESI-MS: m / z = 386 (M + H) +.

Reference Example 52 Synthesis of 3-chloro-4-((1- (5-chloro-3-fluoropyridin-2-yl) piperidin-4-yl) oxy) aniline:

Using the compound of Reference Example 51 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 52) (0.105 g, 0.295 mmol, quantitation ) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.88-1 to 9.96 (m, 2 H), 2.00-2.07 (m, 2 H), 3.30-3. 36 (m, 2 H) , 3.52 (s, 2H), 3.78 to 3.84 (m, 2H), 4.29 to 4.35 (m, 1 H), 6.53 (dd, J = 8.6, 2. 7 Hz, 1 H), 6.74 (d, J = 2.7 Hz, 1 H), 6. 84 (d, J = 8.6 Hz, 1 H), 7. 25 (dd, J = 12.5, 2.0 Hz) , 1 H), 7.96 (d, J = 2.0 Hz, 1 H).
ESI-MS: m / z = 356 (M + H) +.

Example 28 1-Acetyl-N- (3-chloro-4-((1- (5-chloro-3-fluoropyridin-2-yl) piperidin-4-yl) oxy) phenyl) piperidine-2- Carboxamide Synthesis:

Using the compound of Reference Example 52 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 28 below) (0.0251 g, 0.0493 mmol, 72) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 to 1.60 (m, 2H), 1.71 to 1.78 (m, 2H), 1.90 to 1.97 (m, 3H) , 2.00-2.08 (m, 2 H), 2.21 (s, 3 H), 2.26-2.29 (m, 1 H), 3.12-3. 19 (m, 1 H), 3 .37-3.43 (m, 2H), 3.74- 3.80 (m, 3H), 4.47-4. 52 (m, 1H), 5.24-5.26 (m, 1H) , 6.92 (d, J = 9.1 Hz, 1 H), 7. 25 (dd, J = 12.2, 1.8 Hz, 1 H), 7.31 (dd, J = 9.1, 2.7 Hz) , 1 H), 7.63 (d, J = 2.7 Hz, 1 H), 7.96 (d, J = 1.8 Hz, 1 H), 8.32 (s, 1 H).
ESI-MS: m / z = 509 (M + H) ⁺ .

Example 29 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (pyrimidin-2-yl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide

The compound of Reference Example 4 (0.0300 g, 0.0790 mmol) and 2-chloropyrimidine (0.0235 g, 0.158 mmol) are dissolved in ethanol (1.00 mL) and potassium carbonate (0.0327 g, 0.237 mmol) Was added at room temperature. After stirring at 90 ° C. for 8 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 to 97/3) to give the title compound (compound of Example 29 below) (0.0324 g, 0.0707 mmol, 90%) Was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49 to 1.60 (m, 2 H), 1.71 to 1. 78 (m, 2 H), 1.83 to 2.01 (m, 5 H) , 2.21 (s, 3 H), 2. 26-2. 29 (m, 1 H), 3. 12-3. 20 (m, 1 H), 3. 75-3. 82 (m, 3 H), 4 .08-4.14 (m, 2 H), 4.51-4. 56 (m, 1 H), 5.25-5. 26 (m, 1 H), 6.47 (t, J = 4.8 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1 H), 7.31 (dd, J = 9.0, 2.7 Hz, 1 H), 7.64 (d, J = 2.7 Hz, 1 H) ), 8.31 (d, J = 4.8 Hz, 2 H), 8.32 (brs, 1 H).
ESI-MS: m / z = 458 (M + H) ^<+> .

Example 30 Synthesis of 1-Acetyl-N- (3-chloro-4-((1- (5-chloropyrimidin-2-yl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 30) (0.0319 g, 0.0648 mmol, 82) was prepared by the same procedure as in Example 29 except for using 2, 5-dichloropyrimidine in place of 2-chloropyrimidine. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1 to 60 (m, 2 H), 1.71 to 1. 78 (m, 2 H), 1.83 to 1. 98 (m, 5 H) , 2.21 (s, 3 H), 2. 26-2. 29 (m, 1 H), 3. 12-3. 19 (m, 1 H), 3. 74-3. 84 (m, 3 H), 4 .00-4.07 (m, 2 H), 4.52-4.57 (m, 1 H), 5.24-5. 26 (m, 1 H), 6.93 (d, J = 9.0 Hz, 1H), 7.31 (dd, J = 9.0, 2.4 Hz, 1 H), 7.64 (d, J = 2.4 Hz, 1 H), 8.22 (s, 2 H), 8.33 ( s, 1 H).
ESI-MS: m / z = 492 (M + H) ^<+> .

Example 31 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (5-methylpyrimidin-2-yl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 31) (0.0205 g, 0.0434 mmol) according to the procedure of Example 29 except for using 2-chloro-5-methylpyrimidine instead of 2-chloropyrimidine , 55%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49 to 1.60 (m, 2 H), 1.71 to 1.78 (m, 2 H), 1.81 to 2.00 (m, 5 H) , 2.12 (s, 3 H), 2.21 (s, 3 H), 2. 26-2. 29 (m, 1 H), 3. 12-3. 19 (m, 1 H), 3. 68-3 .78 (m, 3H), 4.07-4.13 (m, 2H), 4.49-4.54 (m, 1H), 5.25-5.26 (m, 1H), 6.93 (D, J = 9.0 Hz, 1 H), 7.31 (dd, J = 9.0, 2.4 Hz, 1 H), 7.63 (d, J = 2.4 Hz, 1 H), 8.16 ( s, 2H), 8.32 (s, 1H).
ESI-MS: m / z = 472 (M + H) ⁺ .

Example 32 1-Acetyl-N- (3-chloro-4-((1- (5- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) oxy) phenyl) piperidine-2- Carboxamide Synthesis:

The title compound (hereinafter, the compound of Example 32) (0.0282 g) was prepared by the same procedure as Example 29 except that 2-chloro-5- (trifluoromethyl) pyrimidine was used instead of 2-chloropyrimidine , 0.0536 mmol, 68%) were obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.89-1.98 (m, 5H) , 2.21 (s, 3 H), 2. 26-2. 29 (m, 1 H), 3.1 2-3. 20 (m, 1 H), 3. 75-3. 78 (m, 1 H), 3 .97-4.10 (m, 4H), 4.56-4.61 (m, 1H), 5.25-5.26 (m, 1H), 6.93 (d, J = 8.6 Hz, 1H), 7.32 (dd, J = 8.6, 2.3 Hz, 1 H), 7.65 (d, J = 2.3 Hz, 1 H), 8. 35 (s, 1 H), 8.48 ( s, 2H).
ESI-MS: m / z = 472 (M + H) ⁺ .

Example 33 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (4-methoxypyrimidin-2-yl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The title compound (the compound of Example 33 below) (0.0192 g, 0.0393 mmol) according to the same procedure as Example 29 except for using 2-chloro-4-methoxypyrimidine instead of 2-chloropyrimidine , 75%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.83-2.00 (m, 5H) , 2.21 (s, 3 H), 2. 26-2. 29 (m, 1 H), 3. 12-3. 20 (m, 1 H), 3. 74-3. 81 (m, 3 H), 3 .89 (s, 3 H), 4.07-4. 13 (m, 2 H), 4.50-4. 56 (m, 1 H), 5.25-5. 26 (m, 1 H), 5.97 (D, J = 5.9 Hz, 1 H), 6.93 (d, J = 8.6 Hz, 1 H), 7.31 (dd, J = 8.6, 2.3 Hz, 1 H), 7.64 ( d, J = 2.3 Hz, 1 H), 8.05 (d, J = 5.9 Hz, 1 H), 8.33 (s, 1 H).
ESI-MS: m / z = 488 (M + H) ⁺ .

Example 34 Synthesis of 1-acetyl-N- (3-chloro-4-((1- (4-methylpyrimidin-2-yl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 34) (0.0214 g, 0.0453 mmol) was prepared by the same procedure as in Example 29 except that 2-chloro-4-methylpyrimidine was used instead of 2-chloropyrimidine. , 86%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.59 (m, 2H), 1.71-1.78 (m, 2H), 1.82-2.00 (m, 5H) , 2.21 (s, 3 H), 2. 26-2. 29 (m, 1 H), 2. 33 (s, 3 H), 3. 13-3. 20 (m, 1 H), 3. 72 3 .78 (m, 3H), 4.11-4.18 (m, 2H), 4.49-4.55 (m, 1H), 5.25-5.26 (m, 1H), 6.35 (D, J = 5.0 Hz, 1 H), 6.94 (d, J = 8.6 Hz, 1 H), 7.31 (dd, J = 8.6, 2.7 Hz, 1 H), 7.64 ( d, J = 2.7 Hz, 1 H, 8. 16 (d, J = 5.0 Hz, 1 H), 8.32 (s, 1 H).
ESI-MS: m / z = 472 (M + H) ⁺ .

Example 35 1-Acetyl-N- (3-chloro-4-((1- (4- (trifluoromethyl) pyrimidin-2-yl) piperidin-4-yl) oxy) phenyl) piperidine-2- Carboxamide Synthesis:

The title compound (the compound of Example 35 below) (0. 017 g) according to the same procedure as Example 29 except for using 2-chloro-4- (trifluoromethyl) pyrimidine instead of 2-chloropyrimidine , 0.0222 mmol, 42%) were obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.61 (m, 2 H), 1.72-1. 78 (m, 2 H), 1.88-2.00 (m, 5 H) , 2.21 (s, 3 H), 2. 26-2.29 (m, 1 H), 3. 13-3. 20 (m, 1 H), 3. 75-3. 78 (m, 1 H), 3 .88-3.94 (m, 2H), 4.05-4.12 (m, 2H), 4.54-4.59 (m, 1H), 5.25-5.26 (m, 1H) , 6.73 (d, J = 5.0 Hz, 1 H), 6.93 (d, J = 8.6 Hz, 1 H), 7.32 (dd, J = 8.6, 2.7 Hz, 1 H), 7.65 (d, J = 2.7 Hz, 1 H), 8.34 (s, 1 H), 8. 48 (d, J = 5.0 Hz, 1 H).
ESI-MS: m / z = 548 (M + Na) ⁺ .

Reference Example 53 Synthesis of 4- (2-chloro-4-nitrophenoxy) -1-phenylpiperidine:

Compound of Reference Example 6 (0.200 g, 0.682 mmol), palladium (II) acetate (0.0306 g, 0.136 mmol), tri-tert-butylphosphino tetrafluoroborate (0.0396 g, 0.136 mmol) and Sodium tert-butyloxy (0.229 g, 2.39 mmol) was suspended in toluene (3.41 mL) and iodobenzene (0.115 mL, 1.02 mmol) was added at room temperature. After stirring for 2 hours at 110 ° C., the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5-80 / 20) to give the title compound (hereinafter, the compound of Reference Example 53) (0.210 g, 0.631 mmol, 93) %) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.02-2.10 (m, 2H), 2.13-2.20 (m, 2H), 3.21-3.27 (m, 2H) , 3.45 to 3.51 (m, 2H), 4.71 to 4. 76 (m, 1 H), 6.86 to 6.90 (m, 1 H), 6.97 to 6.99 (m, 2H), 7.03 (d, J = 9.1 Hz, 1H), 7.26-7.31 (m, 2H), 8.15 (dd, J = 9.1, 2.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 333 (M + H) ⁺ .

Reference Example 54 Synthesis of 3-chloro-4-((1-phenylpiperidin-4-yl) oxy) aniline:

The compound of Reference Example 53 (0.378 g, 1.14 mmol) was suspended in ethanol (5.68 mL) and distilled water (2.84 mL), iron powder (0.317 g, 5.68 mmol) and ammonium chloride (0. 304 g, 5.68 mmol) were added at room temperature. After stirring at 80 ° C. for 1 hour, the reaction solution was filtered, distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 50/50), and the title compound (hereinafter, the compound of Reference Example 54) (0.337 g, 1.11 mmol, 98) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.92-2.00 (m, 2 H), 2.03-2.10 (m, 2 H), 3.04-3. 10 (m, 2 H) , 3.52-3.58 (m, 2H), 3.52 (s, 2H), 4.25-4.30 (m, 1H), 6.53 (dd, J = 8.6, 2. 7 Hz, 1 H), 6.74 (d, J = 2.7 Hz, 1 H), 6.82-6. 86 (m, 1 H), 6. 84 (d, J = 8.6 Hz, 1 H), 6. 95-6.97 (m, 2H), 7.25-7.27 (m, 2H).
ESI-MS: m / z = 303 (M + H) ⁺ .

Reference Example 55 Synthesis of tert-butyl 2-((3-chloro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylate:

The compound of Reference Example 54 (0.0800 g, 0.264 mmol) and 1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid (0.0727 g, 0.317 mmol) are dissolved in DMF (1.32 mL) to obtain HATU (0.121 g, 0.317 mmol) and diisopropylethylamine (0.0692 mL, 0.396 mmol) were added at room temperature. After stirring at the same temperature for 16 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 60/40), and the title compound (hereinafter, the compound of Reference Example 55) (0.132 g, 0.257 mmol, 97) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.52 (m, 2H), 1.52 (s, 9H), 1.57-1.69 (m, 3H), 1.95 -2.03 (m, 2 H), 2.06-2.12 (m, 2 H), 2.32-2.35 (m, 1 H), 2.78-2. 85 (m, 1 H), 3 .10-3.16 (m, 2H), 3.48-3.54 (m, 2H), 4.07 (brs, 1H), 4.43-4.48 (m, 1H), 4.83 -4.86 (m, 1 H), 6.83-6.87 (m, 1 H), 6.95 (d, J = 8.6 Hz, 1 H), 6.95-6. 98 (m, 2 H) , 7.25-7.29 (m, 2H), 7.31 (dd, J = 8.6, 2.7 Hz, 1 H), 7.62 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 514 (M + H) ⁺ .

Reference Example 56 Synthesis of N- (3-chloro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 55 (0.130 g, 0.253 mmol) is dissolved in ethyl acetate (1.26 mL), and hydrogen chloride-ethyl acetate solution (4.0 M, 1.26 mL, 5.06 mmol) is added at 0 ° C. The After stirring at room temperature for 3 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (compound of Reference Example 56) (0.0990 g, 0.239 mmol, 95%) Obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.63 (m, 4 H), 1.79-1.84 (m, 1 H), 1.95-2.03 (m, 3 H) , 2.06-2.12 (m, 2H), 2.73-2.80 (m, 1H), 3.04-3.09 (m, 1H), 3.10-3.16 (m, 2H), 3.37 (dd, J = 9.5, 3.2 Hz, 1H), 3.49-3.55 (m, 2H), 4.43-4.48 (m, 1H), 6. 83-6.87 (m, 1 H), 6.95 (d, J = 8.8 Hz, 1 H), 6.95-6. 98 (m, 2 H), 7.25-7. 29 (m, 2 H) ), 7.44 (dd, J = 8.8, 2.3 Hz, 1 H), 7.66 (d, J = 2.3 Hz, 1 H), 8.85 (s, 1 H).
ESI-MS: m / z = 414 (M + H) ⁺ .

Example 36 Synthesis of N- (3-Chloro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) -1- (2-hydroxyacetyl) piperidine-2-carboxamide:

The compound of Reference Example 56 (0.0200 g, 0.0483 mmol) and 2-hydroxyacetic acid (0.00404 g, 0.0531 mmol) were dissolved in DMF (1.00 mL), HATU (0.0202 g, 0.0531 mmol) and Diisopropylethylamine (0.0127 mL, 0.0725 mmol) was added at room temperature. After stirring at the same temperature for 16 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 to 97/3) to give the title compound (hereinafter, the compound of Example 36) (0.0148 g, 0.0314 mmol, 65%) Was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.69 (m, 2H), 1.75-1.81 (m, 2H), 1.90-2.02 (m, 3H) , 2.05-2.11 (m, 2H), 2.28-2.32 (m, 1H), 3.11-3.23 (m, 3H), 3.42-3.46 (m, 1H), 3.48-3.54 (m, 3H), 4.25 (d, J = 15.9 Hz, 1 H), 4.31 (d, J = 15.9 Hz, 1 H), 4.44- 4.49 (m, 1 H), 5.22-5. 23 (m, 1 H), 6.83-6. 87 (m, 1 H), 6.94 (d, J = 9.1 Hz, 1 H), 6.96-6.98 (m, 2 H), 7.25-7. 29 (m, 2 H), 7. 29 (dd, J = 9.1, 2.7 Hz, 1 H), 7.62 (d , J = 2.7 Hz, 1 H), .93 (s, 1H).
ESI-MS: m / z = 472 (M + H) ⁺ .

Example 37 Synthesis of N- (3-Chloro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) -1- (3-hydroxypropanoyl) piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 37) (0.0169 g, 0.0348 mmol, 72%) was carried out according to the same procedure as in Example 36 except for using 3-hydroxypropanoic acid instead of 2-hydroxyacetic acid. ) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.63 (m, 2 H), 1.71-1. 78 (m, 2 H), 1.83-1. 91 (m, 1 H) , 1.94-2.02 (m, 2H), 2.04-2.11 (m, 2H), 2.31-2.34 (m, 1H), 2.64 (dt, J = 16. 3, 5.4 Hz, 1 H), 2.71 (dt, J = 16.3, 5.4 Hz, 1 H), 3.07 (t, J = 6.3 Hz, 1 H), 3.10-3.20 (M, 3 H), 3.48-3. 54 (m, 2 H), 3.79-3. 83 (m, 1 H), 3.94-3. 98 (m, 2 H), 4.43-4 .48 (m, 1 H), 5.35-5.32 (m, 1 H), 6.83-6. 87 (m, 1 H), 6.93 (d, J = 9.1 Hz, 1 H), 6 .95-6.98 (m, 2H , 7.24-7.29 (m, 2H), 7.31 (dd, J = 9.1, 2.3 Hz, 1 H), 7.61 (d, J = 2.3 Hz, 1 H), 8. 16 (s, 1 H).
ESI-MS: m / z = 486 (M + H) ^<+> .

(Reference Example 57) (2- (2-((3-Chloro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) carbamoyl) piperidin-1-yl) -2-oxoethyl) carbamic acid tert Synthesis of -butyl:

The title compound (hereinafter, the compound of Reference Example 57) (0.0340 g) was prepared by the same procedure as in Example 36 except for using 2-((tert-butoxycarbonyl) amino) acetic acid instead of 2-hydroxyacetic acid , 0.0595 mmol, 99%) were obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 (s, 9 H), 1.47-1.62 (m, 2 H), 1.72-1. 86 (m, 3 H), 1.94 -2.02 (m, 2 H), 2.05-2.11 (m, 2 H), 2.34-2.38 (m, 1 H), 3.10-3.22 (m, 3 H), 3 .48-3.54 (m, 2 H), 3.70-3.73 (m, 1 H), 3.94 (dd, J = 16.8, 5.0 Hz, 1 H), 4.11 (dd, J) J = 16.8, 5.0 Hz, 1 H), 4.43-4. 48 (m, 1 H), 5. 28-5. 29 (m, 1 H), 5.42 (brs, 1 H), 6. 83-6.87 (m, 1 H), 6.93 (d, J = 8.6 Hz, 1 H), 6.95-6. 98 (m, 2 H), 7.25-7. 29 (m, 2 H) ), 7.42 (dd, J) 8.6,2.3Hz, 1H), 7.63 (d, J = 2.3Hz, 1H), 8.08 (s, 1H).
ESI-MS: m / z = 571 (M + H) ⁺ .

Example 38 Synthesis of 1- (2-Aminoacetyl) -N- (3-chloro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide

The compound of Reference Example 57 (0.0340 g, 0.0595 mmol) was dissolved in dichloromethane (1.00 mL), and trifluoroacetic acid (0.250 mL, 3.24 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (chloroform / methanol = 100/0 to 97/3) to give the title compound (hereinafter, the compound of Example 38) (0.0235 g, 0.0499 mmol, 84%) Was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.64 (m, 2 H), 1.74-1. 76 (m, 2 H), 1.88 to 2.02 (m, 3 H) , 2.04-2.11 (m, 2 H), 2.28-2.31 (m, 1 H), 3.10-3.17 (m, 3 H), 3.48-3. 54 (m, 2) 2H), 3.58 (d, J = 4.1 Hz, 2H), 3.59-3.67 (m, 1H), 4.43-4.48 (m, 1H), 5.24-5. 25 (m, 1 H), 6.83-6. 87 (m, 1 H), 6.93 (d, J = 9.1 Hz, 1 H), 6.95-6. 97 (m, 2 H), 7. 25-7. 29 (m, 2 H), 7.31 (dd, J = 9.1, 2.3 Hz, 1 H), 7.61 (d, J = 2.3 Hz, 1 H), 8.12 (s , 1 H).
ESI-MS: m / z = 471 (M + H) ^<+> .

(Reference Example 58) (3- (2-((3-Chloro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) carbamoyl) piperidin-1-yl) -3-oxopropyl) carbamic acid Synthesis of tert-butyl:

The title compound (hereinafter, the compound of Reference Example 58) (0. 1) was prepared by the same procedure as in Example 36 except for using 3-((tert-butoxycarbonyl) amino) propanoic acid instead of 2-hydroxyacetic acid. 0345 g, 0.0590 mmol, 98%) were obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.40 (s, 9 H), 1.45-1.57 (m, 2 H), 1.72-1. 75 (m, 2 H), 1.82 -1.88 (m, 1 H), 1.94-2.02 (m, 2 H), 2.04-2.11 (m, 2 H), 2.32-2.35 (m, 1 H), 2 .54-2.70 (m, 2H), 3.10-3.19 (m, 3H), 3.40-3.54 (m, 4H), 3.77-3.80 (m, 1H) , 4.43-4.48 (m, 1H), 5.13 (brs, 1H), 5.29-5.30 (m, 1H), 6.83-6.87 (m, 1H), 6 .93 (d, J = 8.6 Hz, 1 H), 6.96-6.98 (m, 2 H), 7.25-7.29 (m, 2 H), 7.41 (dd, J = 8). 6, 2.3 Hz, 1 H), 7.6 (D, J = 2.3Hz, 1H), 8.35 (s, 1H).
ESI-MS: m / z = 585 (M + H) ^<+> .

Example 39 Synthesis of 1- (3-aminopropanoyl) -N- (3-chloro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 58 instead of the compound of Reference Example 57, and using the same procedure as Example 38 except for the above, the title compound (the compound of Example 39) (0.0209 g, 0.0431 mmol, 72) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.51-1.56 (m, 2H), 1.73-1.76 (m, 3H), 1.89-1.90 (m, 1H) , 1.94-2.02 (m, 2H), 2.04-2.11 (m, 2H), 2.40-2.44 (m, 1H), 2.54 (dt, J = 15. 1, 6.2 Hz, 1 H), 2. 75 (dt, J = 15.1, 6.2 Hz, 1 H), 3.10-3.16 (m, 4 H), 3.48-3. 54 (m , 2H), 3.85-3.88 (m, 1H), 4.42-4.47 (m, 1H), 5.40-5.42 (m, 1H), 6.83-6.87 (M, 1 H), 6.93 (d, J = 8.6 Hz, 1 H), 6.95-6. 97 (m, 2 H), 7.24-7. 29 (m, 2 H), 7.33 (Dd, J = 8.6, 2.3 z, 1H), 7.55 (d, J = 2.3Hz, 1H), 8.79 (s, 1H).
ESI-MS: m / z = 485 (M + H) ⁺ .

Reference Example 59 Synthesis of tert-butyl 4- (2-fluoro-4-nitrophenoxy) piperidine-1-carboxylate:

The title compound (the compound of Reference Example 59 below) in the same manner as in Reference Example 5 except for using 1,2-difluoro-4-nitrobenzene instead of 2-chloro-1-fluoro-4-nitrobenzene (0.248 g, 0.729 mmol, 73%) was obtained as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (s, 9 H), 1.80-1.87 (m, 2 H), 1.94-2.00 (m, 2 H), 3.38 -3.44 (m, 2 H), 3.67-3. 74 (m, 2 H), 4.64-4. 69 (m, 1 H), 7.0 3-7. 07 (m, 1 H), 7 .99-8.06 (m, 2H).
ESI-MS: m / z = 363 (M + Na) ⁺ .

Reference Example 60 Synthesis of 4- (2-fluoro-4-nitrophenoxy) piperidine hydrochloride:

Using the compound of Reference Example 59 instead of the compound of Reference Example 5, and according to the same procedure as Reference Example 6 except the above, the title compound (hereinafter, the compound of Reference Example 60) (0.136 g, 0.492 mmol, 71) %) As a pale yellow solid.
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 1.87-1.96 (m, 2H), 2.15-2.20 (m, 2H), 3.05-3.12 (m, 5 2H), 3.20-3.26 (m, 2H), 4.92-4.96 (m, 1 H), 7.52-7.56 (m, 1 H), 8.11-8.14 ( m, 1 H), 8.19-8. 22 (m, 1 H), 8.96 (s, 2 H).
ESI-MS: m / z = 241 (M + H) ⁺ .

Reference Example 61 Synthesis of 4- (2-fluoro-4-nitrophenoxy) -1-phenylpiperidine:

Using the compound of Reference Example 60 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 53 except the above, the title compound (hereinafter, the compound of Reference Example 61) (0.0726 g, 0.230 mmol, 85) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.99-2.07 (m, 2H), 2.14-2.20 (m, 2H), 3.13-3.19 (m, 2H) , 3.50-3.56 (m, 2 H), 4.64-4. 70 (m, 1 H), 6.86-6.90 (m, 1 H), 6.96-6.98 (m, 2) 2H), 7.06-7. 10 (m, 1 H), 7. 26-7. 30 (m, 2 H), 7.99-8. 07 (m, 2 H).
ESI-MS: m / z = 317 (M + H) ⁺ .

Reference Example 62 Synthesis of 3-fluoro-4-((1-phenylpiperidin-4-yl) oxy) aniline:

The title compound (hereinafter, the compound of Reference Example 62) (0.0527 g, 0.184 mmol, 83) was prepared by using the compound of Reference Example 61 instead of the compound of Reference Example 53 and using the same procedure as Reference Example 54 except the above. %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.88-1 to 9.96 (m, 2 H), 2.03 to 2. 10 (m, 2 H), 2.99 to 3.05 (m, 2 H) , 3.52-3.58 (m, 2 H), 3.55 (s, 2 H), 4.16-4. 22 (m, 1 H), 6.35-6. 38 (m, 1 H), 6 .46 (dd, J = 12.7, 2.7 Hz, 1 H), 6.82-6. 88 (m, 2 H), 6.95-6. 97 (m, 2 H), 7.24-7. 28 (m, 2H).
ESI-MS: m / z = 287 (M + H) ^<+> .

Example 40 Synthesis of 1-Acetyl-N- (3-fluoro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 62 instead of the compound of Reference Example 8, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 40 below) (0.0340 g, 0.0774 mmol, 89) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 to 1.60 (m, 2H), 1.71 to 1.78 (m, 2H), 1.90 to 1.98 (m, 3H) , 2.05-2.10 (m, 2H), 2.21 (s, 3H), 2.26-2.29 (m, 1H), 3.03-3.09 (m, 2H), 3 12-3.19 (m, 1 H), 3.50 to 3.56 (m, 2 H), 3.75-3. 78 (m, 1 H), 4.33-4. 39 (m, 1 H) , 5.24-5.26 (m, 1 H), 6.83-6.87 (m, 1 H), 6.93-6.98 (m, 3 H), 7.03-7.06 (m, 1H), 7.24-7.28 (m, 2H), 7.50 (dd, J = 13.1, 2.3 Hz, 1H), 8.35 (s, 1H).
ESI-MS: m / z = 440 (M + H) ⁺ .

Reference Example 63 Synthesis of tert-butyl (R) -2-((3-chloro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylate:

The compound of Reference Example 54 (0.0500 g, 0.165 mmol) and (R) -1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid (0.0416 g, 0.182 mmol) in DMF (1.10 mL) Dissolve and add HATU (0.0753 g, 0.198 mmol) and diisopropylethylamine (0.0433 mL, 0.248 mmol) at room temperature. After stirring at the same temperature for 16 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 75/25) to give the title compound (hereinafter referred to as the compound of Reference Example 63) (0.078 g, 0.171 mmol) ) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.70 (m, 5 H), 1.52 (s, 9 H), 1.95 to 2.03 (m, 2 H), 2.06 -2.12 (m, 2 H), 2.32-2.35 (m, 1 H), 2.79-2. 86 (m, 1 H), 3.10-3.16 (m, 2 H), 3 .48-3.54 (m, 2 H), 4.06 (brs, 1 H), 4.43-4. 48 (m, 1 H), 4.83-4. 86 (m, 1 H), 6.83 -6.87 (m, 1 H), 6.94-6.98 (m, 3 H), 7.25-7.33 (m, 3 H), 7.62 (d, J = 2.7 Hz, 1 H) .
ESI-MS: m / z = 514 (M + H) ⁺ .

Reference Example 64 Synthesis of (R) -N- (3-chloro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 63 (0.0848 g, 0.165 mmol) is dissolved in ethyl acetate (0.825 mL), and hydrogen chloride-ethyl acetate solution (4.0 M, 0.825 mL, 3.30 mmol) is added at 0 ° C. The After stirring at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (hereinafter, the compound of Reference Example 64) (0.0659 g, 0.159 mmol, 96%) Obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.63 (m, 4 H), 1.80 to 1.84 (m, 1 H), 1.95 to 2.12 (m, 5 H) , 2.73-2.79 (m, 1H), 3.04-3.09 (m, 1H), 3.10-3.16 (m, 2H), 3.36 (dd, J = 9). 5, 3.2 Hz, 1 H), 3.49-3. 55 (m, 2 H), 4.43-4. 48 (m, 1 H), 6.83-6. 87 (m, 1 H), 6. 95 (d, J = 8.8 Hz, 1 H), 6.96-6.98 (m, 2 H), 7.25-7.29 (m, 2 H), 7.44 (dd, J = 8.8) , 2.5 Hz, 1 H), 7.65 (d, J = 2.5 Hz, 1 H), 8. 84 (s, 1 H).
ESI-MS: m / z = 414 (M + H) ⁺ .

Example 41 Synthesis of (R) -1-acetyl-N- (3-chloro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 64 (0.0300 g, 0.0725 mmol) was dissolved in dichloromethane (1.45 mL), triethylamine (0.0152 mL, 0.109 mmol) and acetyl chloride (0.00618 mL, 0.870 mmol) were added at 0 ° C. Added. After stirring for 1 hour at the same temperature, methanol was added to the reaction solution and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 40/60 to 10/90) to give the title compound (compound of Example 41 below) (0.0324 g, 0.0710 mmol, 98) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.56 (m, 2H), 1.71-1.78 (m, 2H), 1.90-2.02 (m, 3H) , 2.04-2.11 (m, 2H), 2.21 (s, 3H), 2.26-2.29 (m, 1H), 3.10-3.20 (m, 3H), 3 .48-3.54 (m, 2 H), 3.74-3. 78 (m, 1 H), 4.42-4. 47 (m, 1 H), 5.25 (d, J = 5.0 Hz, 1H), 6.83-6.87 (m, 1H), 6.92-6.98 (m, 3H), 7.24-7.29 (m, 2H), 7.31 (dd, J = 9.1, 2.7 Hz, 1 H), 7.63 (d, J = 2.7 Hz, 1 H), 8.32 (s, 1 H).
ESI-MS: m / z = 456 (M + H) ⁺ .

Reference Example 65 Synthesis of tert-butyl 2- (N-methylmethylsulfonamido) acetate:

Dissolve 2- (methylamino) acetic acid tert-butyl hydrochloride (0.100 g, 0.550 mmol) in dichloromethane (2.00 mL), triethylamine (0.192 mL, 1.385 mmol) and methanesulfonyl chloride (0.0515 mL) , 0.661 mmol) was added at 0 ° C. After stirring for 3 hours at room temperature, saturated aqueous ammonium chloride solution was added to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 70/30), and the title compound (hereinafter, the compound of Reference Example 65) (0.117 g, 0.524 mmol, 95) %) As a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (s, 9 H), 2.98 (s, 3 H), 3.00 (s, 3 H), 3.98 (s, 2 H).

Reference Example 66 Synthesis of 2- (N-methylmethylsulfonamido) acetic acid:

The compound of Reference Example 65 (0.117 g, 0.524 mmol) was dissolved in acetonitrile (1.50 mL), and hydrogen chloride-ethyl acetate solution (4.0 M, 1.31 mL, 5.24 mmol) was added at 0 ° C. . After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure to give the title compound (hereinafter, the compound of Reference Example 66) (0.0855 g, 0.511 mmol, 98%) as a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.99 (s, 3 H), 3.01 (s, 3 H), 4. 14 (s, 2 H).
ESI-MS: m / z = 168 (M + H) ⁺ .

Example 42 (R) -N- (3-Chloro-4-((1-phenylpiperidin-4-yl) oxy) phenyl) -1- (2- (N-methylmethylsulfonamido) acetyl) piperidine Synthesis of -2-carboxamide:

The compound of Reference Example 64 (0.0318 g, 0.0768 mmol) and the compound of Reference Example 66 (0.0154 g, 0.0922 mmol) are dissolved in DMF (1.00 mL), and HATU (0.0351 g, 0.0922 mmol) is dissolved. And diisopropylethylamine (0.0201 mL, 0.115 mmol) were added at room temperature. After stirring for 2 hours at the same temperature, distilled water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 40/60 to 20/80) to give the title compound (compound of Example 42 below) (0.0334 g, 0.0593 mmol, 77) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.40-2.10 (m, 9 H), 2.32-2.36 (m, 1 H), 3.03 (s, 3 H), 3.03 (S, 3 H), 3.10-3. 16 (m, 2 H), 3.19-3. 27 (m, 1 H), 3.47-3. 54 (m, 2 H), 3.68-3 .72 (m, 1 H), 4. 14 (d, J = 16.8 Hz, 1 H), 4. 24 (d, J = 16.8 Hz, 1 H), 4.44-4. 47 (m, 1 H) , 5.22 (d, J = 4.9 Hz, 1 H), 6.83-6.87 (m, 1 H), 6.92-7.00 (m, 3 H), 7.23-7. m, 3H), 7.66 (d, J = 2.7 Hz, 1 H), 8.00 (brs, 1 H).
ESI-MS: m / z = 564 (M + H) ^<+> .

(Reference Example 67) (R) -2-((3-Chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Synthesis:

The compound of Reference Example 26 (0.100 g, 0.316 mmol) and (R) -1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid (0.0868 g, 0.379 mmol) in DMF (1.58 mL) Dissolve and add HATU (0.144 g, 0.379 mmol) and diisopropylethylamine (0.0827 mL, 0.473 mmol) at room temperature. After stirring at the same temperature for 16 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 75/25), and the title compound (hereinafter, the compound of Reference Example 67) (0.172 g, 0.326 mmol, quantitative) ) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44-1.69 (m, 5 H), 1.52 (s, 9 H), 1.97-2.05 (m, 2 H), 2.07 -2.14 (m, 2H), 2.32-2.35 (m, 1 H), 2.32 (s, 3 H), 2.77-2.86 (m, 3 H), 3.15-3 .21 (m, 2 H), 4.06-4. 08 (m, 1 H), 4.40-4. 45 (m, 1 H), 4.85-4. 85 (m, 1 H), 6.96 -7.00 (m, 1 H), 6.96 (d, J = 9.1 Hz, 1 H), 7.04-7.06 (m, 1 H), 7.14-7. 19 (m, 2 H) , 7.31 (dd, J = 9.1, 2.7 Hz, 1 H), 7.63 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 528 (M + H) ⁺ .

Reference Example 68 Synthesis of (R) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 67 (0.217 g, 0.411 mmol) is dissolved in ethyl acetate (2.06 mL), and hydrogen chloride-ethyl acetate solution (4.0 M, 2.06 mL, 8.22 mmol) is added at 0 ° C. The After stirring at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (compound of Reference Example 68) (0.170 g, 0.397 mmol, 97%) Obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.64 (m, 4 H), 1.80 to 1.85 (m, 1 H), 1.97-2.06 (m, 3 H) , 2.07-2.14 (m, 2H), 2.32 (s, 3H), 2.74-2.82 (m, 3H), 3.05-3.10 (m, 1H), 3 15-3. 21 (m, 2 H), 3. 39 (dd, J = 9.7, 3.4 Hz, 1 H), 4.41-4. 44 (m, 1 H), 6.96-7. 00 (m, 1 H), 6.96 (d, J = 9.1 Hz, 1 H), 7.04-7.06 (m, 1 H), 7.14-7. 19 (m, 2 H), 7. 44 (dd, J = 9.1, 2.7 Hz, 1 H), 7.68 (d, J = 2.7 Hz, 1 H), 8. 90 (s, 1 H).
ESI-MS: m / z = 428 (M + H) ⁺ .

Example 43 Synthesis of (R) -1-acetyl-N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 68 (0.0300 g, 0.0701 mmol) was dissolved in dichloromethane (1.40 mL), and triethylamine (0.0147 mL, 0.105 mmol) and acetyl chloride (0.00598 mL, 0.0841 mmol) were dissolved at 0 ° C. Added. After stirring for 1 hour at the same temperature, methanol was added to the reaction solution and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 40/60 to 10/90), and the title compound (compound of Example 43 below) (0.0273 g, 0.0581 mmol, 83) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 to 1.60 (m, 2 H), 1.71 to 1.78 (m, 2 H), 1.91 to 2.55 (m, 3 H) , 2.07-2.12 (m, 2H), 2.21 (s, 3H), 2.26-2.30 (m, 1H), 2.32 (s, 3H), 2.76-2 .82 (m, 2 H), 3.12-3. 19 (m, 3 H), 3.74-3. 78 (m, 1 H), 4.40-4. 43 (m, 1 H), 5.25 -5.26 (m, 1 H), 6.93-6.99 (m, 2 H), 7.04-7.06 (m, 1 H), 7.15-7.18 (m, 2 H), 7 30 (dd, J = 8.8, 2.3 Hz, 1 H), 7.64 (d, J = 2.3 Hz, 1 H), 8.31 (s, 1 H).
ESI-MS: m / z = 470 (M + H) ⁺ .

Example 44 (R) -N- (3-Chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) -1- (2,2,2-trifluoroacetyl ) Synthesis of piperidine-2-carboxamide:

The compound of Reference Example 68 (0.0276 g, 0.0646 mmol) was dissolved in dichloromethane (1.40 mL), triethylamine (0.0244 mL, 0.162 mmol) and trifluoroacetic anhydride (0.0119 mL, 0.0775 mmol) were dissolved in Added at 0 ° C. After stirring at room temperature for 24 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 60/40), and the title compound (hereinafter, a compound of Example 44) (0.0181 g, 0.0345 mmol, 54) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.57-1.84 (m, 4H), 1.92-2.04 (m, 3H), 2.07-2.14 (m, 2H) , 2.32-2.35 (m, 1 H), 2.32 (s, 3 H), 2.77-2.83 (m, 2 H), 3.15-3. 20 (m, 2 H), 3 .30-3.38 (m, 1 H), 3.97-4.00 (m, 1 H), 4.42-4.46 (m, 1 H), 5.14-5. 15 (m, 1 H) , 6.96-7.00 (m, 1 H), 6.96 (d, J = 9.1 Hz, 1 H), 7.04-7.06 (m, 1 H), 7.15-7. m, 2H), 7.27 (dd, J = 9.1, 2.3 Hz, 1 H), 7.63 (d, J = 2.3 Hz, 1 H), 7.66 (s, 1 H).
ESI-MS: m / z = 524 (M + H) ⁺ .

Example 45 Synthesis of (R) -N2- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) piperidine-1,2-dicarboxamide:

The title compound (hereinafter, the compound of Example 45) (0.0292 g, 0.0620 mmol, 96%) was precipitated as a white solid according to the same procedure as in Example 43 except for using trimethylsilyl isocyanate instead of acetyl chloride Got as.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1 to 65 (m, 2 H), 1. 70 1. 75 (m, 2 H), 1.8 1 to 1. 89 (m, 1 H) , 1.96-2.04 (m, 2H), 2.06-2.13 (m, 2H), 2.28-2.32 (m, 1H), 2.32 (s, 3H), 2 .76-2.82 (m, 2H), 3.10-3.20 (m, 3H), 3.48-3.52 (m, 1H), 4.39-4.44 (m, 1H) , 4.67 (s, 2 H), 4.97-4. 98 (m, 1 H), 6.95 (d, J = 9.1 Hz, 1 H), 6.96-6.99 (m, 1 H) , 7.04-7.06 (m, 1 H), 7.14-7. 19 (m, 2 H), 7.33 (dd, J = 9.1, 2.7 Hz, 1 H), 7.66 (m. d, J = 2.7 Hz, 1 H), 8. 9 (s, 1H).
ESI-MS: m / z = 471 (M + H) ^<+> .

Example 46 (R) -1- (2- (1H-1,2,3-triazol-1-yl) acetyl) -N- (3-chloro-4-((1- (o-tolyl)) Synthesis of piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 68 (0.0400 g, 0.0934 mmol) and 2- (1H-1,2,3-triazol-1-yl) acetic acid (0.0143 g, 0.112 mmol) in DMF (1.00 mL) Dissolve and add HATU (0.0426 g, 0.112 mmol) and diisopropylethylamine (0.0245 mL, 0.140 mmol) at room temperature. After stirring at the same temperature for 16 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 40/60 to 10/90) to give the title compound (compound of Example 46 below) (0.0425 g, 0.0791 mmol, 85) %) As a white solid. When analysis using a chiral column, the retention time of the compound of Example 46 obtained was 20.0 minutes, and the optical purity at that time was 99.9% ee. The analysis conditions using a chiral column are as follows.
Measuring instrument; Shimadzu high performance liquid chromatograph LC-2010CHT
Column; Daicel Chemical Industries, Ltd. CHIRALCEL OZ-3R 0.46 cmφ × 15 cm particle diameter 3 μm
Column temperature: 40 ° C
Mobile phase: (Liquid A) 20 mM aqueous solution of potassium dihydrogen phosphate, (Liquid B) Composition of acetonitrile mobile phase; Liquid A: Liquid B = 45: 55 for 30 minutes.
Flow rate: 1.0 mL / min detection; UV (210 nm)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.68 (m, 2 H), 1.76-1.81 (m, 3 H), 1.97-2.05 (m, 2 H) , 2.07-2.14 (m, 2H), 2.32 (s, 3H), 2.37-2.41 (m, 1H), 2.77-2.82 (m, 2H), 3 .15-3.21 (m, 2H), 3.29-3.36 (m, 1H), 3.72-3.75 (m, 1H), 4.40-4.46 (m, 1H) , 5.27-5.28 (m, 1H), 5.30 (d, J = 15.9 Hz, 1 H), 5.39 (d, J = 15.9 Hz, 1 H), 6.95-7. 00 (m, 2 H), 7.0 4-7. 06 (m, 1 H), 7. 15-7. 19 (m, 2 H), 7. 38 (dd, J = 8.6, 2.7 Hz, 1 H ), 7.75 (d, J = 0). Hz, 1H), 7.78 (d, J = 2.7Hz, 1H), 7.81 (d, J = 0.9Hz, 1H), 8.24 (s, 1H).
ESI-MS: m / z = 537 (M + H) ⁺ .

(Example 47) (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) Synthesis of oxy) phenyl) piperidine-2-carboxamide:

The title was according to the procedure as Example 46 except using 2- (1H-imidazol-1-yl) acetic acid instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid The compound (hereinafter, the compound of Example 47) (0.0246 g, 0.0459 mmol, 98%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44-1.55 (m, 1 H), 1.62-1. 84 (m, 3 H), 1.90-2.04 (m, 3 H) , 2.07-2.13 (m, 2H), 2.22-2.25 (m, 1H), 2.32 (s, 3H), 2.77-2.82 (m, 2H), 3 .15-3.20 (m, 2H), 3.39-3.46 (m, 1H), 3.67-3.70 (m, 1H), 4.40-4.44 (m, 1H) , 4.84 (d, J = 16.8 Hz, 1 H), 4.89 (d, J = 16.8 Hz, 1 H), 5.16-5.17 (m, 1 H), 6.92 (d, J) J = 9.1 Hz, 1 H), 6.96 (s, 1 H), 6.98-7.00 (m, 1 H), 7.04-7.06 (m, 1 H), 7.12-7. 19 (m, 4 H), 7.51 ( , 1H), 7.62 (d, J = 2.3Hz, 1H), 8.15 (s, 1H).
ESI-MS: m / z = 536 (M + H) ⁺ .

(Example 48) (R) -1- (2- (1H-pyrazol-1-yl) acetyl) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) Synthesis of oxy) phenyl) piperidine-2-carboxamide:

The procedure is as in Example 46 except that 2- (1H-pyrazol-1-yl) acetic acid is used instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid, The compound (hereinafter, the compound of Example 48) (0.0246 g, 0.0459 mmol, 98%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.76 (m, 5 H), 1.98-2.06 (m, 2 H), 2.08-2.15 (m, 2 H) , 2. 32 (s, 3 H), 2.5 1-2. 54 (m, 1 H), 2. 78-2. 83 (m, 2 H), 3.02-3. 09 (m, 1 H), 3 .16-3.22 (m, 2 H), 3.63-3.67 (m, 1 H), 4.41-4. 47 (m, 1 H), 4.98 (d, J = 14.5 Hz, 1H), 5.21 (d, J = 14.5 Hz, 1 H), 5.40-5.41 (m, 1 H), 6.38-6. 39 (m, 1 H), 6.96-7. 00 (m, 1 H), 6.98 (d, J = 8.8 Hz, 1 H), 7.05-7.07 (m, 1 H), 7.15-7.19 (m, 2 H), 7. 46 (dd, J = 8.8, 2. Hz, 1 H), 7.52 (d, J = 2.1 Hz, 1 H), 7.56 (d, J = 2.1 Hz, 1 H), 7.67 (d, J = 2.5 Hz, 1 H), 8.86 (s, 1 H).
ESI-MS: m / z = 536 (M + H) ⁺ .

(Example 49) (R) -1- (2- (4H-1,2,4-triazol-4-yl) acetyl) -N- (3-chloro-4-((1- (o-tolyl)) Synthesis of piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Example 46 is repeated except that 2- (4H-1,2,4-triazol-4-yl) acetic acid is used instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid. The same procedure gave the title compound (hereinafter, the compound of Example 49) (0.0389 g, 0.0724 mmol, 77%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.54-1.88 (m, 5 H), 1.94-2.02 (m, 2 H), 2.06-2.11 (m, 2 H) , 2.26-2.31 (m, 1 H), 2.31 (s, 3 H), 2.75-2.81 (m, 2 H), 3.13-3. 19 (m, 2 H), 3 .55-3.69 (m, 2H), 4.39-4.43 (m, 1 H), 4.90 (d, J = 17.2 Hz, 1 H), 5.00 (d, J = 17.7). 2 Hz, 1 H), 5.17-5.18 (m, 1 H), 6.92 (d, J = 8.6 Hz, 1 H), 6.95-6.99 (m, 1 H), 7.03- 7.05 (m, 1 H), 7.14-7. 21 (m, 3 H), 7. 65 (d, J = 2.3 Hz, 1 H), 8. 17 (s, 2 H), 8.58 ( s, 1 H).
ESI-MS: m / z = 537 (M + H) ⁺ .

(Example 50) (R) -1- (2- (1H-1,2,4-triazol-1-yl) acetyl) -N- (3-chloro-4-((1- (o-tolyl)) Synthesis of piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Example 46 except using sodium 2- (1H-1,2,4-triazol-1-yl) acetate instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid According to a similar procedure to that, the title compound (hereinafter, the compound of Example 50) (0.0438 g, 0.0816 mmol, 87%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.52-1.68 (m, 2 H), 1.75-1. 86 (m, 3 H), 1.97-2.04 (m, 2 H) , 2.08-2.13 (m, 2H), 2.32 (s, 3H), 2.35-2.38 (m, 1H), 2.77-2.83 (m, 2H), 3 .15-3.21 (m, 2H), 3.30-3.37 (m, 1H), 3.72-3.75 (m, 1H), 4.42-4.45 (m, 1H) , 5.10 (d, J = 15.4 Hz, 1 H), 5. 20 (d, J = 15.4 Hz, 1 H), 5.25-5. 26 (m, 1 H), 6.94-6. 99 (m, 2 H), 7.0 4-7. 06 (m, 1 H), 7. 15-7. 19 (m, 2 H), 7. 29 (dd, J = 9.1, 2.3 Hz, 1 H ), 7.63 (d, J = 2). Hz, 1H), 8.00 (s, 1H), 8.21 (s, 1H), 8.24 (s, 1H).
ESI-MS: m / z = 537 (M + H) ⁺ .

(Example 51) (R) -1- (2- (2H-1,2,3-triazol-2-yl) acetyl) -N- (3-chloro-4-((1- (o-tolyl)) Synthesis of piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

Example 46 is repeated except that 2- (2H-1,2,3-triazol-2-yl) acetic acid is used instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid. The same procedure gave the title compound (hereinafter, the compound of Example 51) (0.0351 g, 0.0654 mmol, 70%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.62 (m, 2H), 1.69-1.76 (m, 3H), 1.98-2.06 (m, 2H) , 2.08-2.15 (m, 2 H), 2.32 (s, 3 H), 2.47-2.50 (m, 1 H), 2.78-2.83 (m, 2 H), 2 .96-3.03 (m, 1 H), 3.16-3. 21 (m, 2 H), 3.53-3. 56 (m, 1 H), 4.42-4. 47 (m, 1 H) , 5.31 (d, J = 15.0 Hz, 1 H), 5.38-5.39 (m, 1 H), 5.55 (d, J = 15.0 Hz, 1 H), 6.98 (d, J = 9.1 Hz, 1 H), 6.98-7.00 (m, 1 H), 7.05-7.06 (m, 1 H), 7.15-7.19 (m, 2 H), 7. 44 (dd, J = 9.1, 2. Hz, 1H), 7.65 (d, J = 2.7Hz, 1H), 7.73 (s, 2H), 8.46 (s, 1H).
ESI-MS: m / z = 537 (M + H) ⁺ .

Example 52 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) Synthesis of oxy) phenyl) piperidine-2-carboxamide:

Using the procedure of Example 46 except for substituting 2- (1H-tetrazol-1-yl) acetic acid instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid, The compound (hereinafter, the compound of Example 52) (0.0274 g, 0.0509 mmol, 73%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.57-1.81 (m, 3H), 1.88-1.91 (m, 2H), 1.96-2.04 (m, 2H) , 2.07-2.13 (m, 2 H), 2.25-2.29 (m, 1 H), 2. 32 (s, 3 H), 2.77-2.83 (m, 2 H), 3 .15-3.20 (m, 2H), 3.49-3.57 (m, 1H), 3.71-3.74 (m, 1H), 4.41-4.46 (m, 1H) , 5.15-5.16 (m, 1 H), 5.39 (d, J = 16.6 Hz, 1 H), 5.45 (d, J = 16.6 Hz, 1 H), 6.94-7. 00 (m, 2 H), 7.04-7.06 (m, 1 H), 7.14-7. 19 (m, 2 H), 7.22 (dd, J = 8.7, 2.4 Hz, 1 H ), 7.66 (d, J = 2). Hz, 1H), 7.83 (s, 1H), 8.84 (s, 1H).
ESI-MS: m / z = 538 (M + H) ⁺ .

Reference Example 69 Synthesis of ethyl 2- (5-methyl-1,3,4-oxadiazol-2-yl) acetate:

Ethyl 2- (1H-tetrazol-5-yl) acetate (0.500 g, 3.20 mmol) was dissolved in dichloroethane (6.40 mL) and acetic anhydride (0.393 mL, 4.16 mmol) was added at room temperature. After stirring at 100 ° C. for 11 hours, 1 M aqueous sodium hydroxide solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with 1 M aqueous sodium hydroxide solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 70/30 to 40/60), and the title compound (hereinafter, the compound of Reference Example 69) (0.0908 g, 0.534 mmol, 17) %) As a colorless oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.29 (t, J = 7.2 Hz, 3 H), 2.55 (s, 3 H), 3.92 (s, 2 H), 4.23 (q) , J = 7.2 Hz, 2 H).
ESI-MS: m / z = 171 (M + H) ⁺ .

Reference Example 70 Synthesis of sodium 2- (5-methyl-1,3,4-oxadiazol-2-yl) acetate:

The compound of Reference Example 69 (0.0900 g, 0.529 mmol) is dissolved in THF (1.00 mL) and ethanol (1.00 mL), and 1 M aqueous sodium hydroxide solution (1.06 mL, 1.06 mmol) is added at room temperature. The After stirring at the same temperature for 2 hours, the reaction solution was concentrated under reduced pressure to give the title compound (hereinafter, the compound of Reference Example 70) (0.0835 g, 0.509 mmol, 96%) as a white solid.
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 2.41 (s, 3 H), 3.38 (s, 2 H).
ESI-MS: m / z = 143 (M + H) ⁺ .

Example 53 (R) -N- (3-Chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) -1- (2- (5-methyl-1, Synthesis of 3,4-Oxadiazol-2-yl) acetyl) piperidine-2-carboxamide:

Using the compound of Reference Example 70 instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid, and using the same procedure as that of Example 46 except the title compound (Example 53 below). (0.0333 g, 0.0603 mmol, 65%) were obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.63 (m, 3 H), 1.72-1. 75 (m, 2 H), 1.97-2.05 (m, 2 H) , 2.07-2.14 (m, 2H), 2.32 (s, 3H), 2.54-2.62 (m, 1H), 2.58 (s, 3H), 2.76-2 .82 (m, 2 H), 3.16-3. 21 (m, 2 H), 3.24-3. 31 (m, 1 H), 3.58- 3. 61 (m, 1 H), 3.92 (D, J = 16.8 Hz, 1 H), 4.19 (d, J = 16.8 Hz, 1 H), 4.40-4.46 (m, 1 H), 5.50-5.51 (m, 1 H), 6.96-6.99 (m, 1 H), 7.00 (d, J = 8.6 Hz, 1 H), 7.04-7.06 (m, 1 H), 7.15-7. 19 (m, 2 H), 7.61 ( d, J = 8.6,2.7Hz, 1H), 8.03 (d, J = 2.7Hz, 1H), 9.19 (s, 1H).
ESI-MS: m / z = 552 (M + H) ⁺ .

Example 54 (R) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) -1- (2- (pyridin-2-yl) Synthesis of Acetyl) piperidine-2-carboxamide:

Using the same procedure as in Example 46 except for using 2- (pyridin-2-yl) acetic acid hydrochloride instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid, The compound (hereinafter, the compound of Example 54) (0.0390 g, 0.0713 mmol, 76%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.66 (m, 4 H), 1.74-1. 75 (m, 1 H), 2.00 to 2.07 (m, 2 H) , 2.10-2.16 (m, 2H), 2.33 (s, 3H), 2.59-2.61 (m, 1H), 2.79-2.84 (m, 2H), 2 .95-3.03 (m, 1 H), 3.17-3.22 (m, 2 H), 3.65-3.68 (m, 1 H), 4.03 (d, J = 16.3 Hz, 1H), 4.29 (d, J = 16.3 Hz, 1 H), 4.44-4. 48 (m, 1 H), 5.53-5. 54 (m, 1 H), 6.96-7. 00 (m, 1 H), 7.00 (d, J = 8.6 Hz, 1 H), 7.05-7.07 (m, 1 H), 7.15-7.19 (m, 3 H), 7. 26-7.29 (m, 1 H), .42 (dd, J = 8.6, 2.7 Hz, 1 H), 7. 60 (d, J = 2.7 Hz, 1 H), 7.68-7. 72 (m, 1 H), 8.32- 8.33 (m, 1 H), 9.5 4 (s, 1 H).
ESI-MS: m / z = 547 (M + H) ⁺ .

Example 55 (R) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) -1- (2- (pyridin-3-yl) Synthesis of Acetyl) piperidine-2-carboxamide:

Using the same procedure as in Example 46 except for using 2- (pyridin-3-yl) acetic acid hydrochloride instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid, The compound (hereinafter, the compound of Example 55) (0.0316 g, 0.0578 mmol, 62%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.34-1.45 (m, 1 H), 1.55-1. 75 (m, 3 H), 1.89-2.05 (m, 3 H) , 2.07-2.14 (m, 2H), 2.26-2.29 (m, 1H), 2.32 (s, 3H), 2.77-2.83 (m, 2H), 3 .15-3.22 (m, 3H), 3.80-3.87 (m, 1H), 3.83 (s, 2H), 4.41-4.44 (m, 1H), 5.26 (D, J = 5.4 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 1 H), 6.96-7.00 (m, 1 H), 7.04-7.06 (m, 1H), 7.15 to 7.19 (m, 2H), 7.23 (dd, J = 8.8, 2.5 Hz, 1 H), 7.29 (dd, J = 8.2, 5.0 Hz) , 1H), 7.57 (d, J = 2 5 Hz, 1 H), 7.62-7.64 (m, 1 H), 8. 14 (s, 1 H), 8.53 (d, J = 1.8 Hz, 1 H), 8.54-8. m, 1 H).
ESI-MS: m / z = 547 (M + H) ⁺ .

Example 56 (R) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) -1- (2- (pyridin-4-yl) Synthesis of Acetyl) piperidine-2-carboxamide:

Using the same procedure as in Example 46 except for using 2- (pyridin-4-yl) acetic acid hydrochloride instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid, The compound (hereinafter, the compound of Example 56) (0.0360 g, 0.0658 mmol, 70%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.32-1. 42 (m, 1 H), 1.56-1.63 (m, 1 H), 1. 70-1.72 (m, 2 H) , 1.87-2.05 (m, 3 H), 2.07-2.14 (m, 2 H), 2.26-2.29 (m, 1 H), 2. 32 (s, 3 H), 2 .77-2.83 (m, 2H), 3.13-3.20 (m, 3H), 3.75-3.79 (m, 1H), 3.83 (s, 2H), 4.41 -4.44 (m, 1 H), 5. 26-5. 27 (m, 1 H), 6. 94 (d, J = 9.1 Hz, 1 H), 6.96-7.00 (m, 1 H) , 7.04-7.06 (m, 1 H), 7.15-7.22 (m, 5 H), 7.61 (d, J = 2.7 Hz, 1 H), 8.12 (s, 1 H) , 8.58 (d, J = 6.3 Hz, H).
ESI-MS: m / z = 547 (M + H) ⁺ .

(Reference Example 71) (R)-(2- (2- (2-((3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) carbamoyl) piperidin-1-yl) Synthesis of tert-butyl -2-oxoethyl) carbamate:

The compound of Reference Example 64 (0.0800 g, 0.187 mmol) and 2-((tert-butoxycarbonyl) amino) acetic acid (0.0393 g, 0.224 mmol) were dissolved in DMF (1.00 mL), and HATU (0 .0851 g (0.224 mmol) and diisopropylethylamine (0.0490 mL, 0.280 mmol) were added at room temperature. After stirring at the same temperature for 16 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 70/30 to 40/60), and the title compound (hereinafter, the compound of Reference Example 71) (0.101 g, 0.173 mmol, 93) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 (s, 9 H), 1.51-1.62 (m, 2 H), 1.72-1. 87 (m, 3 H), 1.97 -2.13 (m, 4H), 2.32 (s, 3H), 2.32-2.37 (m, 1 H), 2.76-2.82 (m, 2 H), 3.15-3 .22 (m, 3 H), 3.70-3. 73 (m, 1 H), 3.92-3. 97 (m, 1 H), 4.09 4.14 (m, 1 H), 4.41 -4.44 (m, 1 H), 5.28-5. 29 (m, 1 H), 5. 39-5. 44 (m, 1 H), 6.94-6.99 (m, 2 H), 7 .04-7.06 (m, 1 H), 7.14-7. 19 (m, 2 H), 7.41 (dd, J = 8.8, 2.3 Hz, 1 H), 7.64 (d, 7) J = 2.3 Hz, 1 H), 8.07 ( , 1H).
ESI-MS: m / z = 585 (M + H) ^<+> .

Example 57 (R) -1- (2-Aminoacetyl) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) piperidine-2- Carboxamide Synthesis:

The compound of Reference Example 71 (0.100 g, 0.171 mmol) was dissolved in dichloromethane (1.60 mL), and trifluoroacetic acid (0.400 mL, 5.19 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (chloroform / methanol = 100/0 to 98/2) to give the title compound (hereinafter, the compound of Example 57) (0.0752 g, 0.155 mmol, 91%) Was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.64 (m, 2 H), 1.72-1. 76 (m, 2 H), 1.89 to 2. 13 (m, 5 H) , 2.28-2.32 (m, 1 H), 2.32 (s, 3 H), 2.76-2.82 (m, 2 H), 3.15-3. 20 (m, 3 H), 3 .58-3.67 (m, 3 H), 4.40-4. 45 (m, 1 H), 5.24-5.25 (m, 1 H), 6.94-6.99 (m, 2 H) , 7.04-7.06 (m, 1 H), 7.14-7. 19 (m, 2 H), 7.31 (dd, J = 8.6, 2.7 Hz, 1 H), 7.62 (m. d, J = 2.7 Hz, 1 H), 8.13 (s, 1 H).
ESI-MS: m / z = 486 (M + H) ^<+> .

(Reference Example 72) (R)-(3- (2- (2-((3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) carbamoyl) piperidin-1-yl) Synthesis of tert-butyl -3-oxopropyl) carbamate:

Using 3-((tert-butoxycarbonyl) amino) propanoic acid instead of 2-((tert-butoxycarbonyl) amino) acetic acid, and using the same procedure as in Reference Example 71 except for the above, to give the title compound (hereinafter referred to as Reference The compound of Example 72) (0.0548 g, 0.0915 mmol, 97%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41 (s, 9 H), 1.47-1.59 (m, 2 H), 1.72-1. 75 (m, 2 H), 1.82 -1.89 (m, 1 H), 1.96-2.03 (m, 2 H), 2.07-2.13 (m, 2 H), 2.32 (s, 3 H), 2.32-2 .35 (m, 1 H), 2.54-2.71 (m, 2 H), 2.76-2.82 (m, 2 H), 3.12-3. 20 (m, 3 H), 3.41 -3.53 (m, 2 H), 3.77-3. 80 (m, 1 H), 4. 39-4. 45 (m, 1 H), 5.10-5. 15 (m, 1 H), 5 .29-5.30 (m, 1 H), 6.94-6.99 (m, 2 H), 7.04-7.06 (m, 1 H), 7.14-7. 19 (m, 2 H) , 7.39-7.41 (m, 1 H), .66 (d, J = 2.7Hz, 1H), 8.34 (s, 1H).
ESI-MS: m / z = 599 (M + H) ^<+> .

Example 58 (R) -1- (3-Aminopropanoyl) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) piperidine-2 -Synthesis of carboxamide:

Using the compound of Reference Example 72 instead of the compound of Reference Example 71, and using the same procedure as Example 57 except the above, the title compound (the compound of Example 58) (0.0300 g, 0.0601 mmol, 69) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.56 (m, 2 H), 1.73-1. 76 (m, 3 H), 1.96-2.04 (m, 2 H) , 2.07-2.12 (m, 2H), 2.31 (s, 3H), 2.40-2.43 (m, 1H), 2.54 (dt, J = 15.1, 6.). 1 Hz, 1 H), 2.71-2. 82 (m, 3 H), 3.10-3. 20 (m, 5 H), 3.85-3. 88 (m, 1 H), 4. 39-4. 43 (m, 1 H), 5.40-5.41 (m, 1 H), 6.93-6.99 (m, 2 H), 7.04-7. 06 (m, 1 H), 7.14- 7.18 (m, 2H), 7.33 (dd, J = 8.6, 2.3 Hz, 1 H), 7.56 (d, J = 2.3 Hz, 1 H), 8.77 (s, 1 H) ).
ESI-MS: m / z = 499 (M + H) ^<+> .

(Reference Example 73) (R)-(3- (2- (2-((3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) carbamoyl) piperidin-1-yl) Synthesis of tert-butyl 3-oxopropyl) (methyl) carbamate:

Using 3-((tert-butoxycarbonyl) (methyl) amino) propanoic acid instead of 2-((tert-butoxycarbonyl) amino) acetic acid, and using the same procedure as in Reference Example 71 except for the title compound ( Hereinafter, the compound of Reference Example 73 (0.0559 g, 0.0912 mmol, 98%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35-1.49 (m, 3 H), 1.56 (s, 9 H), 1.68-1.74 (m, 2 H), 1.96 -2.03 (m, 2H), 2.06-2.13 (m, 2H), 2.32 (s, 3H), 2.39-2.42 (m, 1 H), 2.54-2 .82 (m, 5 H), 2.92 (s, 3 H), 3.15-3. 28 (m, 3 H), 3.80-3. 83 (m, 1 H), 3.93-3. 96 (M, 1 H), 4.39-4. 45 (m, 1 H), 5. 35-5. 36 (m, 1 H), 6.93-6.99 (m, 2 H), 7.0 4-7 .06 (m, 1 H), 7.14-7. 19 (m, 2 H), 7.56-7.58 (m, 1 H), 7.75-7. 75 (m, 1 H), 8.85 (S, 1 H).
ESI-MS: m / z = 613 (M + H) ^<+> .

Example 59 (R) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) -1- (3- (methylamino) propanoyl) piperidine Synthesis of -2-carboxamide:

Using the compound of Reference Example 73 instead of the compound of Reference Example 71, and using the same procedure as Example 57 except the above, the title compound (the compound of Example 59 below) (0.0318 g, 0.0620 mmol, 70) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.57 (m, 2 H), 1.72-1. 75 (m, 3 H), 1.96-2.12 (m, 4 H) , 2.32 (s, 3 H), 2.39-2.41 (m, 1 H), 2. 45 (s, 3 H), 2.55-2.62 (m, 1 H), 2.76-2 .83 (m, 3 H), 2.93-2.97 (m, 2 H), 3.11-3. 20 (m, 3 H), 3.84-3. 87 (m, 1 H), 4.40 -4.44 (m, 1 H), 5.39-5. 40 (m, 1 H), 6.94-6.99 (m, 2 H), 7.04-7. 06 (m, 1 H), 7 .14-7.19 (m, 2H), 7.33 (dd, J = 8.8, 2.3 Hz, 1 H), 7.53 (d, J = 2.3 Hz, 1 H), 8.67 ( s, 1 H).
ESI-MS: m / z = 513 (M + H) ^<+> .

Example 60 (R) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) -1- (2- (2-cyanoguanidino) acetyl ) Synthesis of piperidine-2-carboxamide:

The compound of Example 57 (0.0350 g, 0.0722 mmol) was dissolved in dichloromethane (1.00 mL) and diphenyl N-cyanocarbonimidate (0.0206 g, 0.0866 mmol) was added at room temperature. After stirring for 3 hours at the same temperature, the reaction solution was concentrated. The crude product obtained was used for the subsequent reaction without purification.
The above crude product was dissolved in acetonitrile (1.00 mL) and aqueous ammonia solution (25%, 0.125 mL, 1.44 mmol) was added at room temperature. After stirring at 50 ° C. for 22 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 to 98/2) to give the title compound (hereinafter, the compound of Example 60) (0.0360 g, 0.0652 mmol, 90%) Was obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 1.34-1.46 (m, 2H), 1.61-1.67 (m, 3H), 1.79-1.86 (m, 2H), 2.02-2.08 (m, 2H), 2.15-2.19 (m, 1H), 2.25 (s, 3H), 2.74-2.80 (m, 2H) , 3.03-3.08 (m, 2H), 3.31-3.39 (m, 1H), 3.61-3.64 (m, 1H), 4.00 (dd, J = 17. 4, 4.3 Hz, 1 H), 4.11 (dd, J = 17.4, 4.3 Hz, 1 H), 4.55-4.58 (m, 1 H), 5.08-5.09 (m , 1 H), 6.92 (brs, 2 H), 6.92-6. 96 (m, 1 H), 7.02-7.03 (m, 1 H), 7.12-7.16 (m, 2 H) ), 7.23 (d, J = 9 1Hz, 1H), 7.42 (dd, J = 9.1,2.7Hz, 1H), 7.75 (d, J = 2.7Hz, 1H), 9.84 (s, 1H).
ESI-MS: m / z = 522 (M + H) ⁺ .

Example 61 (R) -N- (3-Chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) -1- (2- (2-cyano-3-) Synthesis of (Methylguanidino) acetyl) piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 61) (0.0266 g, 0.0470 mmol, 57%) was prepared in the same manner as in Example 60 except for using methylamine-methanol solution instead of an aqueous ammonia solution. Obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 1.32-1.50 (m, 2H), 1.63-1.69 (m, 3H), 1.79-1.86 (m, 5) 2H), 2.03-2.07 (m, 2H), 2.14-2.18 (m, 1H), 2.25 (s, 3H), 2.70 (d, J = 4.6 Hz, 3H), 2.74-2.80 (m, 2H), 3.03-3.07 (m, 2H), 3.37-3. 43 (m, 1H), 3.66-3.69 ( m, 1H), 3.95-4.00 (m, 1H), 4.17 (dd, J = 16.9, 5.0 Hz, 1H), 4.56-4.57 (m, 1H), 5.06-5.07 (m, 1 H), 6.76 (brs, 1 H), 6. 9-6. 96 (m, 1 H), 7.0 1-7. 03 (m, 1 H), 7. 12-7.16 (m, 3H), .22-7.25 (m, 1H), 7.40-7.47 (m, 1H), 7.77 (d, J = 2.3Hz, 1H), 9.87 (s, 1H).
ESI-MS: m / z = 566 (M + H) ⁺ .

Example 62 (R) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) -1- (2-ureidoacetyl) piperidine-2- Carboxamide Synthesis:

The compound of Example 57 (0.0400 g, 0.0825 mmol) is dissolved in dichloromethane (1.00 mL), and triethylamine (0.0287 mL, 0.206 mmol) and trimethylsilyl isocyanate (0.0134 mL, 0.0990 mmol) are dissolved in 0. Added at ° C. After stirring at room temperature for 24 hours, methanol was added to the reaction solution and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 94/6) to give the title compound (compound of Example 62 below) (0.0384 g, 0.0727 mmol, 88%) Obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 1.33-1.44 (m, 2H), 1.61-1.67 (m, 3H), 1.79-1.87 (m, 2H), 2.03-2.08 (m, 2H), 2.15-2.18 (m, 1H), 2.25 (s, 3H), 2.74-2.80 (m, 2H) , 3.03-3.08 (m, 2 H), 3.33-3. 39 (m, 1 H), 3.68-3. 71 (m, 1 H), 3.89 (dd, J = 17. 17). 0, 4.8 Hz, 1 H), 3.98 (dd, J = 17.0, 4.8 Hz, 1 H), 4.55-4.58 (m, 1 H), 5.08-5.09 (m , 1 H), 5.72 (s, 2 H), 6.09 (brs, 1 H), 6.92-6. 96 (m, 1 H), 7.02-7.03 (m, 1 H), 7. 12-7.16 (m, 2H) 7.22 (d, J = 9.1 Hz, 1 H), 7.44 (dd, J = 9.1, 2.3 Hz, 1 H), 7.78 (d, J = 2.3 Hz, 1 H), 9 .82 (s, 1 H).
ESI-MS: m / z = 528 (M + H) ⁺ .

(Reference Example 74) (R) -1- (2- (3-benzoylthioureido) acetyl) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) Synthesis of Phenyl) piperidine-2-carboxamide:

The compound of Example 57 (0.0500 g, 0.103 mmol) was dissolved in dichloromethane (1.00 mL) and benzoyl isothiocyanate (0.0152 mL, 0.113 mmol) was added at room temperature. After stirring for 0.5 hours at the same temperature, methanol was added to the reaction solution and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 50/50) to give the title compound (hereinafter referred to as the compound of Reference Example 74) (0.0501 g, 0.0773 mmol, 75) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.67 (m, 2 H), 1.75-1. 86 (m, 2 H), 1.89-2.04 (m, 3 H) , 2.05-2.13 (m, 2H), 2.31 (s, 3H), 2.33-2.37 (m, 1H), 2.76-2.82 (m, 2H), 3 .14-3.20 (m, 2H), 3.27-3.35 (m, 1H), 3.76-3.79 (m, 1H), 4.39-4.45 (m, 1H) , 4.51 (dd, J = 17.7, 4.3 Hz, 1 H), 4.66 (dd, J = 17.7, 4.3 Hz, 1 H), 5.31-5. 33 (m, 1 H) ), 6.93-6.99 (m, 2H), 7.04-7.05 (m, 1H), 7.14-7.18 (m, 2H), 7.32 (dd, J = 8) .8, 2.5 Hz, 1 H), 7 51-7.55 (m, 2 H), 7.62-7.68 (m, 2 H), 7.88-7.90 (m, 2 H), 8.06 (s, 1 H), 9. 10 ( s, 1 H), 11. 49 (s, 1 H).
ESI-MS: m / z = 648 (M + H) ⁺ .

Example 63 (R) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) -1- (2-thioureidoacetyl) piperidine-2 -Synthesis of carboxamide:

The compound of Reference Example 74 (0.0500 g, 0.0771 mmol) is dissolved in THF (0.500 mL) and methanol (0.500 mL), and 1 M aqueous sodium hydroxide solution (0.154 mL, 0.154 mmol) is added at room temperature. The After stirring for 0.5 hours at the same temperature, 1 M hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 98/2) to give the title compound (compound of Example 63 below) (0.0264 g, 0.0485 mmol, 63%) Obtained as a white solid.
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 1.34-1.48 (m, 2H), 1.62-1.69 (m, 3H), 1.79-1.87 (m, 2H), 2.03-2.08 (m, 2H), 2.17-2.20 (m, 1H), 2.25 (s, 3H), 2.74-2.80 (m, 2H) , 3.03-3.08 (m, 2H), 3.36-3.40 (m, 1H), 3.64-3.67 (m, 1H), 4.29-4.41 (m, 2H), 4.55-4.59 (m, 1 H), 5.10-5.11 (m, 1 H), 6.92-6. 96 (m, 1 H), 7.02-7.03 ( m, 1 H), 7.12-7.16 (m, 2 H), 7.23 (d, J = 9.1 Hz, 1 H), 7.34 (brs, 2 H), 7.43 (dd, J = 9.1, 2.3 Hz, 1 H), 7 69 (brs, 1H), 7.75 (d, J = 2.3Hz, 1H), 9.81 (s, 1H).
ESI-MS: m / z = 544 (M + H) ⁺ .

(Reference Example 75) (R) -N- (2- (2- (2-((3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) carbamoyl) piperidine-1- (2- (2- ( Synthesis of tert-Butyl) -2-oxoethyl) sulfamoylcarbamate:

Chlorosulfonyl isocyanate (0.00790 mL, 0.0908 mmol) was dissolved in dichloromethane (1.00 mL) and tert-butanol (0.00947 mL, 0.0990 mmol) was added at 0 ° C. After stirring for 0.5 hours at the same temperature, the compound of Example 57 (0.0400 g, 0.0825 mmol) and triethylamine (0.0287 mL, 0.206 mmol) were added at 0 ° C. After stirring for 4 hours at room temperature, methanol was added to the reaction solution and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 50/50), and the title compound (hereinafter, the compound of Reference Example 75) (0.0278 g, 0.0419 mmol, 51) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43 (s, 9 H), 1.50-1.66 (m, 2 H), 1.73-1.88 (m, 3 H), 1.96 -2.06 (m, 2H), 2.06-2.12 (m, 2H), 2.32 (s, 3H), 2.32-2.34 (m, 1H), 2.77-2 .82 (m, 2 H), 3.15-3.20 (m, 2 H), 3.25-3. 32 (m, 1 H), 3.61-3. 65 (m, 1 H), 4.12 (D, J = 16.3 Hz, 1 H), 4.19 (d, J = 16.3 Hz, 1 H), 4.40-4. 45 (m, 1 H), 5.23-5.25 (m, 1H), 6.10 (brs, 1H), 6.94-7.00 (m, 2H), 7.04-7.06 (m, 1H), 7.15-7.19 (m, 2H) , 7.33 (dd, J = 9 1,2.7Hz, 1H), 7.64 (d, J = 2.7Hz, 1H), 7.98 (s, 1H).
ESI-MS: m / z = 664 (M + H) ^<+> .

Example 64 (R) -N- (3-Chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) -1- (2- (sulfamoylamino) acetyl ) Synthesis of piperidine-2-carboxamide:

The compound of Reference Example 75 (0.0250 g, 0.0376 mmol) was dissolved in dichloromethane (0.800 mL), and trifluoroacetic acid (0.200 mL, 2.60 mmol) was added at 0 ° C. After stirring for 5 hours at room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/50 to 10/90) to give the title compound (compound of Example 64 below) (0.00821 g, 0.0145 mmol, 39) %) As a white solid.
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 1.47-1.64 (m, 2H), 1.71-1.75 (m, 3H), 1.94-2.02 (m, 2H), 2.06-2.11 (m, 2H), 2.26-2.31 (m, 1H), 2.31 (s, 3H), 2.76-2.81 (m, 2H) , 3.13-3.18 (m, 2H), 3.28-3.34 (m, 1H), 3.55-3.58 (m, 1H), 3.96 (dd, J = 16). 8, 5.0 Hz, 1 H), 4.06 (dd, J = 16.8, 5.0 Hz, 1 H), 4.40-4.42 (m, 1 H), 5.16 (s, 2 H), 5.23-5.24 (m, 1 H), 5.87-5. 90 (m, 1 H), 6.93 (d, J = 8.7 Hz, 1 H), 6.95-6.99 (m) , 1H), 7.03-7.05 m, 1 H), 7.14-7. 18 (m, 2 H), 7.33 (dd, J = 8.7, 2.3 Hz, 1 H), 7.67 (d, J = 2.3 Hz, 1 H) ), 8.20 (s, 1 H).
ESI-MS: m / z = 564 (M + H) ^<+> .

Example 65 (R) -4- (2- (2-((3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) carbamoyl) piperidin-1-yl)- Synthesis of methyl 4-oxobutanoate:

The title compound (hereinafter, the compound of Example 65) (0.0587 g, 0.108 mmol,) according to the procedure as Example 43 except for using methyl 4-chloro-4-oxobutanoate instead of acetyl chloride 93%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.56 (m, 2 H), 1.71-1. 78 (m, 3 H), 1.96-2.04 (m, 2 H) , 2.08-2.13 (m, 2H), 2.32 (s, 3H), 2.42-2.49 (m, 2H), 2.62-2.68 (m, 1H), 2 3.76-2.82 (m, 2H), 2.87-2.94 (m, 1H), 3.03 (ddd, J = 17.0, 10.4, 4.2 Hz, 1 H), 3. 14-3.20 (m, 3 H), 3.74 (s, 3 H), 3.94-3. 97 (m, 1 H), 4. 39-4. 45 (m, 1 H), 5.43- 5.44 (m, 1 H), 6.95 (d, J = 9.1 Hz, 1 H), 6.97-7.00 (m, 1 H), 7.04-7.06 (m, 1 H), 7.14-7.19 (m, 2H , 7.60 (dd, J = 9.1,2.7Hz, 1H), 7.71 (d, J = 2.7Hz, 1H), 8.29 (s, 1H).
ESI-MS: m / z = 542 (M + H) ⁺ .

Example 66 (R) -1- (4-Amino-4-oxobutanoyl) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl ) Synthesis of piperidine-2-carboxamide:

The compound of Example 65 (0.0519 g, 0.0957 mmol) is dissolved in THF (1.00 mL) and methanol (1.00 mL), and 1 M aqueous sodium hydroxide solution (1.01 mL, 1.01 mmol) is added at room temperature. The After stirring for 2 hours at the same temperature, the reaction solution was concentrated. The crude product obtained was used for the subsequent reaction without purification.
The above crude product and ammonium chloride (0.0308 g, 0.575 mmol) are suspended in DMF (1.00 mL), HATU (0.0547 g, 0.144 mmol) and diisopropylethylamine (0.0502 mL, 0.287 mmol) Was added at room temperature. After stirring at the same temperature for 16 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 to 95/5) to give the title compound (compound of Example 66 below) (0.0413 g, 0.0784 mmol, 82%) Was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.39-1.56 (m, 2 H), 1.63-1. 76 (m, 3 H), 1.96-2.13 (m, 4 H) , 2.32 (s, 3 H), 2.40-2. 60 (m, 3 H), 2. 76-2. 81 (m, 2 H), 2.93-2.97 (m, 2 H), 3 .15-3.20 (m, 3 H), 3.95-3.99 (m, 1 H), 4. 39-4. 43 (m, 1 H), 5. 38 (brs, 1 H), 5. 44 -5.45 (m, 1 H), 5.65 (brs, 1 H), 6.93-6.99 (m, 2 H), 7.04-7.06 (m, 1 H), 7.15-7 .19 (m, 2 H), 7.55 (dd, J = 9.1, 2.7 Hz, 1 H), 7.78 (d, J = 2.7 Hz, 1 H), 8.42 (s, 1 H) .
ESI-MS: m / z = 527 (M + H) ^<+> .

Example 67 (R) -N- (3-Chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) -1- (2- (oxetan-3-yl) Synthesis of Acetyl) piperidine-2-carboxamide:

Using the same procedure as in Example 46 except that 2- (oxetan-3-yl) acetic acid was used instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid, the title compound ( The compound of Example 67 (0.0349 g, 0.0663 mmol, 71%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.62 (m, 2 H), 1.72-1.81 (m, 2 H), 1.93-2.04 (m, 3 H) , 2.06-2.13 (m, 2 H), 2.24-2.28 (m, 1 H), 2. 32 (s, 3 H), 2. 76-2.93 (m, 4 H), 3 .15-3.23 (m, 3 H), 3.40-3. 47 (m, 1 H), 3.79-3. 82 (m, 1 H), 4.40-4. 44 (m, 3 H) , 4.94-4.96 (m, 2 H), 5.19-5.20 (m, 1 H), 6.93 (d, J = 9.1 Hz, 1 H), 6.96-7.00 (m. m, 1 H), 7.0 4-7. 06 (m, 1 H), 7. 15-7. 19 (m, 2 H), 7.2 3 (dd, J = 9.1, 2.7 Hz, 1 H), 7.62 (d, J = 2.7 Hz, 1 ), 8.16 (s, 1H).
ESI-MS: m / z = 526 (M + H) ⁺ .

Example 68 (R) -1- (2-acetamidoacetyl) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) piperidine-2- Carboxamide Synthesis:

The compound of Example 57 (0.0400 g, 0.0825 mmol) is dissolved in dichloromethane (1.00 mL), acetyl chloride (0.00704 mL, 0.0990 mmol) and triethylamine (0.0172 mL, 0.124 mmol) are added at 0 ° C. Added. After stirring for 1 hour at the same temperature, methanol was added to the reaction solution and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 98/2) to give the title compound (compound of Example 68 below) (0.0363 g, 0.0689 mmol, 83%) Obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.65 (m, 2H), 1.74-1.88 (m, 3H), 1.96-2.04 (m, 2H) , 2.07-2.13 (m, 2H), 2.08 (s, 3H), 2.32 (s, 3H), 2.32-2.37 (m, 1H), 2.77-2 .82 (m, 2H), 3.15-3.27 (m, 3H), 3.71-3.74 (m, 1H), 4.09 (dd, J = 17.4, 4.3 Hz, 1H), 4.20 (dd, J = 17.4, 4.3 Hz, 1 H), 4.41-4.45 (m, 1 H), 5.26-5.27 (m, 1 H), 6. 51-6.53 (m, 1 H), 6.94-7.00 (m, 2 H), 7.04-7.06 (m, 1 H), 7.15-7. 19 (m, 2 H), 7.37 (dd, J = 8.7, .7Hz, 1H), 7.64 (d, J = 2.7Hz, 1H), 8.02 (s, 1H).
ESI-MS: m / z = 527 (M + H) ^<+> .

Example 69 (R) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) oxy) phenyl) -1- (2- (methylsulfonamido) acetyl) Synthesis of piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 69) (0.0267 g, 0.0474 mmol, 58%) was precipitated in the form of a white solid by the same procedure as in Example 68 except for using methanesulfonyl chloride instead of acetyl chloride. Got as.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.70 (m, 2 H), 1.73-1. 91 (m, 3 H), 1.96 to 2.13 (m, 4 H) , 2.27-2.32 (m, 1 H), 2.32 (s, 3 H), 2.77-2.82 (m, 2 H), 3.00 (s, 3 H), 3.15-3. .20 (m, 2 H), 3.29-3. 37 (m, 1 H), 3.5 9-3. 62 (m, 1 H), 4.04 (dd, J = 16.9, 4.6 Hz, 1 H), 4.08 (dd, J = 16.9, 4.6 Hz, 1 H), 4.41-4.45 (m, 1 H), 5.22-5. 23 (m, 1 H), 60 (t, J = 4.6 Hz, 1 H), 6.95 (d, J = 8.9 Hz, 1 H), 6.96-7.00 (m, 1 H), 7.04-7.06 (m , 1 H), 7.15-7.1 (M, 2H), 7.30 (dd, J = 8.9,2.5Hz, 1H), 7.67 (d, J = 2.5Hz, 1H), 7.94 (s, 1H).
ESI-MS: m / z = 563 (M + H) ^<+> .

Example 70 (R) -N- (3-chloro-4-((1- (o-tolyl) piperidin-4-yl) -oxy) phenyl) -1- (2-cyanoacetyl) piperidine-2 -Synthesis of carboxamide:

The title compound was obtained by the same procedure as in Example 46 except that 2-cyanoacetic acid was used instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid, and the title compound (hereinafter referred to as Example 70) Compound (0.238 g, 0.481 mmol, 76%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.52-1.71 (m, 2H), 1.74-1.86 (m, 2H), 1.89-2.03 (m, 3H) , 2.07-2.14 (m, 2H), 2.24-2.30 (m, 1H), 2.32 (s, 3H), 2.77-2.83 (m, 2H), 3 15-3.20 (m, 2H), 3.40 (td, J = 13.1, 2.7 Hz, 1H), 3.56-3.66 (m, 3H), 4.40-4. 47 (m, 1 H), 5.18 (d, J = 5.0 Hz, 1 H), 6.94-6.99 (m, 2 H), 7.05 (d, J = 7.7 Hz, 1 H), 7.14-7.19 (m, 2H), 7.26-7.29 (m, 1 H), 7.65 (d, J = 2.7 Hz, 1 H), 7.92 (brs, 1 H).
ESI-MS: m / z = 495 (M + H) ^<+> .

Reference Example 76 Synthesis of 4- (4- (2-chloro-4-nitrophenoxy) piperidin-1-yl) benzonitrile:

The title compound (hereinafter, the compound of Reference Example 76) (0.128 g) was prepared according to the same procedure as in Reference Example 41 except for using 4-fluorobenzonitrile instead of 1-fluoro-4- (methylsulfonyl) benzene. , 0.358 mmol, 70%) as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.00-2.15 (m, 4 H), 3.45-3. 50 (m, 2 H), 3.57-3. 63 (m, 2 H) , 4.79-4.83 (m, 1 H), 6.91 (d, J = 9.0 Hz, 2 H), 7.03 (d, J = 9.0 Hz, 1 H), 7.52 (d, J = 9.0 Hz, 2 H), 8. 16 (dd, J = 9.0, 2.7 Hz, 1 H), 8.33 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 358 (M + H) ^<+> .

Reference Example 77 Synthesis of 4- (4- (4-amino-2-chlorophenoxy) piperidin-1-yl) benzonitrile:

The title compound (hereinafter, the compound of Reference Example 77) (0.101 g, 0.308 mmol, 888) was prepared by using the compound of Reference Example 76 in place of the compound of Reference Example 7 and using the same procedure as in Reference Example 8 except for this. %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.89-2.04 (m, 4 H), 3.28-3. 34 (m, 2 H), 3.54 (s, 2 H), 3.64 -3.70 (m, 2H), 4.34-4. 39 (m, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1 H), 6.74 (d, J = 2.7 Hz, 1 H), 6.83 (d, J = 8.6 Hz, 1 H), 6.88 (d, J = 9.1 Hz, 2 H), 7.49 (d, J = 9.1 Hz, 2 H ).
ESI-MS: m / z = 328 (M + H) ⁺ .

(Reference Example 78) (R) -2-((3-Chloro-4-((1- (4-cyanophenyl) piperidin-4-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Composition of:

The compound of Reference Example 77 (0.0600 g, 0.183 mmol) and (R) -1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid (0.0504 g, 0.220 mmol) in DMF (1.00 mL) Dissolve and add HATU (0.0840 g, 0.220 mmol) and diisopropylethylamine (0.0480 mL, 0.275 mmol) at room temperature. After stirring at the same temperature for 16 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 50/50), and the title compound (hereinafter, the compound of Reference Example 78) (0. 100 g, 0.186 mmol, quantitative) ) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.48 (m, 2H), 1.52 (s, 9H), 1.58-1.70 (m, 3H), 1.92 -2.06 (m, 4 H), 2.31-2. 34 (m, 1 H), 2.79-2. 86 (m, 1 H), 3.34-3. 40 (m, 2 H), 3 .60-3.67 (m, 2H), 4.06 (brs, 1H), 4.52-4.57 (m, 1H), 4.83-4.86 (m, 1H), 6.88 (D, J = 9.1 Hz, 2 H), 6.93 (d, J = 8.6 Hz, 1 H), 7.32 (dd, J = 8.6, 2.7 Hz, 1 H), 7.49 ( d, J = 9.1 Hz, 2 H, 7.63 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 539 (M + H) ⁺ .

Reference Example 79 Synthesis of (R) -N- (3-chloro-4-((1- (4-cyanophenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 78 (0.0990 g, 0.184 mmol) is dissolved in ethyl acetate (0.918 mL), and hydrogen chloride-ethyl acetate solution (4.0 M, 0.918 mL, 3.67 mmol) is added at 0 ° C. The After stirring at room temperature for 4 hours, to the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (hereinafter, the compound of Reference Example 79) (0.0653 g, 0.149 mmol, 81%) Obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.64 (m, 4 H), 1.79-1.83 (m, 1 H), 1.92-2.06 (m, 5 H) , 2.73-2.80 (m, 1H), 3.04-3.08 (m, 1H), 3.34-3.40 (m, 3H), 3.60-3.67 (m, 2H), 4.51-4.56 (m, 1H), 6.88 (d, J = 9.1 Hz, 2H), 6.94 (d, J = 8.6 Hz, 1H), 7.46 (d) dd, J = 8.6, 2.7 Hz, 1 H), 7. 49 (d, J = 9.1 Hz, 2 H), 7. 66 (d, J = 2.7 Hz, 1 H), 8. 84 (s , 1 H).
ESI-MS: m / z = 439 (M + H) ⁺ .

EXAMPLE 71 Synthesis of (R) -1-acetyl-N- (3-chloro-4-((1- (4-cyanophenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide

The compound of Reference Example 79 (0.0200 g, 0.0456 mmol) is dissolved in dichloromethane (1.45 mL), triethylamine (0.00953 mL, 0.0683 mmol) and acetyl chloride (0.00389 mL, 0.0547 mmol) are added at 0 ° C. Added. After stirring for 1 hour at the same temperature, methanol was added to the reaction solution and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 to 98/2) to give the title compound (hereinafter, the compound of Example 71) (0.0212 g, 0.0441 mmol, 97%) Was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.61 (m, 2 H), 1.72-1. 78 (m, 2 H), 1.90-2.04 (m, 5 H) , 2.21 (s, 3 H), 2. 26-2. 29 (m, 1 H), 3.1 2-3. 19 (m, 1 H), 3.3 3-3. 39 (m, 2 H), 3 .60-3.66 (m, 2 H), 3.75-3. 78 (m, 1 H), 4.51-4. 56 (m, 1 H), 5.24-5. 26 (m, 1 H) , 6.88 (d, J = 9.1 Hz, 2 H), 6.91 (d, J = 8.6 Hz, 1 H), 7.31 (dd, J = 8.6, 2.7 Hz, 1 H), 7.49 (d, J = 9.1 Hz, 2 H), 7.64 (d, J = 2.7 Hz, 1 H), 8. 35 (s, 1 H).
ESI-MS: m / z = 481 (M + H) ⁺ .

Example 72 (R) -N- (3-chloro-4-((1- (4-cyanophenyl) piperidin-4-yl) oxy) phenyl) -1- (methylsulfonyl) piperidine-2-carboxamide Composition of:

The title compound (hereinafter, the compound of Example 72) (0.0208 g, 0.0402 mmol, 88%) was precipitated in the form of a white solid by the same procedure as in Example 71 except for using methanesulfonyl chloride instead of acetyl chloride. Got as.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49 to 1.57 (m, 1 H), 1.601 to 1.67 (m, 2 H), 1.69 to 1.74 (m, 1 H) , 1.78 to 1.80 (m, 1 H), 1.93 to 2.03 (m, 4 H), 2.45 to 2.48 (m, 1 H), 3.02 (s, 3 H), 3 .13-3.20 (m, 1H), 3.35-3.41 (m, 2H), 3.60-3.67 (m, 2H), 3.90-3.93 (m, 1H) , 4.54-4.59 (m, 2H), 6.89 (d, J = 9.1 Hz, 2 H), 6.95 (d, J = 9.1 Hz, 1 H), 7.33 (dd, J = 9.1, 2.7 Hz, 1 H, 7. 50 (d, J = 9.1 Hz, 2 H), 7.69 (d, J = 2.7 Hz, 1 H), 8.11 (s, 1 H) ).
ESI-MS: m / z = 517 (M + H) ⁺ .

Example 73 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (3-chloro-4-((1- (4-cyanophenyl) piperidin-4-yl) )) Synthesis of oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 79 (0.0200 g, 0.0456 mmol) and 2- (1H-imidazol-1-yl) acetic acid (0.00690 g, 0.0547 mmol) were dissolved in DMF (1.00 mL) to obtain HATU (0). .0208 g, 0.0547 mmol) and diisopropylethylamine (0.0119 mL, 0.0683 mmol) were added at room temperature. After stirring at the same temperature for 16 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (chloroform / methanol = 100/0 to 98/2) to give the title compound (the compound of Example 73 below) (0.0203 g, 0.0371 mmol, 81%) Was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.85 (m, 4 H), 1.91-2.05 (m, 5 H), 2.22-2.26 (m, 1 H) , 3.34-3.44 (m, 3H), 3.59-3.66 (m, 2H), 3.68-3.71 (m, 1H), 4.51-4.56 (m, 1H), 4.86 (d, J = 16.3 Hz, 1 H), 4.90 (d, J = 16.3 Hz, 1 H), 5.15-5.17 (m, 1 H), 6.88 ( d, J = 9.1 Hz, 2H), 6.90 (d, J = 8.6 Hz, 1 H), 6.96 (s, 1 H), 7.13 (s, 1 H), 7.17 (dd, J = 8.6, 2.3 Hz, 1 H, 7.49 (d, J = 9.1 Hz, 2 H), 7.52 (s, 1 H), 7.64 (d, J = 2.3 Hz, 1 H ), 8.12 (s, 1 H) .
ESI-MS: m / z = 547 (M + H) ⁺ .

(Reference Example 80) (R) -2-((3-chloro-4-((1- (4- (trifluoromethoxy) phenyl) piperidin-4-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylic acid Synthesis of acid tert-butyl:

The compound of Reference Example 38 (0.100 g, 0.259 mmol) and (R) -1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid (0.0711 g, 0.310 mmol) in DMF (1.00 mL) Dissolve and add HATU (0.118 g, 0.310 mmol) and diisopropylethylamine (0.0677 mL, 0.388 mmol) at room temperature. After stirring at the same temperature for 16 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 75/25) to give the title compound (hereinafter referred to as the compound of Reference Example 80) (0.124 g, 0.207 mmol, 80) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44-1.69 (m, 5 H), 1.52 (s, 9 H), 1.95-2.10 (m, 4 H), 2.31 -2.34 (m, 1 H), 2.79-2. 86 (m, 1 H), 3.11-3. 17 (m, 2 H), 3.44-3. 50 (m, 2 H), 4 .05-4.08 (brm, 1H), 4.44-4.49 (m, 1H), 4.84-4.85 (m, 1H), 6.91-6.95 (m, 3H) , 7.10 (d, J = 9.1 Hz, 2 H), 7.31 (dd, J = 8.6, 2.3 Hz, 1 H), 7.62 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 598 (M + H) ^<+> .

Reference Example 81 Synthesis of (R) -N- (3-chloro-4-((1- (4- (trifluoromethoxy) phenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 80 (0.120 g, 0.201 mmol) is dissolved in ethyl acetate (1.00 mL), and hydrogen chloride-ethyl acetate solution (4.0 M, 1.00 mL, 4.01 mmol) is added at 0 ° C. The After stirring at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (compound of Reference Example 81) (0.0989 g, 0.199 mmol, 99%) Obtained as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.63 (m, 4 H), 1.79-1.83 (m, 1 H), 1.95-2.11 (m, 5 H) , 2.72-2.79 (m, 1 H), 3.03-3.08 (m, 1 H), 3.11-3.17 (m, 2 H), 3.34 (dd, J = 9). 5, 3.6 Hz, 1 H), 3.45-3.51 (m, 2 H), 4. 45-4. 50 (m, 1 H), 6. 92 (d, J = 9.1 Hz, 2 H), 6.95 (d, J = 9.1 Hz, 1 H), 7. 11 (d, J = 9.1 Hz, 2 H), 7. 45 (dd, J = 9.1, 2.3 Hz, 1 H), 7 .65 (d, J = 2.3 Hz, 1 H), 8.81 (s, 1 H).
ESI-MS: m / z = 498 (M + H) ⁺ .

Example 74 (R) -1-Acetyl-N- (3-chloro-4-((1- (4- (trifluoromethoxy) phenyl) piperidin-4-yl) oxy) phenyl) piperidine-2- Carboxamide Synthesis:

The compound of Reference Example 81 (11.0 g, 22.1 mmol) is dissolved in dichloromethane (45.0 mL), triethylamine (3.69 mL, 26.5 mmol) and acetyl chloride (1.73 mL, 24.3 mmol) are added at 0 ° C. Added. After stirring for 2 hours at the same temperature, distilled water was added to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate / heptane to give the title compound (hereinafter, the compound of Example 74) (11.2 g, 20.8 mmol, 94%) as white crystals. As a result of analysis using a chiral column, the retention time of the compound of Example 74 obtained was 19.1 minutes, and the optical purity at that time was 99.8% ee. The analysis conditions using a chiral column are the same as in Example 46.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.58 (m, 2 H), 1.71 to 1.78 (m, 2 H), 1.89 to 2. 10 (m, 5 H) , 2.21 (s, 3 H), 2.25-2.29 (m, 1 H), 3.10-3. 21 (m, 3 H), 3.44-3. 50 (m, 2 H), 3 .75-3.78 (m, 1 H), 4.44-4. 49 (m, 1 H), 5.25-5.26 (m, 1 H), 6.91-6.93 (m, 3 H) , 7.11 (d, J = 8.6 Hz, 2 H), 7.31 (dd, J = 8.6, 2.3 Hz, 1 H), 7.64 (d, J = 2.3 Hz, 1 H), 8.36 (s, 1 H).
ESI-MS: m / z = 540 (M + H) ⁺ .

Example 75 (R) -N- (3-Chloro-4-((1- (4- (trifluoromethoxy) phenyl) piperidin-4-yl) oxy) phenyl) -1- (methylsulfonyl) piperidine Synthesis of -2-carboxamide:

The title compound (hereinafter, the compound of Example 75) (0.0615 g, 0.107 mmol, 82%) was precipitated as a white solid according to the same procedure as in Example 74 except for using methanesulfonyl chloride instead of acetyl chloride Got as.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49 to 1.80 (m, 5 H), 1.96 to 2.11 (m, 4 H), 2.44 to 2.47 (m, 1 H) , 3.02 (s, 3 H), 3.12-3.22 (m, 3 H), 3.44-3. 50 (m, 2 H), 3.90-3.93 (m, 1 H), 4 .47-4.52 (m, 1 H), 4.59-4.60 (m, 1 H), 6.92 (d, J = 9.1 Hz, 2 H), 6.96 (d, J = 9). 1 Hz, 1 H), 7.11 (d, J = 9.1 Hz, 2 H), 7.32 (dd, J = 9.1, 2.7 Hz, 1 H), 7.68 (d, J = 2.7 Hz) , 1 H), 8.09 (s, 1 H).
ESI-MS: m / z = 576 (M + H) ⁺ .

(Reference Example 82) (R) -2-((3-chloro-4-((1- (4- (difluoromethoxy) phenyl) piperidin-4-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylic acid Synthesis of tert-butyl:

The compound of Reference Example 40 (0.0900 g, 0.244 mmol) and (R) -1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid (0.0671 g, 0.293 mmol) in DMF (1.00 mL) Dissolve and add HATU (0.111 g, 0.293 mmol) and diisopropylethylamine (0.0639 mL, 0.366 mmol) at room temperature. After stirring at the same temperature for 16 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 65/35) to give the title compound (hereinafter referred to as the compound of Reference Example 82) (0.136 g, 0.234 mmol, 96) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.69 (m, 5 H), 1.52 (s, 9 H), 1.95 to 2.11 (m, 4 H), 2.31 -2.34 (m, 1 H), 2.79-2. 86 (m, 1 H), 3.08-13. 13 (m, 2 H), 3.42-3. 48 (m, 2 H), 4 .06 (brs, 1 H), 4.44-4. 49 (m, 1 H), 4.84-4. 85 (m, 1 H), 6.42 (t, J = 74.8 Hz, 1 H), 6 .91-6.95 (m, 3 H), 7.04 (d, J = 9.1 Hz, 2 H), 7.32 (dd, J = 8.6, 2.7 Hz, 1 H), 7.62 ( d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 580 (M + H) ⁺ .

Reference Example 83 Synthesis of (R) -N- (3-chloro-4-((1- (4- (difluoromethoxy) phenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 82 (0.120 g, 0.207 mmol) is dissolved in ethyl acetate (1.03 mL), and hydrogen chloride-ethyl acetate solution (4.0 M, 1.03 mL, 4.14 mmol) is added at 0 ° C. The After stirring at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (compound of Reference Example 83) (0.0933 g, 0.194 mmol, 94%) Obtained as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.68 (m, 4 H), 1.82-1. 85 (m, 1 H), 1.94-2.10 (m, 5 H) , 2.79-2.86 (m, 1 H), 3.07-3.18 (m, 3 H), 3.41-3. 47 (m, 2 H), 3.57-3. 60 (m, 3) 1 H), 4.43-4. 48 (m, 1 H), 6.42 (t, J = 74.5 Hz, 1 H), 6.91-6.93 (m, 3 H), 7.04 (d, 7) J = 9.1 Hz, 2 H), 7.44 (dd, J = 8.8, 2.7 Hz, 1 H), 7.71 (d, J = 2.7 Hz, 1 H), 9.27 (s, 1 H) ).
ESI-MS: m / z = 480 (M + H) ⁺ .

Example 76 (R) -1-Acetyl-N- (3-chloro-4-((1- (4- (difluoromethoxy) phenyl) piperidin-4-yl) oxy) phenyl) piperidine-2-carboxamide Composition of:

The compound of Reference Example 83 (0.0400 g, 0.0833 mmol) is dissolved in dichloromethane (1.00 mL), triethylamine (0.0174 mL, 0.125 mmol) and acetyl chloride (0.00711 mL, 0.100 mmol) are added at 0 ° C. Added. After stirring for 1 hour at the same temperature, methanol was added to the reaction solution and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 60/40 to 10/90) to give the title compound (compound of Example 76 below) (0.0385 g, 0.0738 mmol, 89) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.61 (m, 2 H), 1.71 to 1.78 (m, 2 H), 1.89 to 2. 10 (m, 5 H) , 2.21 (s, 3 H), 2. 26-2.29 (m, 1 H), 3.07-3. 20 (m, 3 H), 3.42-3. 48 (m, 2 H), 3 .75-3.78 (m, 1 H), 4.43-4. 48 (m, 1 H), 5.24-5. 26 (m, 1 H), 6.42 (t, J = 74.8 Hz, 1H), 6.91-6.93 (m, 3H), 7.04 (d, J = 9.1 Hz, 2H), 7.31 (dd, J = 8.7, 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1 H), 8.33 (s, 1 H).
ESI-MS: m / z = 522 (M + H) ⁺ .

Example 77 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4-((1- (4- (difluoromethoxy) phenyl) piperidine- Synthesis of 4-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 83 (0.0400 g, 0.0833 mmol) and 2- (1H-tetrazol-1-yl) acetic acid (0.0128 g, 0.100 mmol) were dissolved in DMF (1.00 mL) to obtain HATU (0). .0380 g, 0.100 mmol) and diisopropylethylamine (0.0218 mL, 0.125 mmol) were added at room temperature. After stirring at the same temperature for 16 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate / methanol = 100/0 to 97/3) to give the title compound (hereinafter, the compound of Example 77) (0.0350 g, 0.0593 mmol, 71%) Was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.57-1.80 (m, 3 H), 1.83-1. 91 (m, 2 H), 1.94-2.02 (m, 2 H) , 2.03-2.10 (m, 2H), 2.23-2.27 (m, 1H), 3.08-3.13 (m, 2H), 3.41-3.47 (m, 2) 2H), 3.50-3.57 (m, 1 H), 3.70-3.74 (m, 1 H), 4.44-4. 49 (m, 1 H), 5.14-5. 15 ( m, 1 H), 5. 39 (d, J = 16.5 Hz, 1 H), 5. 44 (d, J = 16.5 Hz, 1 H), 6.42 (t, J = 74.6 Hz, 1 H), 6.90-6.94 (m, 3 H), 7.04 (d, J = 8.7 Hz, 2 H), 7. 20 (dd, J = 8.9, 2.7 Hz, 1 H), 7.65 (D, J = 2.7 Hz, H), 7.94 (s, 1H), 8.83 (s, 1H).
ESI-MS: m / z = 590 (M + H) ⁺ .

Reference Example 84 Synthesis of tert-butyl 3- (2-chloro-4-nitrophenoxy) piperidine-1-carboxylate:

3-Hydroxypiperidine-1-carboxylic acid tert-butyl (0.378 g, 1.88 mmol) and sodium hydride (55 wt% mineral oil dispersion, 0.0889 g, 2.05 mmol) are suspended in DMF (1.71 mL) After becoming cloudy and stirring at 0 ° C. for 30 minutes, 2-chloro-1-fluoro-4-nitrobenzene (0.300 g, 1.71 mmol) dissolved in DMF (1.71 mL) was added at the same temperature. After stirring at the same temperature for 2.5 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 75/25) to give the title compound (hereinafter referred to as the compound of Reference Example 84) (0.566 g, 1.59 mmol, 91) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ , mixture of conformers) δ: 1.35 to 1.43 (brm, 9H), 1.56 to 1.59 (m, 1 H), 1.95-2. 05 (m, 3 H), 3.50-3.79 (brm, 4 H), 4. 46-4. 48 (m, 1 H), 7.04 (brs, 1 H), 8. 15 (dd, J = 9.1, 2.7 Hz, 1 H), 8.30 (s, 1 H).
ESI-MS: m / z = 379 (M + Na) ⁺ .

Reference Example 85 Synthesis of 3- (2-chloro-4-nitrophenoxy) -1-phenylpiperidine:

The compound of Reference Example 84 (0.200 g, 0.561 mmol) was dissolved in ethyl acetate (1.40 mL), and hydrogen chloride-ethyl acetate solution (4.0 M, 2.80 mL, 11.2 mmol) was added at room temperature. . After stirring for 2 hours at the same temperature, a saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product is dissolved in toluene (1.00 mL), iodobenzene (0.0650 mL, 0.584 mmol), palladium (II) acetate (0.0175 g, 0.0780 mmol), tri-tert-butylphosphino Tetrafluoroborate (0.0226 g, 0.0780 mmol) and tert-butyloxysodium (0.112 g, 1.17 mmol) were added at room temperature. After stirring for 1 hour at 120 ° C., the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 75/25) to give the title compound (hereinafter, the compound of Reference Example 85) (0.0912 g, 0.274 mmol, 49). %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.71-1.86 (m, 2 H), 1.99-2.03 (m, 1 H), 2.22-2.25 (m, 1 H) , 2.89-2.96 (m, 1 H), 3.06 (dd, J = 12.2, 8.6 Hz, 1 H), 3.50-3.54 (m, 1 H), 3.78- 3.82 (m, 1 H), 4.60-4. 66 (m, 1 H), 6.86-6. 90 (m, 1 H), 6.92-6. 94 (m, 2 H), 7. 07 (d, J = 9.1 Hz, 1 H), 7.25-7.29 (m, 2 H), 8. 15 (dd, J = 9.1, 2.7 Hz, 1 H), 8.31 (d , J = 2.7 Hz, 1 H).
ESI-MS: m / z = 333 (M + H) ⁺ .

Reference Example 86 Synthesis of 3-chloro-4-((1-phenylpiperidin-3-yl) oxy) aniline:

The compound of Reference Example 85 (0.0900 g, 0.270 mmol) was dissolved in ethanol (1.35 mL) and distilled water (0.675 mL), iron powder (0.0755 g, 1.35 mmol) and ammonium chloride (0. 0723 g, 1.35 mmol) was added at room temperature. After stirring at 80 ° C. for 4 hours, the reaction solution was filtered, distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 70/30), and the title compound (hereinafter, the compound of Reference Example 86) (0.0592 g, 0.196 mmol, 72) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.64-1.76 (m, 2H), 1.92-1.98 (m, 1H), 2.15-2.18 (m, 1H) , 2.82-2.88 (m, 1 H), 2.94 (dd, J = 11.8, 9.1 Hz, 1 H), 3.45-3. 49 (m, 1 H), 3.53 ( brs, 2H), 3.74-3.79 (m, 1 H), 4.18-4.24 (m, 1 H), 6.52 (dd, J = 8.6, 2.7 Hz, 1 H), 6.74 (d, J = 2.7 Hz, 1 H), 6.81-6.86 (m, 1 H), 6.88 (d, J = 8.6 Hz, 1 H), 6.90-6.93 (M, 2H), 7.22-7.26 (m, 2H).
ESI-MS: m / z = 303 (M + H) ⁺ .

EXAMPLE 78 Synthesis of 1-acetyl-N- (3-chloro-4-((1-phenylpiperidin-3-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 86 (0.0300 g, 0.0991 mmol) and 1-acetylpiperidine-2-carboxylic acid (0.0204 g, 0.119 mmol) were dissolved in DMF (1.00 mL), and HATU (0.0490 g, 0.129 mmol) and diisopropylethylamine (0.0260 mL, 0.149 mmol) were added at room temperature. After stirring for 19 hours at the same temperature, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 40/60 to 10/90) to give the title compound (compound of Example 78 below) (0.0365 g, 0.0800 mmol, 81) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.60 (m, 2H), 1.69-1.78 (m, 4H), 1.94-1.97 (m, 2H) , 2.17-2.21 (m, 1 H), 2.21 (s, 3 H), 2.26-2.29 (m, 1 H), 2.83-2 2.89 (m, 1 H), 2 .95 (dd, J = 11.8, 8.6 Hz, 1 H), 3.12-3.20 (m, 1 H), 3.47-3. 51 (m, 1 H), 3.75-3. 80 (m, 2 H), 4.32-4.39 (m, 1 H), 5.25 (d, J = 5.4 Hz, 1 H), 6.83-6.86 (m, 1 H), 6. 91-6.93 (m, 2H), 6.97 (d, J = 9.1 Hz, 1H), 7.23-7.32 (m, 3H), 7.63-7.66 (m, 1H) ), 8.32 (s, 1 H).
ESI-MS: m / z = 456 (M + H) ⁺ .

Reference Example 87 Synthesis of tert-butyl (S) -3- (2-chloro-4-nitrophenoxy) piperidine-1-carboxylate:

The title compound was obtained in the same manner as in Reference Example 84 except for using tert-butyl (S) -3-hydroxypiperidine-1-carboxylate instead of tert-butyl 3-hydroxypiperidine-1-carboxylate Hereinafter, the compound of Reference Example 87 (0.403 g, 1.13 mmol, 76%) was obtained as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ , conformer mixture) δ: 1.35-1. 43 (brm, 9 H), 1.55-1. 57 (m, 1 H), 1.95-2. 05 (brm, 3H), 3.41-3.88 (brm, 4H), 4.44-4.49 (m, 1H), 7.05 (brs, 1H), 8.15 (dd, J = 9.1, 2.7 Hz, 1 H), 8.30 (brs, 1 H).
ESI-MS: m / z = 379 (M + Na) ⁺ .

Reference Example 88 Synthesis of tert-butyl (R) -3- (2-chloro-4-nitrophenoxy) piperidine-1-carboxylate:

The title compound was obtained in the same manner as in Reference Example 84 except that tert-butyl (R) -3-hydroxypiperidine-1-carboxylate was used instead of tert-butyl 3-hydroxypiperidine-1-carboxylate. Hereinafter, the compound of Reference Example 88 (0.307 g, 0.860 mmol, 58%) was obtained as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ , mixture of conformers) δ: 1.35-1. 43 (brm, 9 H), 1.55-1. 58 (m, 1 H), 1.95-2. 05 (brm, 3H), 3.41-3.88 (brm, 4H), 4.44-4.49 (m, 1H), 7.05 (brs, 1H), 8.15 (dd, J = 9.1, 2.7 Hz, 1 H), 8.30 (brs, 1 H).
ESI-MS: m / z = 379 (M + Na) ⁺ .

Reference Example 89 Synthesis of (S) -3- (2-chloro-4-nitrophenoxy) -1-phenylpiperidine:

The title compound (hereinafter, the compound of Reference Example 89) (0.284 g, 0.853 mmol, 78) was prepared by using the compound of Reference Example 87 instead of the compound of Reference Example 84 and using the same procedure as in Reference Example 85 except the above. %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.71-1.86 (m, 2 H), 1.99-2.03 (m, 1 H), 2.22-2.25 (m, 1 H) , 2.89-2.96 (m, 1 H), 3.06 (dd, J = 12.2, 8.6 Hz, 1 H), 3.49-3. 54 (m, 1 H), 3.78- 3.82 (m, 1 H), 4.59-4. 66 (m, 1 H), 6.86-6. 90 (m, 1 H), 6.92-6. 94 (m, 2 H), 7. 07 (d, J = 9.1 Hz, 1 H), 7.25-7.29 (m, 2 H), 8. 14 (dd, J = 9.1, 2.7 Hz, 1 H), 8.31 (d , J = 2.7 Hz, 1 H).
ESI-MS: m / z = 333 (M + H) ⁺ .

Reference Example 90 Synthesis of (R) -3- (2-chloro-4-nitrophenoxy) -1-phenylpiperidine:

The title compound (hereinafter, the compound of Reference Example 90) (0.234 g, 0.703 mmol, 86) was prepared by using the compound of Reference Example 88 instead of the compound of Reference Example 84 and using the same procedure as in Reference Example 85 except the above. %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.71-1.86 (m, 2 H), 1.99-2.03 (m, 1 H), 2.22-2.25 (m, 1 H) , 2.89-2.96 (m, 1 H), 3.06 (dd, J = 11.8, 8.6 Hz, 1 H), 3.50-3.54 (m, 1 H), 3.78- 3.82 (m, 1 H), 4.59-4. 66 (m, 1 H), 6.86-6. 90 (m, 1 H), 6.92-6. 94 (m, 2 H), 7. 07 (d, J = 9.1 Hz, 1 H), 7.24-7.29 (m, 2 H), 8. 15 (dd, J = 9.1, 2.7 Hz, 1 H), 8.31 (d , J = 2.7 Hz, 1 H).
ESI-MS: m / z = 333 (M + H) ⁺ .

Reference Example 91 Synthesis of (S) -3-chloro-4-((1-phenylpiperidin-3-yl) oxy) aniline:

Using the compound of Reference Example 89 instead of the compound of Reference Example 85, and according to the same procedure as Reference Example 86 except the above, the title compound (the compound of Reference Example 91) (0.260 g, 0.859 mmol, quantitative) ) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.62-1.76 (m, 2H), 1.92-1.98 (m, 1H), 2.14-2.18 (m, 1H) , 2.82-2.88 (m, 1 H), 2.94 (dd, J = 12.0, 8.8 Hz, 1 H), 3.45-3. 49 (m, 1 H), 3.52 (m. brs, 2H), 3.74-3.79 (m, 1 H), 4.17-4. 24 (m, 1 H), 6.52 (dd, J = 8.6, 2.7 Hz, 1 H), 6.73 (d, J = 2.7 Hz, 1 H), 6.81-6.86 (m, 1 H), 6.87 (d, J = 8.6 Hz, 1 H), 6.91-6.93 (M, 2H), 7.22-7.26 (m, 2H).
ESI-MS: m / z = 303 (M + H) ⁺ .

Reference Example 92 Synthesis of (R) -3-chloro-4-((1-phenylpiperidin-3-yl) oxy) aniline:

Using the compound of Reference Example 90 instead of the compound of Reference Example 85, and according to the same procedure as Reference Example 86 except the above, the title compound (the compound of Reference Example 92) (0.215 g, 0.710 mmol, quantitative) ) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.62-1.76 (m, 2H), 1.92-1.98 (m, 1H), 2.15-2.17 (m, 1H) , 2.82-2.88 (m, 1 H), 2.94 (dd, J = 11.8, 9.1 Hz, 1 H), 3.45-3. 49 (m, 1 H), 3.52 (m. brs, 2H), 3.75-3. 79 (m, 1H), 4.17-4. 24 (m, 1H), 6.52 (dd, J = 8.6, 2.7 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1 H), 6.82-6. 85 (m, 1 H), 6.87 (d, J = 8.6 Hz, 1 H), 6.91-6.93 (M, 2H), 7.22-7.26 (m, 2H).
ESI-MS: m / z = 303 (M + H) ⁺ .

(Reference Example 93) (R) -2-((3-chloro-4-(((S) -1-phenylpiperidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Synthesis:

The compound of Reference Example 91 (0.0500 g, 0.165 mmol) and (R) -1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid (0.0454 g, 0.198 mmol) in DMF (1.10 mL) Dissolve and add HATU (0.0817 g, 0.215 mmol) and diisopropylethylamine (0.0433 mL, 0.248 mmol) at room temperature. After stirring for 15 hours at the same temperature, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 75/25), and the title compound (hereinafter, the compound of Reference Example 93) (0.0750 g, 0.146 mmol, 88) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.54 (m, 2 H), 1.52 (s, 9 H), 1.60-1. 79 (m, 5 H), 1.93 -1.99 (m, 1H), 2.17-2.20 (m, 1H), 2.31-2.35 (m, 1H), 2.79-2.89 (m, 2H), 2 .96 (dd, J = 11.8, 9.1 Hz, 1H), 3.47-3.52 (m, 1H), 3.77-3.81 (m, 1H), 4.07 (brs, brs, 1H), 4.33-4.40 (m, 1H), 4.84-4.85 (m, 1H), 6.83-6.86 (m, 1H), 6.91-6.93 m, 2 H), 6.99 (d, J = 8.6 Hz, 1 H), 7.2 3-7. 27 (m, 2 H), 7. 30 (dd, J = 8.6, 2.5 Hz, 1 H ), 7.64 (d, J = 2) 5Hz, 1H).
ESI-MS: m / z = 514 (M + H) ⁺ .

(Reference Example 94) (R) -2-((3-Chloro-4-(((R) -1-phenylpiperidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Synthesis:

The title compound (hereinafter, the compound of Reference Example 94) (0.0750 g, 0.146 mmol, 88) was prepared by using the compound of Reference Example 92 instead of the compound of Reference Example 91 and using the same procedure as in Reference Example 93 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.58 (m, 2 H), 1.52 (s, 9 H), 1.59-1.79 (m, 5 H), 1.93 -1.99 (m, 1 H), 2.17-2.20 (m, 1 H), 2.32-2.35 (m, 1 H), 2.79-2.89 (m, 2 H), 2 .96 (dd, J = 12.0, 8.8 Hz, 1 H), 3.47-3. 51 (m, 1 H), 3.77-3. 81 (m, 1 H), 4.06 (brs, brs, 1H), 4.33-4.40 (m, 1H), 4.84-4.85 (m, 1H), 6.83-6.86 (m, 1H), 6.91-6.93 m, 2H), 6.99 (d, J = 9.1 Hz, 1 H), 7.22-7.27 (m, 2 H), 7.29 (dd, J = 9.1, 2.7 Hz, 1 H) ), 7.65 (d, J = 2) 7Hz, 1H).
ESI-MS: m / z = 514 (M + H) ⁺ .

Reference Example 95 Synthesis of (R) -N- (3-chloro-4-(((S) -1-phenylpiperidin-3-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 93 (0.0750 g, 0.146 mmol) is dissolved in ethyl acetate (1.00 mL), and hydrogen chloride-ethyl acetate solution (4.0 M, 0.729 mL, 2.92 mmol) is added at 0 ° C. The After stirring at room temperature for 3 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (hereinafter referred to as the compound of Reference Example 95) (0.0547 g, 0.132 mmol, 91%) Obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.49 (m, 2H), 1.51-1.64 (m, 2H), 1.66-1.76 (m, 2H) , 1.78-1.83 (m, 1 H), 1.93-1. 98 (m, 1 H), 2.00-2.05 (m, 1 H), 2.17-2.20 (m, 1H), 2.72-2.79 (m, 1 H), 2.83-2 2.89 (m, 1 H), 2.96 (dd, J = 11.8, 9.1 Hz, 1 H), 3. 03-3.08 (m, 1H), 3.34 (dd, J = 9.5, 3.6 Hz, 1H), 3.47-3.51 (m, 1H), 3.77-3.81 (M, 1 H), 4.33-4. 40 (m, 1 H), 6.82-6. 86 (m, 1 H), 6.91-6. 93 (m, 2 H), 6.99 (d , J = 9.1 Hz, 1 H), 7. 3-7.27 (m, 2H), 7.42 (dd, J = 9.1, 2.7 Hz, 1 H), 7.68 (d, J = 2.7 Hz, 1 H), 8.81 (brs , 1 H).
ESI-MS: m / z = 414 (M + H) ⁺ .

Reference Example 96 Synthesis of (R) -N- (3-chloro-4-(((R) -1-phenylpiperidin-3-yl) oxy) phenyl) piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Reference Example 96) (0.0551 g, 0.133 mmol, 91) was prepared by using the compound of Reference Example 94 instead of the compound of Reference Example 93 and using the same procedure as in Reference Example 95 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.50 (m, 2H), 1.51-1.65 (m, 2H), 1.66-1.78 (m, 2H) , 1.78-1.83 (m, 1 H), 1.93-1. 98 (m, 1 H), 2.00-2.05 (m, 1 H), 2.17-2.20 (m, 1H), 2.72-2.79 (m, 1 H), 2.83-2 2.89 (m, 1 H), 2.96 (dd, J = 11.8, 9.1 Hz, 1 H), 3. 03-3.08 (m, 1H), 3.34 (dd, J = 9.5, 3.6 Hz, 1H), 3.47-3.51 (m, 1H), 3.77-3.81 (M, 1 H), 4.33-4. 40 (m, 1 H), 6.82-6. 86 (m, 1 H), 6.91-6. 93 (m, 2 H), 6.99 (d , J = 9.1 Hz, 1 H), 7. 3-7.27 (m, 2H), 7.42 (dd, J = 8.6, 2.7 Hz, 1 H), 7.68 (d, J = 2.7 Hz, 1 H), 8.81 (brs , 1 H).
ESI-MS: m / z = 414 (M + H) ⁺ .

Example 79 Synthesis of (R) -1-acetyl-N- (3-chloro-4-(((S) -1-phenylpiperidin-3-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 95 (0.0250 g, 0.0604 mmol) is dissolved in dichloromethane (1.00 mL), triethylamine (0.0126 mL, 0.0906 mmol) and acetyl chloride (0.00515 mL, 0.725 mmol) are added at 0 ° C. Added. After stirring for 1 hour at the same temperature, methanol was added to the reaction solution and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 40/60 to 10/90), and the title compound (compound of Example 79 below) (0.0205 g, 0.0449 mmol, 75) %) As a white solid. As a result of analysis using a chiral column, the retention time of the obtained compound of Example 79 was 39.5 minutes, and the optical purity at that time was 99.5% ee. The analysis conditions using a chiral column are as follows.
Measuring instrument; Shimadzu high performance liquid chromatograph LC-2010CHT
Column; Daicel Chemical Industries, Ltd. CHIRALCEL OD-RH 0.46 cmφ × 15 cm particle diameter 5 μm
Column temperature: 40 ° C
Mobile phase: (Liquid A) Distilled water, (Liquid B) Composition of acetonitrile mobile phase; Liquid A: Liquid B = 50: 50 The solution was sent for 60 minutes.
Flow rate: 0.5 mL / min detection; UV (210 nm)
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.60 (m, 2H), 1.69-1.79 (m, 4H), 1.90-1.98 (m, 2H) , 2.15-2.21 (m, 1 H), 2.21 (s, 3 H), 2.26-2.29 (m, 1 H), 2.83-2 2.89 (m, 1 H), 2 .95 (dd, J = 11.8, 8.8 Hz, 1 H), 3.12-3.20 (m, 1 H), 3.47-3. 51 (m, 1 H), 3.74-3. 80 (m, 2 H), 4.32-4.39 (m, 1 H), 5.25 (d, J = 5.0 Hz, 1 H), 6.83-6.86 (m, 1 H), 6. 91-6.93 (m, 2H), 6.97 (d, J = 8.8 Hz, 1 H), 7.23-7.25 (m, 2 H), 7.31 (dd, J = 8.8) , 2.5 Hz, 1 H), 7.64 d, J = 2.5Hz, 1H), 8.32 (brs, 1H).
ESI-MS: m / z = 456 (M + H) ⁺ .

EXAMPLE 80 Synthesis of (R) -1-acetyl-N- (3-chloro-4-(((R) -1-phenylpiperidin-3-yl) oxy) phenyl) piperidine-2-carboxamide

Using the compound of Reference Example 96 instead of the compound of Reference Example 95, and using the same procedure as Example 79 except for the above, the title compound (the compound of Example 80 below) (0.0258 g, 0.0566 mmol, 94) %) As a white solid. As a result of analysis using a chiral column, the retention time of the obtained compound of Example 80 was 39.4 minutes, and the optical purity at that time was 99.5% ee. The analysis conditions using a chiral column are the same as in Example 79.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.60 (m, 2H), 1.69-1.78 (m, 4H), 1.90-1.97 (m, 2H) , 2.15-2.21 (m, 1 H), 2.21 (s, 3 H), 2.26-2.29 (m, 1 H), 2.83-2 2.89 (m, 1 H), 2 .95 (dd, J = 11.8, 8.6 Hz, 1 H), 3.12-3.20 (m, 1 H), 3.47-3. 51 (m, 1 H), 3.74-3. 80 (m, 2 H), 4.32-4.39 (m, 1 H), 5.25 (d, J = 5.0 Hz, 1 H), 6.83-6.86 (m, 1 H), 6. 91-6.93 (m, 2H), 6.97 (d, J = 9.1 Hz, 1 H), 7.23-7.25 (m, 2 H), 7.29 (dd, J = 9.1) , 2.5 Hz, 1 H), 7.65 d, J = 2.5Hz, 1H), 8.32 (brs, 1H).
ESI-MS: m / z = 456 (M + H) ⁺ .

Example 81 (R) -N- (3-chloro-4-(((S) -1-phenylpiperidin-3-yl) oxy) phenyl) -1- (methylsulfonyl) piperidine-2-carboxamide Synthesis:

The title compound (hereinafter, the compound of Example 81) (0.0341 g, 0.0693 mmol, 96%) was prepared as a white solid by the same procedure as in Example 79 except for using methanesulfonyl chloride instead of acetyl chloride Got as.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.61 (m, 2H), 1.64-1.80 (m, 5H), 1.94-1.98 (m, 1H) , 2.18-2.20 (m, 1 H), 2.44-2.46 (m, 1 H), 2.83-2.90 (m, 1 H), 2.96 (dd, J = 11. 8, 9.1 Hz, 1 H), 3.02 (s, 3 H), 3.15-3. 23 (m, 1 H), 3.48-3. 52 (m, 1 H), 3.77-3. 81 (m, 1 H), 3.89-3. 93 (m, 1 H), 4.35-4. 42 (m, 1 H), 4.58-4.61 (m, 1 H), 6.84- 6.86 (m, 1 H), 6.91-6.93 (m, 2 H), 7.00 (d, J = 9.1 Hz, 1 H), 7.23-7.27 (m, 2 H), 7.32 (dd, J = 9.1, 2 3Hz, 1H), 7.68 (d, J = 2.3Hz, 1H), 8.08 (s, 1H).
ESI-MS: m / z = 492 (M + H) ^<+> .

Example 82 (R) -N- (3-chloro-4-(((R) -1-phenylpiperidin-3-yl) oxy) phenyl) -1- (methylsulfonyl) piperidine-2-carboxamide Synthesis:

The title compound (hereinafter, the compound of Example 82) was prepared by the same procedure as Example 79 except that the compound of Reference Example 96 was used instead of the compound of Reference Example 95, and methanesulfonyl chloride was used instead of acetyl chloride. (0.0334 g, 0.0679 mmol, 94%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.61 (m, 2 H), 1.63-1.80 (m, 5 H), 1.93-2.00 (m, 1 H) , 2.17-2.20 (m, 1 H), 2.44-2.46 (m, 1 H), 2.83-2.90 (m, 1 H), 2.96 (dd, J = 11. 8, 8.6 Hz, 1 H), 3.02 (s, 3 H), 3.16-3. 23 (m, 1 H), 3.48-3. 52 (m, 1 H), 3.77-3. 81 (m, 1 H), 3.89-3. 93 (m, 1 H), 4.35-4. 42 (m, 1 H), 4.59-4. 60 (m, 1 H), 6.84- 6.86 (m, 1 H), 6.91-6.93 (m, 2 H), 7.00 (d, J = 9.1 Hz, 1 H), 7.23-7.27 (m, 2 H), 7.32 (dd, J = 9.1, 2 7Hz, 1H), 7.69 (d, J = 2.7Hz, 1H), 8.10 (s, 1H).
ESI-MS: m / z = 492 (M + H) ^<+> .

Example 83 (R) -N- (3-Chloro-4-(((S) -1-phenylpiperidin-3-yl) oxy) phenyl) -1- (2- (N-methylmethylsulfonamide) Synthesis of)) acetyl) piperidine-2-carboxamide:

Using the compound of Reference Example 95 instead of the compound of Reference Example 64, and using the procedure of Example 42 except for the above, the title compound (the compound of Example 83 below) (0.0416 g, 0.0739 mmol, quantitation ) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1 to 1.97 (m, 8 H), 2.16 to 2.21 (m, 1 H), 2.30 to 2.37 (m, 1 H) , 2.80 to 2.88 (m, 1 H), 2.95 (dd, J = 11.8, 8.9 Hz, 1 H), 3.03 (s, 6 H), 3.20 to 3.27 (m. m, 1 H), 3.46 to 3.52 (m, 1 H), 3.66 to 3. 73 (m, 1 H), 3.75 to 3. 81 (m, 1 H), 4. 15 (d, 5) J = 16.8 Hz, 1 H), 4.23 (d, J = 16.8 Hz, 1 H), 4.34-4.38 (m, 1 H), 5.22 (d, J = 4.6 Hz, 1 H ), 6.84 (t, J = 7.3 Hz, 1 H), 6.91-6.93 (m, 2 H), 6.97 (d, J = 8.8 Hz, 1 H), 7.22-7 .30 (m, 3 H), 7 67 (d, J = 2.7Hz, 1H), 8.00 (brs, 1H).
ESI-MS: m / z = 564 (M + H) ^<+> .

Example 84 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4-(((S) -1-phenylpiperidin-3-yl) Synthesis of oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 95 is used instead of the compound of Reference Example 64, and 2- (1H-tetrazol-1-yl) acetic acid instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid The title compound (hereinafter, the compound of Example 84) (0.0466 g, 0.0889 mmol, 92%) was obtained as a white solid by the same procedure as Example 46 except for the above.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.59-1.80 (m, 5 H), 1.87-1.98 (m, 3 H), 2.16-2.19 (m, 1 H) , 2.24-2.28 (m, 1 H), 2.83-2.90 (m, 1 H), 2.96 (dd, J = 11.8, 8.6 Hz, 1 H), 3.47- 3.57 (m, 2H), 3.70-3.79 (m, 2H), 4.34-4.40 (m, 1H), 5.14-5.16 (m, 1H), 5. 38 (d, J = 16.8 Hz, 1 H), 5. 45 (d, J = 16.8 Hz, 1 H), 6.83-6.87 (m, 1 H), 6.91-6.93 (m) , 2H), 6.97 (d, J = 9.1 Hz, 1 H), 7.22-7.26 (m, 3 H), 7.65 (d, J = 2.7 Hz, 1 H), 7.88 (S, 1 H), 8.84 s, 1H).
ESI-MS: m / z = 524 (M + H) ⁺ .

(Reference Example 97) Synthesis of (S) -3- (2-chloro-4-nitrophenoxy) pyrrolidine-1-carboxylic acid tert-butyl:

(S) 3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl (0.336 g, 1.79 mmol) and sodium hydride (55 wt% mineral oil dispersion, 0.0821 g, 1.88 mmol) in DMF (1. After suspending in 71 mL) and stirring at 0 ° C. for 1 hour, 2-chloro-1-fluoro-4-nitrobenzene (0.300 g, 1.71 mmol) dissolved in DMF (1.71 mL) was added at the same temperature. . After stirring at the same temperature for 1.5 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 70/30), and the title compound (hereinafter, the compound of Reference Example 97) (0.534 g, 1.56 mmol, 91) %) As a yellow solid.
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 1.40 (s, 9 H), 2.10-2.21 (m, 2 H), 3.33-3. 37 (m, 1 H), 3 .42-3.50 (m, 2H), 3.58-3.66 (m, 1H), 5.30 (brs, 1H), 7.45 (d, J = 9.1 Hz, 1H), 8 .23 (dd, J = 9.1, 2.7 Hz, 1 H), 8.34 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 365 (M + Na) ⁺ .

Reference Example 98 Synthesis of (S) -3- (2-chloro-4-nitrophenoxy) -1-phenylpyrrolidine:

The compound of Reference Example 97 (0.200 g, 0.618 mmol) was dissolved in ethyl acetate (1.55 mL), and hydrogen chloride-ethyl acetate solution (4.0 M, 3.10 mL, 12.4 mmol) was added at room temperature. . After stirring at the same temperature for 1 hour, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product is dissolved in toluene (1.55 mL), iodobenzene (0.103 mL, 0.927 mmol), palladium (II) acetate (0.0278 g, 0.124 mmol), tri-tert-butylphosphino Tetrafluoroborate (0.0360 g, 0.124 mmol) and tert-butyloxysodium (0.178 g, 1.85 mmol) were added at room temperature. After stirring for 1 hour at 110 ° C., the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 70/30), and the title compound (hereinafter, the compound of Reference Example 98) (0.151 g, 0.474 mmol, 77) %) As a yellow solid.
¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 2.22-2.26 (m, 1 H), 2.37-2.46 (m, 1 H), 3.38-3. 42 (m, 1 2) 3H), 3.74 (dd, J = 11.6, 4.8 Hz, 1 H), 5.45-5.48 (m, 1 H), 6.57-6.59 (m, 2 H), 6. 61-6.65 (m, 1 H), 7.15-7. 19 (m, 2 H), 7. 50 (d, J = 9.1 Hz, 1 H), 8. 25 (dd, J = 9.1) , 2.7 Hz, 1 H), 8.33 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 319 (M + H) ⁺ .

Reference Example 99 Synthesis of (S) -3-chloro-4-((1-phenylpyrrolidin-3-yl) oxy) aniline:

The compound of Reference Example 98 (0.150 g, 0.471 mmol) was dissolved in ethanol (2.35 mL) and distilled water (1.18 mL), iron powder (0.131 g, 2.35 mmol) and ammonium chloride (0. 126 g, 2.35 mmol) were added at room temperature. After stirring at 80 ° C. for 1.5 hours, the reaction solution was filtered, distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 70/30), and the title compound (hereinafter, the compound of Reference Example 99) (0.126 g, 0.436 mmol, 93) %) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.16-2.25 (m, 1 H), 2.31-2.38 (m, 1 H), 3.43 (ddd, J = 8.6, 8.6, 3.2 Hz, 1 H), 3.50 to 3.63 (m, 5 H), 4.95 to 4.94 (m, 1 H), 6.53 (dd, J = 8.6, 2 .7 Hz, 1 H), 6.57-6.60 (m, 2 H), 6.67-6.71 (m, 1 H), 6.73 (d, J = 2.7 Hz, 1 H), 6.80 (D, J = 8.6 Hz, 1 H), 7.22-7.26 (m, 2 H).
ESI-MS: m / z = 289 (M + H) ⁺ .

(Reference Example 100) (R) -2-((3-chloro-4-(((S) -1-phenylpyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Synthesis:

The compound of Reference Example 99 (0.0600 g, 0.208 mmol) and (R) -1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid (0.0572 g, 0.249 mmol) in DMF (1.04 mL) Dissolve and add HATU (0.103 g, 0.270 mmol) and diisopropylethylamine (0.0544 mL, 0.312 mmol) at room temperature. After stirring for 15 hours at the same temperature, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 75/25), and the title compound (hereinafter, the compound of Reference Example 100) (0.0865 g, 0.173 mmol, 83) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.52 (m, 2H), 1.52 (s, 9H), 1.58-1.69 (m, 3H), 2.22 −2.39 (m, 3H), 2.79-2.86 (m, 1H), 3.43−3.59 (m, 3H), 3.69 (dd, J = 10.9, 5. 0 Hz, 1 H), 4.07 (brs, 1 H), 4.84-4. 85 (m, 1 H), 5.01-5. 05 (m, 1 H), 6.58-6. 60 (m, 1) 2H), 6.68-6.72 (m, 1H), 6.91 (d, J = 9.1 Hz, 1H), 7.22-7.26 (m, 2H), 7.35 (dd, J = 9.1, 2.3 Hz, 1 H), 7.59 (d, J = 2.3 Hz, 1 H), 8.14 (brs, 1 H).
ESI-MS: m / z = 500 (M + H) ⁺ .

Reference Example 101 Synthesis of (R) -N- (3-chloro-4-(((S) -1-phenylpyrrolidin-3-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 100 (0.0800 g, 0.160 mmol) is dissolved in ethyl acetate (0.800 mL), and hydrogen chloride-ethyl acetate solution (4.0 M, 0.800 mL, 3.20 mmol) is added at 0 ° C. The After stirring at room temperature for 1 hour, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (hereinafter referred to as the compound of Reference Example 101) (0.0637 g, 0.159 mmol, 99%) Obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.61 (m, 4 H), 1.79-1.83 (m, 1 H), 2.00-2.05 (m, 1 H) , 2.22-2.39 (m, 2H), 2.72-2.79 (m, 1 H), 3.03-3.08 (m, 1 H), 3.34 (dd, J = 9). 5, 3.2 Hz, 1 H), 3.46 (ddd, J = 8.6, 8.6, 3.2 Hz, 1 H), 3.50 to 3.59 (m, 2 H), 3.69 (dd , J = 10.9, 5.0 Hz, 1 H), 5.02-5.05 (m, 1 H), 6.58-6.60 (m, 2 H), 6.68-6.72 (m, 2) 1H), 6.91 (d, J = 8.6 Hz, 1 H), 7.22-7.26 (m, 2 H), 7.48 (dd, J = 8.6, 2.3 Hz, 1 H), 7.62 (d, J = 2.3 H , 1H), 8.80 (s, 1H).
ESI-MS: m / z = 400 (M + H) ⁺ .

Example 85 Synthesis of (R) -1-Acetyl-N- (3-chloro-4-(((S) -1-phenylpyrrolidin-3-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 101 (0.0250 g, 0.0625 mmol) is dissolved in dichloromethane (1.00 mL), and triethylamine (0.0131 mL, 0.0938 mmol) and acetyl chloride (0.00533 mL, 0.0750 mmol) are dissolved at 0 ° C. Added. After stirring for 1 hour at the same temperature, methanol was added to the reaction solution and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 40/60 to 10/90), and the title compound (the compound of Example 85 below) (0.0271 g, 0.0613 mmol, 98) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.60 (m, 2 H), 1.71-1. 78 (m, 2 H), 1.89-2.01 (m, 1 H) , 2.21 (s, 3 H), 2.23-2.38 (m, 3 H), 3. 12-3. 20 (m, 1 H), 3. 43-3. 59 (m, 3 H), 3 .68 (dd, J = 10.9, 5.0 Hz, 1 H), 3.75-3. 78 (m, 1 H), 5.01-5. 04 (m, 1 H), 5.25 (d, J = 5.4 Hz, 1 H), 6.57-6.59 (m, 2 H), 6.68-6.72 (m, 1 H), 6.89 (d, J = 8.6 Hz, 1 H), 7.22-7.26 (m, 2H), 7.35 (dd, J = 8.6, 2.7 Hz, 1 H), 7.59 (d, J = 2.7 Hz, 1 H), 8.33 (S, 1 H).
ESI-MS: m / z = 442 (M + H) ⁺ .

Example 86 (R) -N- (3-chloro-4-(((S) -1-phenylpyrrolidin-3-yl) oxy) phenyl) -1- (2- (N-methyl methyl sulfonamide) Synthesis of)) acetyl) piperidine-2-carboxamide:

Using the compound of Reference Example 101 instead of the compound of Reference Example 64, and using the procedure of Example 42 except for the above, the title compound (the compound of Example 86) (0.0352 g, 0.0641 mmol, 63) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.56-1.75 (m, 5 H), 2.24-2.34 (m, 3 H), 3.03 (s, 3 H), 3.03 (S, 3 H), 3.20-3. 27 (m, 1 H), 3.43-3. 59 (m, 3 H), 3.65-3. 73 (m, 2 H), 4. 14 (d , J = 16.8 Hz, 1 H), 4.24 (d, J = 16.8 Hz, 1 H), 5.00-5.05 (m, 1 H), 5. 19-5. 24 (m, 1 H) , 6.57-6.59 (m, 2H), 6.68-6.72 (m, 1 H), 6.89 (d, J = 8.8 Hz, 1 H), 7.22-7.34 (d m, 3H), 7.63 (d, J = 2.4 Hz, 1 H), 8.00 (s, 1 H).
ESI-MS: m / z = 550 (M + H) ⁺ .

(Reference Example 102) Synthesis of (S) -3- (2-chloro-4-nitrophenoxy) pyrrolidine hydrochloride:

The compound of Reference Example 97 (1.68 g, 4.90 mmol) was dissolved in ethyl acetate (4.90 mL), and hydrogen chloride-ethyl acetate solution (4.0 M, 18.4 mL, 73.5 mmol) was added at room temperature. . After stirring for 3 hours at the same temperature, the reaction solution was concentrated under reduced pressure to give the title compound (hereinafter, the compound of Reference Example 102) (1.36 g, 4.87 mmol, 99%) as a white solid.
¹ H-NMR (400 MHz, DMSO-d ₆ ) δ: 2.16-2.22 (m, 1 H), 2.25-2.34 (m, 1 H), 3.23-3. 31 (m, 1) 1H), 3.35-3.44 (m, 2H), 3.59 (dd, J = 13.4, 4.8 Hz, 1H), 5.40-5.43 (m, 1H), 7. 46 (d, J = 9.1 Hz, 1 H), 8. 25 (dd, J = 9.1, 2.7 Hz, 1 H), 8.37 (d, J = 2.7 Hz, 1 H), 9.27 (Brs, 2H).
ESI-MS: m / z = 243 (M + H) ⁺ .

Reference Example 103 Synthesis of (S) -3-chloro-4-((1- (2-fluorophenyl) pyrrolidin-3-yl) oxy) aniline

Compound of Reference Example 102 (0.200 g, 0.717 mmol), palladium (II) acetate (0.0322 g, 0.143 mmol), tri-tert-butylphosphino tetrafluoroborate (0.0416 g, 0.143 mmol), and Sodium tert-butyloxy (0.207 g, 2.15 mmol) was suspended in toluene (1.79 mL) and 1-fluoro-2-iodobenzene (0.124 mL, 1.08 mmol) was added at room temperature. After stirring at 110 ° C. for 8 hours, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product is dissolved in THF (3.12 mL), ethanol (6.18 mL) and distilled water (3.12 mL), iron powder (0.160 g, 2.87 mmol) and ammonium chloride (0.384 g, 7.17 mmol) was added at room temperature. After stirring at 70 ° C. for 2 hours, the reaction solution was filtered, distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 70/30), and the title compound (hereinafter, the compound of Reference Example 103) (0.0370 g, 0.121 mmol, 17) %) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.12 to 2.21 (m, 1 H), 2.26 to 2. 31 (m, 1 H), 3.44 to 3.51 (m, 3 H) , 3.55-3.59 (m, 1 H), 3.62-3.69 (m, 1 H), 3.82 (ddd, J = 11.6, 5.2, 3.2 Hz, 1 H), 4.85-4.89 (m, 1 H), 6.53 (dd, J = 8.8, 2.8 Hz, 1 H), 6.66-6.71 (m, 2 H), 6.73 (d , J = 2.8 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 1 H), 6.95-7.02 (m, 2 H).
ESI-MS: m / z = 307 (M + H) ⁺ .

(Reference Example 104) (R) -2-((3-chloro-4-(((S) -1- (2-fluorophenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carvone Synthesis of acid tert-butyl:

The title compound (hereinafter, the compound of Reference Example 104) (0.0512 g, 0.0988 mmol, 82) was prepared by using the compound of Reference Example 103 instead of the compound of Reference Example 99 and following the same procedure as in Reference Example 100 %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.54 (m, 11 H), 1.59-1.69 (m, 3 H), 2.18-2.34 (m, 3 H) , 2.78-2.86 (m, 1 H), 3.46-3. 50 (m, 1 H), 3.56 (brd, J = 11.6 Hz, 1 H), 3.60-3. m, 1H), 3.90 (ddd, J = 11.6, 5.2, 3.2 Hz, 1H), 4.04-4.08 (m, 1H), 4.83-4.86 (m , 1 H), 4.96-5.00 (m, 1 H), 6.67-6.74 (m, 2 H), 6.89 (d, J = 8.8 Hz, 1 H), 6.96-7 .03 (m, 2 H), 7.33 (dd, J = 8.8, 2.8 Hz, 1 H), 7. 60 (d, J = 2.8 Hz, 1 H), 8.12 (brs, 1 H) .
ESI-MS: m / z = 518 (M + H) ⁺ .

Example 87 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (2-fluorophenyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2- Carboxamide Synthesis:

The compound of Reference Example 104 (0.0510 g, 0.0985 mmol) was dissolved in dichloromethane (1.00 mL), and trifluoroacetic acid (0.246 mL, 3.21 mmol) was added at 0 ° C. After stirring for 2 hours at room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product was dissolved in dichloromethane (1.00 mL) and triethylamine (0.0160 mL, 0.118 mmol) and acetic anhydride (0.0102 mL, 0.108 mmol) were added at 0 ° C. After stirring at the same temperature for 1.5 hours, methanol was added to the reaction solution and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 50/50) to give the title compound (compound of Example 87 below) (0.0377 g, 0.0820 mmol, 83) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.60 (m, 2 H), 1.70-1. 78 (m, 2 H), 1.87-1.99 (m, 1 H) , 2.20 (s, 3 H), 2.2 1-2. 31 (m, 3 H), 3. 19 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3.45 3.50 (m, 1H), 3.55 (brd, J = 11.6 Hz, 1 H), 3.60-3.66 (m, 1 H), 3.76 (brd, J = 13.2 Hz, 1 H ), 3.89 (ddd, J = 11.6, 4.8, 3.2 Hz, 1 H), 4.95-4. 98 (m, 1 H), 5.25 (brd. J = 4.8 Hz, 1H), 6.67-6.73 (m, 2H), 6.86 (d, J = 8.8 Hz, 1H), 6.95-7.02 (m, 2H), 7.32 (dd, J = .8,2.4Hz, 1H), 7.60 (d, J = 2.4Hz, 1H), 8.39 (brs, 1H).
ESI-MS: m / z = 460 (M + H) ⁺ .

Reference Example 105 Synthesis of (S) -3-chloro-4-((1- (3-fluorophenyl) pyrrolidin-3-yl) oxy) aniline

The title compound (hereinafter, the compound of Reference Example 105) (0.176 g) was prepared by the same procedure as in Reference Example 103 using 1-bromo-3-fluorobenzene instead of 1-fluoro-2-iodobenzene , 0.574 mmol, 80%) as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15 to 2.24 (m, 1 H), 2.32 to 2.39 (m, 1 H), 3.41 (ddd, J = 8.8, 8.8, 2.8 Hz, 1H), 3.48-3.60 (m, 5H), 4.89-4.93 (m, 1H), 6.25 (ddd, J = 16.4, 2 .4, 2.4 Hz, 1 H), 6.32 (dd, J = 8.8, 2.4, 0.8 Hz, 1 H), 6.37 (dddd, J = 8.4, 8.4, 2 .4, 0.8 Hz, 1 H), 6.53 (dd, J = 8.4, 2.8 Hz, 1 H), 6.73 (d, J = 2.8 Hz, 1 H), 6.80 (d, J) J = 8.4 Hz, 1 H), 7.15 (ddd, J = 8.8, 8.4, 7.6 Hz, 1 H).
ESI-MS: m / z = 307 (M + H) ⁺ .

(Reference Example 106) (R) -2-((3-chloro-4-(((S) -1- (3-fluorophenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carvone Synthesis of acid tert-butyl:

The title compound (hereinafter, the compound of Reference Example 106) (0.254 g, 0.490 mmol, 88) was prepared by using the compound of Reference Example 105 instead of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44-1.69 (m, 14 H), 2.21-2. 39 (m, 3 H), 2.79-2. 86 (m, 1 H) , 3.44 (ddd, J = 8.8, 8.8, 2.8 Hz, 1 H), 3.50 (brd, J = 11.2 Hz, 1 H), 3.56 (ddd, J = 9.2 , 9.2, 6.8 Hz, 1 H), 3. 65 (dd, J = 9.2, 5.2 Hz, 1 H), 4.02-4.10 (m, 1 H), 4.84-4. 86 (m, 1 H), 5.01-5. 05 (m, 1 H), 6. 26 (ddd, J = 12.4, 2.4, 2.4 Hz, 1 H), 6.33 (ddd, J = 8.4, 2.4, 0.8 Hz, 1 H), 6. 38 (dddd, J = 8.4, 8.4, 2.4, 0.8 Hz, 1 H), 6. 91 (d, J = 8.8 Hz, 1 , 7.15 (ddd, J = 8.4, 8.4, 6.8 Hz, 1 H), 7.36 (dd, J = 8.8, 2.4 Hz, 1 H), 7.60 (d, J = 2.4 Hz, 1 H), 8. 15 (brs, 1 H).
ESI-MS: m / z = 518 (M + H) ⁺ .

Example 88 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (3-fluorophenyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2- Carboxamide Synthesis:

Using the compound of Reference Example 106 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 88) (0.202 g, 0.439 mmol, 90) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.62 (m, 2 H), 1.72-1. 78 (m, 2 H), 1.90 to 2.01 (m, 1 H) , 2.21 (s, 3H), 2.24-2.29 (m, 2H), 2.33-2.39 (m, 1H), 3.16 (ddd, J = 13.2, 13.3. 2, 2.8 Hz, 1 H), 3.43 (ddd, J = 8.8, 8.8, 3.2 Hz, 1 H), 3.49 (brd, J = 10.8 Hz, 1 H), 3.56 (Ddd, J = 9.2, 9.2, 6.8 Hz, 1 H), 3.64 (dd, J = 10.8, 4.8 Hz, 1 H), 3.76 (brd, J = 13.2 Hz , 1H), 5.00-5.04 (m, 1H), 5.25 (brd, J = 5.2 Hz, 1H), 6.25 (ddd, J = 12.4, 2.4, 2. 4H , 1 H), 6.32 (dd, J = 8.4, 2.0 Hz, 1 H), 6. 38 (ddd, J = 8.4, 8.4, 2.0 Hz, 1 H), 6.89 (6 d, J = 8.8 Hz, 1 H), 7. 15 (ddd, J = 8.4, 8.4, 7.2 Hz, 1 H), 7. 35 (dd, J = 8.8, 2.4 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1 H), 8. 35 (brs, 1 H).
ESI-MS: m / z = 460 (M + H) ⁺ .

Reference Example 107 Synthesis of (S) -3-chloro-4-((1- (4-fluorophenyl) pyrrolidin-3-yl) oxy) aniline:

The title compound (hereinafter, the compound of Reference Example 107) (0.0900 g) was prepared by the same procedure as Reference Example 103 except for using 1-fluoro-4-iodobenzene instead of 1-fluoro-2-iodobenzene. , 0.293 mmol, 71%) as a pale yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.16-2.25 (m, 1 H), 2.31-2. 37 (m, 1 H), 3.38 (ddd, J = 8.5, 8.5, 3.2 Hz, 1 H), 3.44-3.47 (m, 1 H), 3.50-3.54 (m, 3 H), 3.58 (dd, J = 10.5, 4) .9 Hz, 1 H), 4.89-4.92 (m, 1 H), 6.49 (dd, J = 9.0, 4.4 Hz, 2 H), 6.53 (dd, J = 8.5, 2.9 Hz, 1 H), 6.73 (d, J = 2.9 Hz, 1 H), 6.79 (d, J = 8.5 Hz, 1 H), 6.92-6. 97 (m, 2 H).
ESI-MS: m / z = 307 (M + H) ⁺ .

(Reference Example 108) (R) -2-((3-chloro-4-(((S) -1- (4-fluorophenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carvone Synthesis of acid tert-butyl:

The title compound (hereinafter, the compound of Reference Example 108) (0.150 g, 0.290 mmol, 99) was prepared by using the compound of Reference Example 107 in place of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.52-1.74 (m, 5 H), 1.52 (s, 9 H), 2.20-2.40 (m, 3 H), 2.80 -2.86 (m, 1 H), 3.40 (ddd, J = 8.4, 8.4, 3.3 Hz, 1 H), 3.44-3. 47 (m, 1 H), 3.49- 3.55 (m, 1 H), 3.66 (dd, J = 10.6, 5.0 Hz, 1 H), 4.00-4. 13 (m, 1 H), 4.84-4. 85 (m , 1H), 5.01-5.04 (m, 1H), 6.49 (dd, J = 9.0, 4.4 Hz, 2 H), 6.90 (d, J = 8.8 Hz, 1 H) , 6.93-6.97 (m, 2H), 7.34 (dd, J = 8.8, 2.4 Hz, 1 H), 7.59 (d, J = 2.4 Hz, 1 H).
ESI-MS: m / z = 519 (M + H) ^<+> .

Example 89 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (4-fluorophenyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2- Carboxamide Synthesis:

Using the compound of Reference Example 108 instead of the compound of Reference Example 104, and according to the same procedure as Example 87 except the above, the title compound (the compound of Example 89 below) (0.113 g, 0.246 mmol, 85) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.61 (m, 2 H), 1.71 to 1. 78 (m, 2 H), 1.87 to 1. 98 (m, 1 H) , 2.20 (s, 3 H), 2.22-2.36 (m, 3 H), 3. 20 (ddd, J = 13.1, 13.1, 2.6 Hz, 1 H), 3.39 (m. ddd, J = 8.4, 8.4, 3.4 Hz, 1 H), 3.43-3.46 (m, 1 H), 3.48-3. 55 (m, 1 H), 3.65 (dd , J = 10.6, 5.0 Hz, 1 H), 3.74-3.78 (m, 1 H), 4.99-5.02 (m, 1 H), 5.24-5. 26 (m, 1 H), 6.49 (dd, J = 9.0, 4.1 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 1 H), 6.92-6. 97 (m, 2 H), 7.33 (dd, J = 8 8,2.7Hz, 1H), 7.60 (d, J = 2.7Hz, 1H), 8.42 (s, 1H).
ESI-MS: m / z = 460 (M + H) ⁺ .

Reference Example 109 Synthesis of (S) -3-chloro-4-((1- (2-chlorophenyl) pyrrolidin-3-yl) oxy) aniline

The title compound (hereinafter, the compound of Reference Example 109) (0.0200 g) was prepared according to the same procedure as in Reference Example 103 except for using 1-chloro-2-iodobenzene instead of 1-fluoro-2-iodobenzene. , 0.0619 mmol, 15%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.16-2.36 (m, 2H), 3.38-3.45 (m, 2H), 3.62-3.68 (m, 1H) , 3.65 (brs, 2H), 3.97 (dd, J = 11.0, 5.4 Hz, 1H), 4.86-4.88 (m, 1H), 6.52 (dd, J =) 8.7, 2.8 Hz, 1 H), 6.72 (d, J = 2.8 Hz, 1 H), 6.78 (d, J = 8.7 Hz, 1 H), 6.79-6.84 (m , 1H), 6.95 (dd, J = 8.3, 1.2 Hz, 1 H), 7.14-7.18 (m, 1 H), 7.30 (dd, J = 8.0, 1. 5 Hz, 1 H).
ESI-MS: m / z = 324 (M + H) ⁺ .

(Reference Example 110) (R) -2-((3-Chloro-4-(((S) -1- (2-chlorophenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylic acid Synthesis of tert-butyl:

The title compound (hereinafter, the compound of Reference Example 110) (0.0250 g, 0.0468 mmol, 76) was prepared by using the compound of Reference Example 109 instead of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.69 (m, 5 H), 1.51 (s, 9 H), 2.25-2.33 (m, 3 H), 2.79 −2.85 (m, 1 H), 3.40-3. 45 (m, 2 H), 3.59-3. 65 (m, 1 H), 4.03 (dd, J = 11.2, 5. 4 Hz, 1 H), 4.06 (brs, 1 H), 4.83-4. 85 (m, 1 H), 4.96-5.00 (m, 1 H), 6.81-6.86 (m, 1) 1H), 6.88 (d, J = 8.8 Hz, 1 H), 6.96 (dd, J = 8.0, 1.5 Hz, 1 H), 7.15 to 7.19 (m, 1 H), 7.28-7.33 (m, 2H), 7.60 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 535 (M + H) ⁺ .

Example 90 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (2-chlorophenyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2-carboxamide Composition of:

Using the compound of Reference Example 110 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 90 below) (0.0178 g, 0.0373 mmol, 80) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.54 (m, 2H), 1.71-1.77 (m, 2H), 1.90-1.96 (m, 1H) , 2.20 (s, 3 H), 2.24-2.29 (m, 3 H), 3.12-3. 19 (m, 1 H), 3.41-3. 44 (m, 2 H), 3 .59-3.65 (m, 1 H), 3.74-3. 77 (m, 1 H), 4.02 (dd, J = 11.0, 5.4 Hz, 1 H), 4.95-4. 99 (m, 1 H), 5.24-5.25 (m, 1 H), 6.81-6.83 (m, 1 H), 6.86 (d, J = 9.0 Hz, 1 H), 6. 95-6.97 (m, 1 H), 7.15-7. 19 (m, 1 H), 7.29-7.34 (m, 2 H), 7.60 (d, J = 2.4 Hz, 1 H ), 8.31 (s, 1 H).
ESI-MS: m / z = 477 (M + H) ⁺ .

Reference Example 111 Synthesis of (S) -3-chloro-4-((1- (3-chlorophenyl) pyrrolidin-3-yl) oxy) aniline:

The title compound (hereinafter, the compound of Reference Example 111) (0.0400 g) was prepared according to the same procedure as in Reference Example 103 except for using 1-chloro-3-iodobenzene instead of 1-fluoro-2-iodobenzene. , 0.124 mmol, 30%) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14-2.23 (m, 1 H), 2.33-2.38 (m, 1 H), 3.38-3. 43 (m, 1 H) , 3.47-3.50 (m, 1H), 3.53-3.59 (m, 4H), 4.89-4.92 (m, 1H), 6.42-6.44 (m, 1H), 6.52-6.54 (m, 2H), 6.63-6.65 (m, 1H), 6.73 (d, J = 2.9 Hz, 1 H), 6.79 (d, 7) J = 8.5 Hz, 1 H), 7.10-7.14 (m, 1 H).
ESI-MS: m / z = 324 (M + H) ⁺ .

(Reference Example 112) (R) -2-((3-Chloro-4-(((S) -1- (3-chlorophenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylic acid Synthesis of tert-butyl:

The title compound (hereinafter, the compound of Reference Example 112) (0.0550 g, 0.103 mmol, 83) was prepared by using the compound of Reference Example 111 instead of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.69 (m, 5 H), 1.45 (s, 9 H), 2.20-2.39 (m, 3 H), 2.81 -2.87 (m, 1 H), 3.41-3.59 (m, 3 H), 3.64 (dd, J = 11.0, 4.9 Hz, 1 H), 4.06 (brs, 1 H) , 4.84-4.85 (m, 1 H), 5.01-5. 03 (m, 1 H), 6.44 (dd, J = 8.3, 2.0 Hz, 1 H), 6.53- 6.54 (m, 1 H), 6.64-6. 67 (m, 1 H), 6. 90 (d, J = 8.8 Hz, 1 H), 711-7. 15 (m, 1 H), 7.34 (dd, J = 8.8, 2.7 Hz, 1 H), 7.60 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 535 (M + H) ⁺ .

Example 91 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (3-chlorophenyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2-carboxamide Composition of:

Using the compound of Reference Example 112 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 91 below) (0.0400 g, 0.0840 mmol, 81) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1 to 1.58 (m, 2H), 1.70 to 1.78 (m, 2H), 1.90 to 1.97 (m, 1H) , 2.21 (s, 3 H), 2.22-2.29 (m, 2 H), 2.33-2.38 (m, 1 H), 3.13-3. 20 (m, 1 H), 3 41-3.46 (m, 1 H), 3.47-3. 50 (m, 1 H), 3.52-3. 58 (m, 1 H), 3.63 (dd, J = 10.9, 4.8 Hz, 1 H), 3.75-3. 78 (m, 1 H), 5.01-5. 03 (m, 1 H), 5.24-5. 26 (m, 1 H), 6.42- 6.45 (m, 1 H), 6.53-6.54 (m, 1 H), 6.64-6. 67 (m, 1 H), 6.88 (d, J = 8.8 Hz, 1 H), 7.11-7.14 (m, 1H) 7.35 (dd, J = 8.8,2.6Hz, 1H), 7.60 (d, J = 2.6Hz, 1H), 8.36 (s, 1H).
ESI-MS: m / z = 477 (M + H) ⁺ .

Reference Example 113 Synthesis of (S) -3-chloro-4-((1- (4-chlorophenyl) pyrrolidin-3-yl) oxy) aniline:

Using 1-chloro-4-iodobenzene instead of 1-fluoro-2-iodobenzene, and using the same procedure as in Reference Example 103 except for this, the title compound (hereinafter, the compound of Reference Example 113) (2.00 g, 6.19 mmol, 43%) were obtained as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15-2.24 (m, 1 H), 2.22-2.37 (m, 1 H), 3.37-3. 58 (m, 6 H) , 4.89-4.92 (m, 1 H), 6.48 (d, J = 9.0 Hz, 2 H), 6.53 (dd, J = 8.5, 2.8 Hz, 1 H), 6. 72 (d, J = 2.8 Hz, 1 H), 6.79 (d, J = 8.5 Hz, 1 H), 7.16 (d, J = 9.0 Hz, 2 H).
ESI-MS: m / z = 323 (M + H) ⁺ .

(Reference Example 114) (R) -2-((3-chloro-4-(((S) -1- (4-chlorophenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylic acid Synthesis of tert-butyl:

Using the compound of Reference Example 113 instead of the compound of Reference Example 99, and using the same procedure as Reference Example 100 except the above, the title compound (the compound of Reference Example 114) (3.25 g, 6.08 mmol, 98) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.67 (m, 5 H), 1.52 (s, 9 H), 2.21-2. 38 (m, 3 H), 2.83 -2.89 (m, 1 H), 3.39-3. 56 (m, 3 H), 3.63 (dd, J = 10.7, 4.9 Hz, 1 H), 4.06 (brs, 1 H) , 4.84-4.86 (m, 1 H), 5.00-5.03 (m, 1 H), 6.48 (d, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 1 H), 7.17 (d, J = 8.8 Hz, 2 H), 7.31 (dd, J = 8.8, 2.2 Hz, 1 H), 7.60 (d, J = 2) .2 Hz, 1 H), 8. 25 (brs, 1 H).
ESI-MS: m / z = 534 (M + H) ^<+> .

Example 92 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (4-chlorophenyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2-carboxamide Composition of:

The title compound (hereinafter, the compound of Example 92) (2.40 g, 5.04 mmol, 83) was prepared by using the compound of Reference Example 114 in place of the compound of Reference Example 104 and using the same procedure as Example 87 except the above. %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.62 (m, 2 H), 1.70-1. 78 (m, 2 H), 1.85-1. 95 (m, 1 H) , 2.18 (s, 3 H), 2.21-2. 37 (m, 3 H), 3. 19-3. 26 (m, 1 H), 3. 38-3. 56 (m, 3 H), 3 .63 (dd, J = 10.7, 4.9 Hz, 1 H), 3.74-3.78 (m, 1 H), 4.99-5.02 (m, 1 H), 5.25 (d, J = 4.9 Hz, 1 H), 6.47 (d, J = 9.0 Hz, 2 H), 6.86 (d, J = 8.8 Hz, 1 H), 7.16 (d, J = 9.0 Hz) , 2H), 7.32 (dd, J = 8.8, 2.5 Hz, 1 H), 7.61 (d, J = 2.5 Hz, 1 H), 8.48 (s, 1 H).
ESI-MS: m / z = 476 (M + H) ^<+> .

Reference Example 115 Synthesis of (S) -3-chloro-4-((1- (3-methoxyphenyl) pyrrolidin-3-yl) oxy) aniline

The title compound (hereinafter, the compound of Reference Example 115) (0.0570 g) was prepared according to the same procedure as in Reference Example 103 except that 1-iodo-3-methoxybenzene was used instead of 1-fluoro-2-iodobenzene. , 0.179 mmol, 43%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15-2.24 (m, 1 H), 2.31-2. 36 (m, 1 H), 3.39-3. 45 (m, 1 H) , 3.49-3.61 (m, 5H), 3.80 (s, 3H), 4.89-4.91 (m, 1H), 6.12-6.13 (m, 1H), 6 .20-6.22 (m, 1 H), 6.26-6. 29 (m, 1 H), 6.52 (dd, J = 8.6, 2.7 Hz, 1 H), 6.73 (d, J = 2.7 Hz, 1 H), 6.79 (d, J = 8.6 Hz, 1 H), 7.12-7.16 (m, 1 H).
ESI-MS: m / z = 319 (M + H) ⁺ .

(Reference Example 116) (R) -2-((3-chloro-4-(((S) -1- (3-methoxyphenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carvone Synthesis of acid tert-butyl:

The title compound (hereinafter, the compound of Reference Example 116) (0.0500 g, 0.151 mmol, 96) was prepared by using the compound of Reference Example 115 instead of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.40 to 1.52 (m, 2 H), 1.52 (s, 9 H), 1.53-1.69 (m, 3 H), 2.21 -2.37 (m, 3H), 2.81-2.87 (m, 1H), 3.44 (ddd, J = 8.6, 8.6, 3.2 Hz, 1 H), 3.48- 3.51 (m, 1 H), 3.52-3. 58 (m, 1 H), 3.67 (dd, J = 10.9, 5.0 Hz, 1 H), 3.80 (s, 3 H), 4.06 (brs, 1 H), 4.84-4. 85 (m, 1 H), 5.00-5.03 (m, 1 H), 6.12-6. 13 (m, 1 H), 6. 21 (dd, J = 8.0, 2.0 Hz, 1 H), 6. 28 (dd, J = 7.9, 2.3 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 1 H) , 7.12-7.16 ( , 1H), 7.33 (dd, J = 8.8,2.4Hz, 1H), 7.59 (d, J = 2.4Hz, 1H).
ESI-MS: m / z = 531 (M + H) ⁺ .

Example 93 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (3-methoxyphenyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2- Carboxamide Synthesis:

Using the compound of Reference Example 116 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 93 below) (0.0460 g, 0.0975 mmol, 65) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.63 (m, 2 H), 1.71 to 1. 78 (m, 2 H), 1.87 to 1.99 (m, 1 H) , 2.20 (s, 3 H), 2.23-2.36 (m, 3 H), 3.15-3. 23 (m, 1 H), 3.41-3. 47 (m, 1 H), 3 47-3.50 (m, 1 H), 3.52-3. 58 (m, 1 H), 3.66 (dd, J = 10.9, 5.0 Hz, 1 H), 3.74-3. 78 (m, 1 H), 3. 80 (s, 3 H), 4.99-5.0 2 (m, 1 H), 5.24-5. 26 (m, 1 H), 6.1 1-6. 13 ( m, 1 H), 6. 20 (dd, J = 8.2, 1.8 Hz, 1 H), 6. 28 (dd, J = 8.2, 2.3 Hz, 1 H), 6.87 (d, J = 9.1 Hz, 1 H), 7.14 dd, J = 8.2, 8.2 Hz, 1 H, 7.33 (dd, J = 9.1, 2.3 Hz, 1 H), 7.59 (d, J = 2.3 Hz, 1 H), 8 .40 (s, 1 H).
ESI-MS: m / z = 472 (M + H) ⁺ .

Reference Example 117 Synthesis of (S) -3-chloro-4-((1- (4-methoxyphenyl) pyrrolidin-3-yl) oxy) aniline:

The title compound (hereinafter, the compound of Reference Example 117) (0.0570 g) was prepared according to the same procedure as in Reference Example 103 except that 1-iodo-4-methoxybenzene was used instead of 1-fluoro-2-iodobenzene. , 0.179 mmol, 43%) as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.19-2.27 (m, 1 H), 2.29-2.34 (m, 1 H), 3.34-3. 39 (m, 1 H) , 3.43-3.54 (m, 4 H), 3.59 (dd, J = 10.5, 5.1 Hz, 1 H), 3.76 (s, 3 H), 4.89-4. m, 1 H), 6.51-6.56 (m, 3 H), 6.73 (d, J = 2.7 Hz, 1 H), 6.79 (d, J = 8.8 Hz, 1 H), 6. 85 (d, J = 9.0 Hz, 2 H).
ESI-MS: m / z = 319 (M + H) ⁺ .

(Reference Example 118) (R) -2-((3-chloro-4-(((S) -1- (4-methoxyphenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carvone Synthesis of acid tert-butyl:

The title compound (hereinafter, the compound of Reference Example 118) (0.0800 g, 0.151 mmol, 96) was prepared by using the compound of Reference Example 117 instead of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.51 (m, 2H), 1.51 (s, 9H), 1.54-1.69 (m, 3H), 2.26 -2.32 (m, 3 H), 2.81-2. 88 (m, 1 H), 3.36-3. 41 (m, 1 H), 3.42-3. 45 (m, 1 H), 3 .47-3.53 (m, 1 H), 3.67 (dd, J = 10.6, 5.2 Hz, 1 H), 3.76 (s, 3 H), 4.05 (brs, 1 H), 4 .84-4.85 (m, 1H), 5.00-5.01 (m, 1H), 6.55 (d, J = 9.0 Hz, 2H), 6.85 (d, J = 9. 0 Hz, 2 H), 6.88 (d, J = 9.0 Hz, 1 H), 7.32 (dd, J = 9.0, 2.4 Hz, 1 H), 7.59 (d, J = 2.4 Hz) , 1 H).
ESI-MS: m / z = 531 (M + H) ⁺ .

Example 94 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (4-methoxyphenyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2- Carboxamide Synthesis:

Using the compound of Reference Example 118 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 94) (0.0530 g, 0.112 mmol, 74) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.61 (m, 2 H), 1.71 to 1.77 (m, 2 H), 1.89 to 1. 95 (m, 1 H) , 2.20 (s, 3 H), 2.25-2. 32 (m, 3 H), 3.14-3. 22 (m, 1 H), 3. 36-3. 41 (m, 1 H), 3 .42-3.45 (m, 1 H), 3.46-3.53 (m, 1 H), 3.66 (dd, J = 10.6, 5.2 Hz, 1 H), 3.74-3. 78 (m, 1 H), 3.76 (s, 3 H), 4.99-5.01 (m, 1 H), 5.24-5. 26 (m, 1 H), 6.55 (d, J = 9.0 Hz, 2 H), 6.84-6.88 (m, 3 H), 7.33 (dd, J = 8.9, 2.7 Hz, 1 H), 7.59 (d, J = 2.7 Hz) , 1H), 8.37 (s, 1 H) .
ESI-MS: m / z = 472 (M + H) ⁺ .

Reference Example 119 Synthesis of (S) -3-chloro-4-((1- (o-tolyl) pyrrolidin-3-yl) oxy) aniline:

The title compound (hereinafter, the compound of Reference Example 119) (0.150 g) was prepared by the same procedure as in Reference Example 103 using 1-bromo-2-methylbenzene instead of 1-fluoro-2-iodobenzene , 0.495 mmol, 69%) were obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.19-2.30 (m, 2H), 2.33 (s, 3H), 3.21 (ddd, J = 9.2, 7.2, 4.8 Hz, 1 H), 3.33 (dd, J = 10.8, 2.8 Hz, 1 H), 3.47-3. 53 (m, 3 H), 3.59 (dd, J = 10.8) , 5.6 Hz, 1 H), 4.84-4.89 (m, 1 H), 6.52 (dd, J = 8.8, 2.8 Hz, 1 H), 6.74 (d, J = 2. 8 Hz, 1 H), 6.78 (d, J = 8.8 Hz, 1 H), 6.87 (ddd, J = 7.2, 7.2, 0.8 Hz, 1 H), 6.94 (dd, J = 8.8, 0.8 Hz, 1 H), 7.1 1-7. 15 (m, 2 H).
ESI-MS: m / z = 303 (M + H) ⁺ .

(Reference Example 120) (R) -2-((3-Chloro-4-(((S) -1- (o-tolyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylic acid Synthesis of tert-butyl:

The title compound (hereinafter, the compound of Reference Example 120) (0.212 g, 0.412 mmol, 83) was prepared by using the compound of Reference Example 119 instead of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.73 (m, 14 H), 2.20-2.25 (m, 1 H), 2.28-2.35 (m, 5 H) , 2.78-2.86 (m, 1 H), 3.23 (ddd, J = 8.8, 7.6, 4.4 Hz, 1 H), 3.34 (dd, J = 10.8, 2 4. 8 (Hz, 1 H), 3.47 (ddd, J = 9.6, 8.0, 8.0 Hz, 1 H), 3.63 (dd, J = 10.8, 5.6 Hz, 1 H); 04-4.10 (m, 1 H), 4.83-4. 85 (m, 1 H), 4.94-4.99 (m, 1 H), 6.86-6. 91 (m, 2 H), 6.95 (dd, J = 8.8, 1.6 Hz, 1 H), 7.12-7.15 (m, 2 H), 7.33 (dd, J = 9.2, 2.8 Hz, 1 H) , 7.60 (d, J = .8Hz, 1H), 8.10 (brs, 1H).
ESI-MS: m / z = 514 (M + H) ⁺ .

Example 95 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (o-tolyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2-carboxamide Composition of:

Using the compound of Reference Example 120 instead of the compound of Reference Example 104, and according to the same procedure as Example 87 except the above, the title compound (the compound of Example 95 below) (0.185 g, 0.406 mmol, 98) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.51-1.62 (m, 2 H), 1.70-1. 79 (m, 2 H), 1.89-1. 98 (m, 1 H) , 2.18-2.33 (m, 9H), 3.15 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3.22 (ddd, J = 8.4, 7 .2, 4.4 Hz, 1 H), 3.33 (dd, J = 10.8, 2.8 Hz, 1 H), 3.47 (ddd, J = 8.8, 7.6, 7.6 Hz, 1 H ), 3.62 (dd, J = 10.8, 6.0 Hz, 1 H), 3.73-3.79 (m, 1 H), 4.94-4. 98 (m, 1 H), 5.24 -5.26 (m, 1 H), 6.84-6. 90 (m, 2 H), 6.94 (dd, J = 8.8, 1.2 Hz, 1 H), 7.12-7.15 ( m, 2H), 7.3 (Dd, J = 8.8,2.8Hz, 1H), 7.60 (d, J = 2.8Hz, 1H), 8.29 (brs, 1H).
ESI-MS: m / z = 456 (M + H) ⁺ .

Reference Example 121 Synthesis of (S) -3-chloro-4-((1- (m-tolyl) pyrrolidin-3-yl) oxy) aniline:

The title compound (hereinafter, the compound of Reference Example 121) (0.100 g) was prepared according to the same procedure as in Reference Example 103 except for using 1-bromo-3-methylbenzene instead of 1-fluoro-2-iodobenzene , 0.330 mmol, 46%) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.20 (ddd, J = 13.6, 8.8, 5.2 Hz, 1 H), 2.30-2.36 (m, 4 H); 42 (ddd, J = 8.8, 8.8, 3.2 Hz, 1 H), 3.48-3.52 (m, 3 H), 3.56 (dd, J = 9.2, 2.0 Hz, 1 H), 3.60 (dd, J = 11.2, 5.2 Hz, 1 H), 4.89-4.93 (m, 1 H), 6.40-6.41 (m, 2 H), 6. 51-6.55 (m, 2 H), 6.73 (d, J = 2.8 Hz, 1 H), 6. 80 (d, J = 8.8 Hz, 1 H), 7. 13 (dd, J = 8) .8, 8.0 Hz, 1 H).
ESI-MS: m / z = 303 (M + H) ⁺ .

(Reference Example 122) (R) -2-((3-Chloro-4-(((S) -1- (m-tolyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylic acid Synthesis of tert-butyl:

The title compound (hereinafter, the compound of Reference Example 122) (0.151 g, 0.294 mmol, 89) was prepared by using the compound of Reference Example 121 instead of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35-1.69 (m, 14 H), 2.23-2.38 (m, 6 H), 2.82 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3.42-3. 58 (m, 3 H), 3. 68 (dd, J = 10.8, 5.2 Hz, 1 H), 4.04-4.08 (M, 1 H), 4.84-4. 86 (m, 1 H), 5.01-5. 04 (m, 1 H), 6.40-6.41 (m, 2 H), 6.53 (d , J = 7.7 Hz, 1 H), 6.90 (d, J = 8.8 Hz, 1 H), 7.13 (dd, J = 8.6, 7.7 Hz, 1 H), 7.36 (dd, J J = 8.8, 2.8 Hz, 1 H), 7.58 (d, J = 2.8 Hz, 1 H), 8. 16 (brs, 1 H).
ESI-MS: m / z = 514 (M + H) ⁺ .

Example 96 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (m-tolyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2-carboxamide Composition of:

Using the compound of Reference Example 122 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 96) (0.119 g, 0.261 mmol, 89 %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.51-1.57 (m, 2 H), 1. 70-1. 79 (m, 2 H), 1. 90-1. 98 (m, 1 H) , 2.21 (s, 3 H), 2.23-2.37 (m, 6 H), 3. 16 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3.42- 3.58 (m, 3H), 3.65-3.70 (m, 1 H), 3.74-3. 79 (m, 1 H), 5.00-5.04 (m, 1 H), 5. 25 (brd, J = 4.8 Hz, 1 H), 6.40-6.41 (m, 2 H), 6.53 (dd, J = 7.6, 0.8 Hz, 1 H), 6.89 (d , J = 8.8 Hz, 1 H), 7.13 (dd, J = 8.8, 7.6 Hz, 1 H), 7.35 (dd, J = 8.8, 2.8 Hz, 1 H), 7. 59 (d, J = 2.8 z, 1H), 8.31 (brs, 1H).
ESI-MS: m / z = 456 (M + H) ⁺ .

Reference Example 123 Synthesis of (S) -3-chloro-4-((1- (p-tolyl) pyrrolidin-3-yl) oxy) aniline:

The title compound (hereinafter, the compound of Reference Example 123) (0.160 g) was prepared by the same procedure as in Reference Example 103 using 1-bromo-4-methylbenzene instead of 1-fluoro-2-iodobenzene , 0.528 mmol, 74%) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.16-2.24 (m, 1 H), 2.25 (s, 3 H), 2.29-2.35 (m, 1 H), 3.39 (Ddd, J = 8.8, 8.8, 3.6 Hz, 1 H), 3.46-3.56 (m, 4 H), 3.59 (dd, J = 10.4, 5.2 Hz, 1 H ), 4.89-4.93 (m, 1 H), 6.49-6. 54 (m, 3 H), 6.73 (d, J = 2.8 Hz, 1 H), 6. 80 (d, J) = 8.8 Hz, 1 H), 7.04 (d, J = 8.0 Hz, 2 H).
ESI-MS: m / z = 303 (M + H) ⁺ .

(Reference Example 124) (R) -2-((3-Chloro-4-(((S) -1- (p-tolyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carboxylic acid Synthesis of tert-butyl:

The title compound (hereinafter, the compound of Reference Example 124) (0.129 g, 0.251 mmol, 48) was prepared by using the compound of Reference Example 123 instead of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.71 (m, 14 H), 2.25-2.37 (m, 6 H), 2.78-2.86 (m, 1 H) , 3.42 (ddd, J = 8.8, 8.8, 3.6 Hz, 1 H), 3.47 (brd, J = 11.8 Hz, 1 H), 3.52 (ddd, J = 8.8 , 8.8, 7.2 Hz, 1 H), 3.67 (dd, J = 10.8, 5.2 Hz, 1 H), 4.04-4.09 (m, 1 H), 4.84-4. 85 (m, 1 H), 5.00-5.0 4 (m, 1 H), 6.51 (d, J = 8.4 Hz, 2 H), 6. 90 (d, J = 8.8 Hz, 1 H), 7.05 (d, J = 8.4 Hz, 2 H), 7. 35 (dd, J = 8.8, 2.4 Hz, 1 H), 7.58 (d, J = 2.4 Hz, 1 H), 8 .12 (brs 1H).
ESI-MS: m / z = 514 (M + H) ⁺ .

Example 97 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (p-tolyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2-carboxamide Composition of:

Using the compound of Reference Example 124 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 97 below) (0.107 g, 0.235 mmol, 93) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.60 (m, 2 H), 1.71-1. 78 (m, 2 H), 1.89-1. 97 (m, 1 H) , 2.21 (s, 3 H), 2.25-2.37 (m, 6 H), 3.18 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3.39- 3.55 (m, 3 H), 3.67 (dd, J = 10.8, 5.2 Hz, 1 H), 3.76 (brd, J = 13.2 Hz, 1 H), 4.99-5.03 (M, 1 H), 5.25 (brd, J = 5.2 Hz, 1 H), 6.51 (d, J = 8.8 Hz, 2 H), 6.88 (d, J = 8.8 Hz, 1 H) , 7.05 (d, J = 8.8 Hz, 2 H), 7.34 (dd, J = 8.8, 2.4 Hz, 1 H), 7.59 (d, J = 2.4 Hz, 1 H), 8.31 brs, 1H).
ESI-MS: m / z = 456 (M + H) ⁺ .

Reference Example 125 Synthesis of (S) -3-chloro-4-((1- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) oxy) aniline:

Title compound (hereinafter, the compound of Reference Example 125) in the same manner as in Reference Example 103 except for using 1-iodo-2- (trifluoromethyl) benzene instead of 1-fluoro-2-iodobenzene (0.079 g, 0.223 mmol, 31%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.13-2.21 (m, 1 H), 2.24-2.30 (m, 1 H), 3.35 (ddd, J = 8.8, 8.8, 3.6 Hz, 1 H), 3.42 (brd, J = 10.8 Hz, 1 H), 3.51 (brs, 2 H), 3.67 (ddd, J = 9.6, 9.6) , 6.8 Hz, 1 H), 3.76 (dd, J = 11.6, 5.2 Hz, 1 H), 4.85-4.89 (m, 1 H), 6.52 (dd, J = 8. 8, 2.8 Hz, 1 H), 6.73 (d, J = 2.8 Hz, 1 H), 6.78 (d, J = 8.8 Hz, 1 H), 6.93 (dd, J = 8.0) , 8.0 Hz, 1 H), 7.12 (d, J = 8.0 Hz, 1 H), 7.41 (ddd, J = 8.0, 8.0, 2.0 Hz, 1 H), 7.58 (d dd, J = .0,1.6Hz, 1H).
ESI-MS: m / z = 357 (M + H) ⁺ .

(Reference Example 126) (R) -2-((3-chloro-4-(((S) -1- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl:

The title compound (hereinafter, the compound of Reference Example 126) (0.124 g, 0.218 mmol, 97) was prepared by using the compound of Reference Example 125 instead of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.69 (m, 14 H), 2.22-2.34 (m, 3 H), 2.82 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3. 36 (ddd, J = 9.6, 6.8, 3.6 Hz, 1 H), 3.41 (brd, J = 11.2 Hz, 1 H), 3 60-3.66 (m, 1 H), 3.82 (dd, J = 10.8, 5.2 Hz, 1 H), 4.03-4.08 (m, 1 H), 4.83-4. 85 (m, 1 H), 4.96-5.00 (m, 1 H), 6.88 (d, J = 9.2 Hz, 1 H), 6.96 (dd, J = 8.0, 7.2 Hz , 1H), 7.15 (d, J = 8.4 Hz, 1 H), 7.31 (dd, J = 9.2, 2.8 Hz, 1 H), 7.40-7.44 (m, 1 H) , 7.59 dd, J = 8.0,1.6Hz, 1H), 7.62 (d, J = 2.8Hz, 1H), 8.14 (brs, 1H).
ESI-MS: m / z = 568 (M + H) ⁺ .

Example 98 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (2- (trifluoromethyl) phenyl) pyrrolidin-3-yl) oxy) phenyl) Synthesis of piperidine-2-carboxamide:

Using the compound of Reference Example 126 instead of the compound of Reference Example 104, and according to the same procedure as Example 87 except the above, the title compound (the compound of Example 98) (0.0990 g, 0.194 mmol, 89) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.57 (m, 2 H), 1. 70-1. 78 (m, 2 H), 1. 90-1. 98 (m, 1 H) , 2.18-2.29 (m, 6H), 3.11-3.18 (m, 1H), 3.33-3.42 (m, 2H), 3.60-3.66 (m, 1H), 3.73-3.83 (m, 2H), 4.96-4.99 (m, 1H), 5.23-5.26 (m, 1H), 6.87 (d, J = 9.2 Hz, 1 H), 6.96 (dd, J = 8.0, 7.6 Hz, 1 H), 7.15 (d, J = 8.0 Hz, 1 H), 7.32 (dd, J = 9 .2, 2.8 Hz, 1 H), 7.40-7.44 (m, 1 H), 7.58 (dd, J = 8.0, 1.6 Hz, 1 H), 7.61 (d, J = 2.8 Hz, 1 H), 8.30 ( rs, 1H).
ESI-MS: m / z = 510 (M + H) ⁺ .

Reference Example 127 Synthesis of (S) -3-chloro-4-((1- (3- (trifluoromethyl) phenyl) pyrrolidin-3-yl) oxy) aniline

Title compound (hereinafter, the compound of Reference Example 127) in the same manner as in Reference Example 103 except for using 1-iodo-3- (trifluoromethyl) benzene instead of 1-fluoro-2-iodobenzene (0.154 g, 0.432 mmol, 60%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.16-2.25 (m, 1 H), 2.35-2.42 (m, 1 H), 3.46 (ddd, J = 8.4, 8.4, 3.2 Hz, 1 H), 3.52-3. 56 (m, 3 H), 3.58-3. 65 (m, 2 H), 4.92-4. 95 (m, 1 H), 6.54 (dd, J = 8.8, 2.8 Hz, 1 H), 6. 70 (J = 8.0, 2.4 Hz, 1 H), 6.73-6.75 (m, 2 H), 6 81 (d, J = 8.8 Hz, 1 H), 6.91 (d, J = 8.0 Hz, 1 H), 7.30 (dd, J = 8.0, 8.0 Hz, 1 H).
ESI-MS: m / z = 357 (M + H) ⁺ .

(Reference Example 128) (R) -2-((3-chloro-4-(((S) -1- (3- (trifluoromethyl) phenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl:

The title compound (hereinafter, the compound of Reference Example 128) (0.230 g, 0.405 mmol, 94) was prepared by using the compound of Reference Example 127 instead of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44-1.71 (m, 14 H), 2.23-2.42 (m, 3 H), 2.82 (ddd, J = 13.2, 13.2, 2.4 Hz, 1 H), 3. 49 (ddd, J = 8.8, 8.8, 2.8 Hz, 1 H), 3.54 (brd, J = 10.8 Hz, 1 H), 3 .61 (ddd, J = 9.2, 9.2, 6.8 Hz, 1 H), 3.69 (dd, J = 10.8, 4.8 Hz, 1 H), 4.03-4.09 (m , 1H), 4.84-4.85 (m, 1H), 5.04-5.07 (m, 1H), 6.71 (dd, J = 8.8, 2.4 Hz, 1H), 6 .75 (brs, 1 H), 6.91-6.93 (m, 2 H), 7.31 (dd, J = 8.4, 7.6 Hz, 1 H) 7.37 (dd, J = 8.8 , 2.8 z, 1H), 7.60 (d, J = 2.8Hz, 1H), 8.16 (brs, 1H).
ESI-MS: m / z = 568 (M + H) ⁺ .

Example 99 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (3- (trifluoromethyl) phenyl) pyrrolidin-3-yl) oxy) phenyl) Synthesis of piperidine-2-carboxamide:

Using the compound of Reference Example 128 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (compound of Example 99 below) (0.0920 g, 0.180 mmol, 89) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.61 (m, 2 H), 1.71-1. 79 (m, 2 H), 1.90-2.02 (m, 1 H) , 2.21 (s, 3H), 2.23-2.31 (m, 2H), 2.36-2.42 (m, 1H), 3.15 (ddd, J = 13.2, 13.3. 2, 2.8 Hz, 1 H), 3. 49 (ddd, J = 8.8, 8.8, 2.8 Hz, 1 H), 3.53 (brd, J = 10.8 Hz, 1 H), 3.60 (Ddd, J = 9.2, 9.2, 6.8 Hz, 1 H), 3.68 (dd, J = 10.8, 5.2 Hz, 1 H), 3.74-3. 79 (m, 1 H) ), 5.03-5.07 (m, 1 H), 5.25 (brd, J = 5.2 Hz, 1 H), 6. 70 (dd, J = 8.8, 2.8 Hz, 1 H), 6 .74 (b s, 1 H), 6.89-6. 93 (m, 2 H), 7. 29-7. 33 (m, 1 H), 7. 36 (dd, J = 8.8, 2.8 Hz, 1 H), 7.60 (d, J = 2.8 Hz, 1 H), 8.34 (brs, 1 H).
ESI-MS: m / z = 532 (M + Na) ⁺ .

Reference Example 129 Synthesis of (S) -3-chloro-4-((1- (4- (trifluoromethyl) phenyl) pyrrolidin-3-yl) oxy) aniline:

Title compound (following, compound of Reference Example 129) in the same manner as in Reference Example 103 except for using 1-iodo-4- (trifluoromethyl) benzene instead of 1-fluoro-2-iodobenzene (0.0300 g, 0.0841 mmol, 20%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15 to 2.24 (m, 1 H), 2.36 to 2.41 (m, 1 H), 3.45 to 3.66 (m, 6 H) , 4.91-4.95 (m, 1 H), 6.53 (dd, J = 8.5, 2.9 Hz, 1 H), 6.57 (d, J = 8.8 Hz, 2 H), 6. 73 (d, J = 2.9 Hz, 1 H), 6.80 (d, J = 8.5 Hz, 1 H), 7. 45 (d, J = 8.8 Hz, 2 H).
ESI-MS: m / z = 357 (M + H) ⁺ .

(Reference Example 130) (R) -2-((3-chloro-4-(((S) -1- (4- (trifluoromethyl) phenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl:

The title compound (hereinafter, the compound of Reference Example 130) (0.0300 g, 0.0528 mmol, 63) was prepared by using the compound of Reference Example 129 instead of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.69 (m, 5 H), 1.51 (s, 9 H), 2.21-2. 42 (m, 3 H), 2.81 -2.88 (m, 1 H), 3.47-3.69 (m, 4 H), 4.06 (brs, 1 H), 4.85-4. 85 (m, 1 H), 5.03-5 .06 (m, 1 H), 6.57 (d, J = 8.8 Hz, 2 H), 6. 90 (d, J = 9.0 Hz, 1 H), 7. 34 (dd, J = 9.0, 2.4 Hz, 1 H), 7. 45 (d, J = 8.8 Hz, 2 H), 7.60 (d, J = 2.4 Hz, 1 H).
ESI-MS: m / z = 568 (M + H) ⁺ .

Example 100 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (4- (trifluoromethyl) phenyl) pyrrolidin-3-yl) oxy) phenyl) Synthesis of piperidine-2-carboxamide:

Using the compound of Reference Example 130 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 100) (0.0250 g, 0.0490 mmol, 92) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.61 (m, 2 H), 1.71-1. 78 (m, 2 H), 1.89- 1. 96 (m, 1 H) , 2.21 (s, 3 H), 2.23-2.30 (m, 2 H), 2. 36-2.41 (m, 1 H), 3. 13-3. 20 (m, 1 H), 3 .47-3.52 (m, 1 H), 3.53-3.56 (m, 1 H), 3.58-3.69 (m, 2 H), 3.75-3. 78 (m, 1 H) , 5.03-5.05 (m, 1 H), 5.24-5.25 (m, 1 H), 6.57 (d, J = 8.8 Hz, 2 H), 6.89 (d, J = 8.8 Hz, 1 H), 7. 35 (dd, J = 8.8, 2.4 Hz, 1 H), 7. 45 (d, J = 8.8 Hz, 2 H), 7.60 (d, J = 2) .4 Hz, 1 H), 8.39 (s, H).
ESI-MS: m / z = 510 (M + H) ⁺ .

Reference Example 131 Synthesis of (S) -3-chloro-4-((1- (2- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) oxy) aniline

Title compound (hereinafter, the compound of Reference Example 131) in the same manner as in Reference Example 103 except for using 1-iodo-2- (trifluoromethoxy) benzene instead of 1-fluoro-2-iodobenzene (0.0814 g, 0.218 mmol, 4.6%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.09-2.18 (m, 1 H), 2.26-2.32 (m, 1 H), 3.42-3. 54 (m, 4 H) , 3.69 (ddd, J = 9.2, 9.2, 6.8 Hz, 1 H), 3.82 (dd, J = 10.8, 4.8 Hz, 1 H), 4.85-4.88 (M, 1 H), 6.52 (dd, J = 8.8, 2.8 Hz, 1 H), 6.71-6.75 (m, 2 H), 6.77-6.80 (m, 2 H) , 7.13-7.17 (m, 2H).
ESI-MS: m / z = 373 (M + H) ⁺ .

(Reference Example 132) (R) -2-((3-chloro-4-(((S) -1- (2- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl:

The title compound (hereinafter, the compound of Reference Example 132) (0.125 g, 0.214 mmol, 98) was prepared by using the compound of Reference Example 131 in place of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.72 (m, 14 H), 2.15-2.24 (m, 1 H), 2.27-2.34 (m, 2 H) , 2.78-2.85 (m, 1H), 3.46 (ddd, J = 8.4, 8.4, 2.8 Hz, 1 H), 3.52 (brd, J = 11.2 Hz, 1 H ), 3.67 (ddd, J = 9.2, 9.2, 6.4 Hz, 1 H), 3.89 (dd, J = 11.2, 4.8 Hz, 1 H), 4.03-4. 08 (m, 1 H), 4.83-4. 85 (m, 1 H), 4.96-5.00 (m, 1 H), 6.73-6.80 (m, 2 H), 6. 90 ( d, J = 8.8 Hz, 1 H), 7.14-7. 17 (m, 2 H), 7.33 (dd, J = 8.8, 2.8 Hz, 1 H), 7.60 (d, J = 2.8 Hz, 1 H , 8.14 (brs, 1H).
ESI-MS: m / z = 584 (M + H) ⁺ .

Example 101 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (2- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) oxy) phenyl) Synthesis of piperidine-2-carboxamide:

Using the compound of Reference Example 132 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except for the above, the title compound (the compound of Example 101 below) (0.101 g, 0.192 mmol, 88) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.60 (m, 2 H), 1.71-1. 77 (m, 2 H), 1.89-1.99 (m, 1 H) , 2, 15-2, 31 (m, 6 H), 3. 15 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3.46 (ddd, J = 8.8, 8 .8, 2.8 Hz, 1 H), 3.51 (brd, J = 11.2 Hz, 1 H), 3.66 (ddd, J = 9.6, 9.6, 6.4 Hz, 1 H); 73-3.79 (m, 1 H), 3.89 (dd, J = 11.2, 5.2 Hz, 1 H), 4.96-4.99 (m, 1 H), 5.24-5.25 (M, 1 H), 6.75 (dd, J = 8.4, 7.2 Hz, 1 H), 6.79 (d, J = 8.4 Hz, 1 H), 6.88 (d, J = 8). 8 Hz, 1 H), .13-7.17 (m, 2H), 7.33 (dd, J = 8.8, 2.4 Hz, 1 H), 7.59 (d, J = 2.4 Hz, 1 H), 8.31 (d brs, 1 H).
ESI-MS: m / z = 526 (M + H) ⁺ .

Reference Example 133 Synthesis of (S) -3-chloro-4-((1- (3- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) oxy) aniline:

Title compound (hereinafter, the compound of Reference Example 133) in the same manner as in Reference Example 103 except for using 1-iodo-3- (trifluoromethoxy) benzene instead of 1-fluoro-2-iodobenzene (0.108 g, 0.290 mmol, 40%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15-2.24 (m, 1 H), 2.33-2.40 (m, 1 H), 3.43 (ddd, J = 9.2, 9.2, 3.2 Hz, 1 H), 3.49-3. 61 (m, 5 H), 4.95-4. 94 (m, 1 H), 6. 37 (brs, 1 H), 6. 47 ( dd, J = 8.0, 2.4 Hz, 1 H), 6.52-6. 55 (m, 2 H), 6.73 (d, J = 2.8 Hz, 1 H), 6. 80 (d, J = 8.8 Hz, 1 H), 7. 20 (dd, J = 8.0, 8.0 Hz, 1 H).
ESI-MS: m / z = 373 (M + H) ⁺ .

(Reference Example 134) (R) -2-((3-chloro-4-(((S) -1- (3- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl:

The title compound (hereinafter, the compound of Reference Example 134) (0.166 g, 0.284 mmol, 98) was prepared by using the compound of Reference Example 133 in place of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.72 (m, 14 H), 2.21-2. 40 (m, 3 H), 2.78-2.86 (m, 1 H) , 3.45 (ddd, J = 8.8, 8.8, 2.8 Hz, 1 H), 3.51 (brd, J = 10.8 Hz, 1 H), 3.57 (ddd, J = 9.2) , 9.2, 6.8 Hz, 1 H), 3.66 (dd, J = 10.8, 4.8 Hz, 1 H), 4.03-4.10 (m, 1 H), 4.84-4. 86 (m, 1 H), 5.02-5.05 (m, 1 H), 6.37 (brs, 1 H), 6.47 (dd, J = 8.4, 2.4 Hz, 1 H), 6. 54 (brd, J = 8.4 Hz, 1 H), 6. 91 (d, J = 9.2 Hz, 1 H), 7. 20 (dd, J = 8.4, 8.4 Hz, 1 H), 7.36 (Dd J = 9.2,2.8Hz, 1H), 7.60 (d, J = 2.8Hz, 1H), 8.15 (brs, 1H).
ESI-MS: m / z = 606 (M + Na) ⁺ .

(Example 102) (R) -1-acetyl-N- (3-chloro-4-(((S) -1- (3- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) oxy) phenyl) Synthesis of piperidine-2-carboxamide:

Using the compound of Reference Example 134 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 102 below) (0.139 g, 0.264 mmol, 93) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.51-1.59 (m, 2 H), 1.71-1. 79 (m, 2 H), 1.89-1. 98 (m, 1 H) , 2.21 (s, 3H), 2.29-2.31 (m, 2H), 2.34-2.40 (m, 1H), 3.15 (ddd, J = 13.2, 13.3. 2, 3.2 Hz, 1 H), 3. 45 (ddd, J = 8.8, 8.8, 3.2 Hz, 1 H), 3.50 (brd, J = 10.8 Hz, 1 H), 3.57 (Ddd, J = 8.8, 8.8, 6.8 Hz, 1 H), 3.65 (dd, J = 10.8, 5.2 Hz, 1 H), 3.74-3.80 (m, 1 H) ), 5.01-5.05 (m, 1 H), 5.25 (brd, J = 5.6 Hz, 1 H), 6.37 (brs, 1 H), 6.47 (dd, J = 8.4) , 2.4 z, 1 H), 6.54 (brd, J = 8.4 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 1 H), 7. 20 (dd, J = 8.4, 8.4 Hz , 1 H), 7.36 (dd, J = 8.8, 2.4 Hz, 1 H), 7.60 (d, J = 2.4 Hz, 1 H), 8.34 (brs, 1 H).
ESI-MS: m / z = 526 (M + H) ⁺ .

Reference Example 135 Synthesis of (S) -3-chloro-4-((1- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) oxy) aniline

[1345] The title compound (hereinafter, the compound of Reference Example 135) was prepared by the same procedure as Reference Example 103 using 1-iodo-4- (trifluoromethoxy) benzene instead of 1-fluoro-2-iodobenzene (0.0950 g, 0.255 mmol, 62%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15-2.24 (m, 1 H), 2.33-2.38 (m, 1 H), 3.41 (ddd, J = 8.6, 8.6, 2.9 Hz, 1 H), 3.48-3. 60 (m, 5 H), 4.9 1-4. 93 (m, 1 H), 6.5 1 (d, J = 9.1 Hz, 2 H ), 6.53-6.55 (m, 1 H), 6.73 (d, J = 2.7 Hz, 1 H), 6.80 (d, J = 8.6 Hz, 1 H), 7.09 (d , J = 9.1 Hz, 2 H).
ESI-MS: m / z = 373 (M + H) ⁺ .

(Reference Example 136) (R) -2-((3-chloro-4-(((S) -1- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl:

The title compound (hereinafter, the compound of Reference Example 136) (0.130 g, 0.223 mmol, 92) was prepared by using the compound of Reference Example 135 instead of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.48 (m, 2 H), 1.52 (s, 9 H), 1.56-1.69 (m, 3 H), 2.21 -2.39 (m, 3 H), 2.82-2.89 (m, 1 H), 3.44 (ddd, J = 8.6, 8.6, 2.9 Hz, 1 H), 3.49 ( d, J = 10.9 Hz, 1 H), 3.53-3.59 (m, 1 H), 3.66 (dd, J = 10.9, 5.0 Hz, 1 H), 4.07 (brs, 1 H) ), 4.85-4.86 (m, 1 H), 5.01-5. 04 (m, 1 H), 6.51 (d, J = 9.1 Hz, 2 H), 6.89 (d, J) = 9.1 Hz, 1 H), 7.09 (d, J = 9.1 Hz, 2 H), 7.32 (dd, J = 9.1, 2.3 Hz, 1 H), 7.61 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 584 (M + H) ⁺ .

Example 103 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) oxy) phenyl) Synthesis of piperidine-2-carboxamide:

Using the compound of Reference Example 136 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except for the above, the title compound (the compound of Example 103 below) (0.0650 g, 0.124 mmol, 56) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.65 (m, 2 H), 1.71 to 1.78 (m, 2 H), 1.88-1 to 98 (m, 1 H) , 2.20 (s, 3 H), 2.23-2.29 (m, 2 H), 2.33-2.38 (m, 1 H), 3.16-3. 23 (m, 1 H), 3 3.43 (ddd, J = 8.6, 8.6, 2.9 Hz, 1 H), 3.47-3. 50 (m, 1 H), 3.52-3. 59 (m, 1 H), 3. 65 (dd, J = 10.7, 4.9 Hz, 1 H), 3.74-3.78 (m, 1 H), 5.01-5.03 (m, 1 H), 5.24-5.26 (M, 1 H), 6.51 (d, J = 9.0 Hz, 2 H), 6.87 (d, J = 8.8 Hz, 1 H), 7.09 (d, J = 9.0 Hz, 2 H) , 7.33 (dd, J = 8. , 2.4Hz, 1H), 7.60 (d, J = 2.4Hz, 1H), 8.43 (s, 1H).
ESI-MS: m / z = 526 (M + H) ⁺ .

Reference Example 137 Synthesis of (S) -3-chloro-4-((1- (4-chloro-3-methylphenyl) pyrrolidin-3-yl) oxy) aniline

Title compound (hereinafter, the compound of Reference Example 137) in the same manner as in Reference Example 103 except for using 1-chloro-4-iodo-2-methylbenzene instead of 1-fluoro-2-iodobenzene (0.0080 g, 0.024 mmol, 6%) was obtained as a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14-2.23 (m, 1 H), 2.32 (s, 3 H), 2.32-2.36 (m, 1 H), 3.38 (Ddd, J = 8.7, 8.7, 3.0 Hz, 1 H), 3.45-3. 47 (m, 1 H), 3.50-3.58 (m, 4 H), 4.89- 4.91 (m, 1 H), 6. 34 (dd, J = 8.8, 2.7 Hz, 1 H), 6.41 (d, J = 2.7 Hz, 1 H), 6.53 (dd, J = 8.5, 2.7 Hz, 1 H), 6. 73 (d, J = 2.7 Hz, 1 H), 6. 79 (d, J = 8.5 Hz, 1 H), 7. 15 (d, J = 8.8 Hz, 1 H).
ESI-MS: m / z = 337 (M + H) ⁺ .

(Reference Example 138) (R) -2-((3-chloro-4-(((S) -1- (4-chloro-3-methylphenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl:

Using the compound of Reference Example 137 instead of the compound of Reference Example 99, and using the same procedure as Reference Example 100 except the above, the title compound (the compound of Reference Example 138 below) (0.0110 g, 0.0201 mmol, 85) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.69 (m, 5 H), 1.51 (s, 9 H), 2.21-2. 38 (m, 3 H), 2.32 (S, 3 H), 2.81-2. 87 (m, 1 H), 3.41 (ddd, J = 8.6, 8.6, 3.1 Hz, 1 H), 3.44-3. m, 1 H), 3.52 (ddd, J = 8.9, 8.9, 7.0 Hz, 1 H), 3.63 (dd, J = 10.9, 5.0 Hz, 1 H), 4.06 (Brs, 1 H), 4.84-4. 85 (m, 1 H), 5.00-5.03 (m, 1 H), 6. 34 (dd, J = 8.8, 2.9 Hz, 1 H) , 6.42 (d, J = 2.9 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 1 H), 7. 15 (d, J = 8.8 Hz, 1 H), 7. 34 (d dd, J = 8.8, 2 4Hz, 1H), 7.59 (d, J = 2.4Hz, 1H).
ESI-MS: m / z = 548 (M + H) ^<+> .

Example 104 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (4-chloro-3-methylphenyl) pyrrolidin-3-yl) oxy) phenyl) Synthesis of piperidine-2-carboxamide:

Using the compound of Reference Example 138 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 104 below) (0.0070 g, 0.014 mmol, 71) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.88-1.96 (m, 1H) , 2.20-2.36 (m, 3 H), 2. 20 (s, 3 H), 2. 32 (s, 3 H), 3.15-3. 22 (m, 1 H), 3.38-3 .55 (m, 3 H), 3.63 (dd, J = 10.9, 5.0 Hz, 1 H), 3.74-3. 78 (m, 1 H), 5.00-5.02 (m, 1H), 5.24-5.26 (m, 1H), 6.34 (dd, J = 8.7, 2.8 Hz, 1 H), 6.41 (d, J = 2.8 Hz, 1 H), 6.87 (d, J = 8.6 Hz, 1 H), 7. 15 (d, J = 8.7 Hz, 1 H), 7.34 (dd, J = 8.6, 2.4 Hz, 1 H), 7 .59 (d, J = 2.4 Hz 1H), 8.39 (s, 1H).
ESI-MS: m / z = 491 (M + H) ⁺ .

Reference Example 139 Synthesis of (S) -3-chloro-4-((1- (pyridin-2-yl) pyrrolidin-3-yl) oxy) aniline:

The title compound (hereinafter, the compound of Reference Example 139) (0.0190 g, 0.0656 mmol) was prepared by using 2-iodopyridine instead of 1-fluoro-2-iodobenzene and using the same procedure as in Reference Example 103 except the above. , 16%) as a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14-2.23 (m, 1 H), 2.34-2.39 (m, 1 H), 3.53 (brs, 2 H), 3.60 -3.65 (m, 1 H), 3.67-3. 73 (m, 2 H), 3.76-3. 79 (m, 1 H), 4.89-4.92 (m, 1 H), 6 .38 (d, J = 8.5 Hz, 1 H), 6.50-6.56 (m, 2 H), 6.71 (d, J = 2.7 Hz, 1 H), 6.81 (d, J = 8.5 Hz, 1 H), 7.44 (ddd, J = 8.5, 7.1, 2.0 Hz, 1 H), 8.16 (dd, J = 5.0, 2.0 Hz, 1 H).
ESI-MS: m / z = 290 (M + H) ⁺ .

(Reference Example 140) (R) -2-((3-Chloro-4-(((S) -1- (pyridin-2-yl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1- ( Synthesis of tert-butyl carboxylic acid:

Using the compound of Reference Example 139 instead of the compound of Reference Example 99, and using the same procedure as Reference Example 100 except for this, the title compound (hereinafter, the compound of Reference Example 140) (0.0350 g, 0.0699 mmol, quantitation ) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.69 (m, 5 H), 1.51 (s, 9 H), 2.21-2. 42 (m, 3 H), 2.82 -2.85 (m, 1 H), 3.62-3. 73 (m, 2 H), 3.78 (d, J = 3.2 Hz, 2 H), 4.07 (brs, 1 H), 4.84 -4. 85 (m, 1 H), 5.0 1-5. 04 (m, 1 H), 6. 39 (d, J = 8.5 Hz, 1 H), 6. 55 (dd, J = 7.1, 5.0 Hz, 1 H), 6.92 (d, J = 8.8 Hz, 1 H), 7.32 (dd, J = 8.8, 2.7 Hz, 1 H), 7.45 (ddd, J = 8 5, 7. 1, 2.0 Hz, 1 H), 7.61 (d, J = 2.7 Hz, 1 H), 8.02 (brs, 1 H), 8. 16 (dd, J = 5.0, 2.0 Hz, 1 H).
ESI-MS: m / z = 501 (M + H) ⁺ .

Example 105 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (pyridin-2-yl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2 -Synthesis of carboxamide:

Using the compound of Reference Example 140 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 105 below) (0.0250 g, 0.0564 mmol, 86) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 to 1.67 (m, 2 H), 1.70 to 1. 78 (m, 2 H), 1.89 to 1. 98 (m, 1 H) , 2.21 (s, 3 H), 2.22-2.29 (m, 2 H), 2.35-2.41 (m, 1 H), 3.13-3. 20 (m, 1 H), 3 .63-3.72 (m, 2H), 3.75-3.78 (m, 3H), 5.00-5.04 (m, 1H), 5.24-5.26 (m, 1H) , 6.39 (d, J = 8.5 Hz, 1 H), 6.55 (dd, J = 7.1, 5.4 Hz, 1 H), 6. 90 (d, J = 8.8 Hz, 1 H), 7.32 (dd, J = 8.8, 2.7 Hz, 1 H), 7. 45 (ddd, J = 8.5, 7.1, 2.0 Hz, 1 H), 7.61 (d, J = 2.7 Hz, 1 H), 8. 16 ( d, J = 5.4,2.0Hz, 1H), 8.33 (s, 1H).
ESI-MS: m / z = 443 (M + H) ⁺ .

Reference Example 141 Synthesis of (S) -3-chloro-4-((1- (5-chloropyridin-2-yl) pyrrolidin-3-yl) oxy) aniline:

The title compound (hereinafter referred to as the compound of Reference Example 141) (0.0250 g) was prepared by using 5-chloro-2-iodopyridine instead of 1-fluoro-2-iodobenzene, and using the same procedure as in Reference Example 103 except the above. , 0.0771 mmol, 19%) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14-2.23 (m, 1 H), 2.34-2.41 (m, 1 H), 3.53 (brs, 2 H), 3.57 -3.62 (m, 1 H), 3.63-3. 71 (m, 2 H), 3.74-3. 77 (m, 1 H), 4.89-4.91 (m, 1 H), 6 6. 32 (d, J = 9.0 Hz, 1 H), 6.53 (dd, J = 8.7, 2.8 Hz, 1 H), 6.72 (d, J = 2.8 Hz, 1 H), 6. 81 (d, J = 8.7 Hz, 1 H), 7.39 (dd, J = 9.0, 2.7 Hz, 1 H), 8.08 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 324 (M + H) ⁺ .

(Reference Example 142) (R) -2-((3-Chloro-4-(((S) -1- (5-chloropyridin-2-yl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl:

The title compound (hereinafter, the compound of Reference Example 142) (0.0390 g, 0.0728 mmol, 95) was prepared by using the compound of Reference Example 141 instead of the compound of Reference Example 99 and using the same procedure as in Reference Example 100 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.69 (m, 5 H), 1.52 (s, 9 H), 2.20-2.41 (m, 3 H), 2.79 -2.86 (m, 1 H), 3.59-3. 78 (m, 4 H), 4.05 (brs, 1 H), 4.84-4. 85 (m, 1 H), 5.00-5 .03 (m, 1 H), 6.33 (d, J = 8.8 Hz, 1 H), 6.91 (d, J = 9.0 Hz, 1 H), 7.32 (dd, J = 9.0, 2.0 Hz, 1 H), 7. 40 (dd, J = 8.8, 2.4 Hz, 1 H), 7.61 (d, J = 2.0 Hz, 1 H), 8.08 (d, J = 2) .4 Hz, 1 H).
ESI-MS: m / z = 536 (M + H) ⁺ .

Example 106 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (5-chloropyridin-2-yl) pyrrolidin-3-yl) oxy) phenyl) Synthesis of piperidine-2-carboxamide:

Using the compound of Reference Example 142 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 106 below) (0.0170 g, 0.0356 mmol, 49) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.61 (m, 2 H), 1.70-1. 78 (m, 2 H), 1.87-1. 98 (m, 1 H) , 2.19-2.28 (m, 2 H), 2.20 (s, 3 H), 2.35-2.40 (m, 1 H), 3.16-3. 24 (m, 1 H), 3 .58-3.78 (m, 5 H), 4.99-5.02 (m, 1 H), 5.24-5. 26 (m, 1 H), 6.32 (d, J = 9.0 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1 H), 7.31 (dd, J = 8.9, 2.6 Hz, 1 H), 7.39 (dd, J = 9.0, 2) .6 Hz, 1 H), 7.61 (d, J = 2.6 Hz, 1 H), 8.08 (d, J = 2.6 Hz, 1 H), 8.43 (brs, 1 H).
ESI-MS: m / z = 477 (M + H) ⁺ .

Reference Example 143 Synthesis of (S) -3- (2-chloro-4-nitrophenoxy) -1- (3,5-dimethylphenyl) pyrrolidine:

Compound of Reference Example 102 (0.250 g, 0.896 mmol), palladium (II) acetate (0.0402 g, 0.179 mmol), tri-tert-butylphosphino tetrafluoroborate (0.0520 g, 0.179 mmo) and Sodium tert-butyloxy (0.258 g, 2.69 mmol) was suspended in toluene (2.24 mL) and 1-bromo-3,5-dimethylbenzene (0.497 g, 2.69 mmol) was added at room temperature. After stirring at 110 ° C. for 22 hours, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100/0 to 85/15), and the title compound (hereinafter, the compound of Reference Example 143) (0.202 g, 0.582 mmol, 65) %) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.28 (s, 6 H), 2.34-2.41 (m, 2 H), 3.48-3. 58 (m, 3 H), 3.80 (Dd, J = 10.9, 5.0 Hz, 1 H), 5.17-5.20 (m, 1 H), 6.24 (s, 2 H), 6.41 (s, 1 H), 7.00 (D, J = 9.1 Hz, 1 H), 8.17 (dd, J = 9.1, 2.7 Hz, 1 H), 8.30 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 347 (M + H) ⁺ .

Reference Example 144 Synthesis of (S) -3-chloro-4-((1- (3,5-dimethylphenyl) pyrrolidin-3-yl) oxy) aniline:

The compound of Reference Example 143 (0.202 g, 0.582 mmol) is dissolved in THF (2.53 mL), ethanol (5.02 mL) and distilled water (2.53 mL), and iron powder (0.130 g, 2.33 mmol) ) And acetic acid (0.333 mL, 5.82 mmol) were added at room temperature. After stirring at 70 ° C. for 1 hour, the reaction solution was filtered, distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100/0 to 70/30), and the title compound (hereinafter, the compound of Reference Example 144) (0.138 g, 0.436 mmol, 75) %) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14-2.23 (m, 1 H), 2.27 (s, 6 H), 2.29-2.35 (m, 1 H), 3.41 (Ddd, J = 8.6, 8.6, 3.5 Hz, 1 H), 3.49-3. 54 (m, 4 H), 3.59 (dd, J = 10.6, 5.2 Hz, 1 H ), 4.88-4.92 (m, 1 H), 6.22 (s, 2 H), 6. 37 (s, 1 H), 6.53 (dd, J = 8.6, 2.7 Hz, 1 H) ), 6.73 (d, J = 2.7 Hz, 1 H), 6. 80 (d, J = 8.6 Hz, 1 H).
ESI-MS: m / z = 317 (M + H) ⁺ .

(Reference Example 145) (R) -2-((3-Chloro-4-(((S) -1- (3,5-dimethylphenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1 Synthesis of tert-butyl carboxylic acid:

The compound of Reference Example 144 (0.138 g, 0.436 mmol) and (R) -1- (tert-butoxycarbonyl) piperidine-2-carboxylic acid (0.110 g, 0.479 mmol) in DMF (4.36 mL) Dissolve and add HATU (0.199 g, 0.523 mmol) and diisopropylethylamine (0.0990 mL, 0.566 mmol) at room temperature. After stirring for 19 hours at the same temperature, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100/0 to 80/20), and the title compound (hereinafter, the compound of Reference Example 145) (0.210 g, 0.398 mmol, 91) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.72 (m, 14 H), 2.20-2.37 (m, 9 H), 2.82 (ddd, J = 13.6, 11.8, 1.4 Hz, 1 H), 3.46-3. 52 (m, 3 H), 3. 67 (dd, J = 10.9, 5.0 Hz, 1 H), 4.04-4.09 (M, 1 H), 4.84-4. 85 (m, 1 H), 5.00-5. 04 (m, 1 H), 6.23 (s, 2 H), 6. 38 (s, 1 H), 6.90 (d, J = 9.1 Hz, 1 H), 7.36 (dd, J = 9.1, 2.7 Hz, 1 H), 7.57 (d, J = 2.7 Hz, 1 H), 8 .13 (brs, 1 H).
ESI-MS: m / z = 528 (M + H) ⁺ .

(Reference Example 146) (R) -N- (3-chloro-4-(((S) -1- (3,5-dimethylphenyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2-carboxamide Synthesis:

The compound of Reference Example 145 (0.210 g, 0.398 mmol) was dissolved in dichloromethane (3.98 mL), and trifluoroacetic acid (0.994 mL, 12.9 mmol) was added at 0 ° C. After stirring at room temperature for 1.5 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with dichloromethane. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (hereinafter, the compound of Reference Example 146) (0.165 g, 0.386 mmol, 97%) Obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.62 (m, 4H), 1.79-1.85 (m, 1H), 2.00-2.05 (m, 1H) , 2.20-2.37 (m, 8 H), 2.72-2.79 (m, 1 H), 3.06 (ddd, J = 12.2, 4.3, 3.4 Hz, 1 H), 3.34 (dd, J = 9.5, 3.6 Hz, 1 H), 3.41-3.57 (m, 3 H), 3.67 (dd, J = 10.9, 5.0 Hz, 1 H) , 5.00-5.04 (m, 1 H), 6.23 (s, 2 H), 6. 38 (s, 1 H), 6. 91 (d, J = 9.1 Hz, 1 H), 7.49 (Dd, J = 9.1, 2.7 Hz, 1 H), 7.61 (d, J = 2.7 Hz, 1 H), 8.80 (s, 1 H).
ESI-MS: m / z = 428 (M + H) ⁺ .

Example 107 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (3,5-dimethylphenyl) pyrrolidin-3-yl) oxy) phenyl) piperidine Synthesis of 2-carboxamide:

The compound of Reference Example 146 (0.165 g, 0.386 mmol) is dissolved in dichloromethane (3.98 mL), triethylamine (0.0720 mL, 0.517 mmol) and acetic anhydride (0.0450 mL, 0.478 mmol) are added at 0 ° C. Added. After stirring for 4 hours at room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100/0 to 30/70) to give the title compound (compound of Example 107 below) (0.132 g, 0.281 mmol, 71) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.63 (m, 2 H), 1.70-1. 78 (m, 2 H), 1.89-1. 98 (m, 1 H) , 2.21 (s, 3 H), 2.22-2. 37 (m, 9 H), 3. 16 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3.41- 3.56 (m, 3 H), 3.66 (dd, J = 10.9, 5.0 Hz, 1 H), 3.74-3. 79 (m, 1 H), 4.99-5.03 (m , 1H), 5.25 (brd, J = 5.9 Hz, 1 H), 6.22 (s, 2 H), 6.38 (s, 1 H), 6.88 (d, J = 9.1 Hz, 1 H) ), 7.36 (dd, J = 9.1, 2.7 Hz, 1 H), 7.58 (d, J = 2.7 Hz, 1 H), 8.32 (brs, 1 H).
ESI-MS: m / z = 470 (M + H) ⁺ .

Example 108 (R) -N- (3-chloro-4-(((S) -1- (3,5-dimethylphenyl) pyrrolidin-3-yl) oxy) phenyl) -1- (methylsulfonyl) ) Synthesis of piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 108) (0.125 g, 0.247 mmol, 71%) was white-colored in the same manner as in Example 107 except for using methanesulfonyl chloride instead of acetic anhydride. Obtained as a solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49 to 1.74 (m, 4 H), 1.76 to 1.82 (m, 1 H), 2.22 to 2.37 (m, 8 H) , 2.44-2.47 (m, 1 H), 3.02 (s, 3 H), 3.15-3. 22 (m, 1 H), 3.42-3. 57 (m, 3 H), 3 .68 (dd, J = 10.6, 5.2 Hz, 1 H), 3.88-3.94 (m, 1 H), 4.59-4.60 (m, 1 H), 5.01-5. 05 (m, 1 H), 6.23 (s, 2 H), 6. 38 (s, 1 H), 6. 91 (d, J = 8.6 Hz, 1 H), 7. 36 (dd, J = 8). 6, 2.7 Hz, 1 H), 7.64 (d, J = 2.7 Hz, 1 H), 8.09 (brs, 1 H).
ESI-MS: m / z = 506 (M + H) ⁺ .

Example 109 (R) -1- (2- (1H-1,2,3-triazol-1-yl) acetyl) -N- (3-chloro-4-(((S) -1- ( Synthesis of 3,5-Dimethylphenyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2-carboxamide:

The compound of Reference Example 146 (0.150 g, 0.350 mmol) and 2- (1H-1,2,3-triazol-1-yl) acetic acid (0.0535 g, 0.421 mmol) in DMF (3.51 mL) Dissolve and add HATU (0.160 g, 0.421 mmol) and diisopropylethylamine (0.0918 mL, 0.526 mmol) at room temperature. After stirring at the same temperature for 18 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 85/15 to 40/60), and the title compound (the compound of Example 109 below) (0.146 g, 0.272 mmol, 78) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.67 (m, 2 H), 1.74-1. 83 (m, 3 H), 2.18-2.43 (m, 9 H) , 3.33 (ddd, J = 14.0, 13.2, 2.8 Hz, 1H), 3.41-3.49 (m, 2H), 3.53 (ddd, J = 9.1, 9) .1, 6.8 Hz, 1 H), 3.67 (dd, J = 10.6, 5.2 Hz, 1 H), 3.70-3.75 (m, 1 H), 4.99-5.03 ( m, 1 H), 5. 28 (brd, J = 5.2 Hz, 1 H), 5. 30 (d, J = 15.6 Hz, 1 H), 5. 39 (d, J = 15.6 Hz, 1 H), 6.23 (s, 2 H), 6. 38 (s, 1 H), 6. 90 (d, J = 9.1 Hz, 1 H), 7.41 (dd, J = 9.1, 2.7 Hz, 1 H ), 7.7 (D, J = 2.7 Hz, 1 H), 7.74 (d, J = 0.9 Hz, 1 H), 7.81 (d, J = 0.9 Hz, 1 H), 8. 28 (brs, 1H).
ESI-MS: m / z = 537 (M + H) ⁺ .

Example 110 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4-(((S) -1- (3,5-dimethylphenyl) Synthesis of)) pyrrolidin-3-yl) oxy) phenyl) piperidine-2-carboxamide:

Using the same procedure as in Example 109 except for using 2- (1H-tetrazol-1-yl) acetic acid instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid, The compound (hereinafter, the compound of Example 110) (0.168 g, 0.312 mmol, 89%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.52-1.92 (m, 5 H), 2.18-2.32 (m, 9 H), 3.39-3. 56 (m, 4 H) , 3.63-3.70 (m, 2H), 4.96-4.99 (m, 1H), 5.13 (brd, J = 3.2 Hz, 1 H), 5.36 (d, J = 17.2 Hz, 1 H), 5.41 (d, J = 17.2 Hz, 1 H), 6.21 (s, 2 H), 6.37 (s, 1 H), 6.84 (d, J = 9. 1 Hz, 1 H), 7.21 (dd, J = 9.1, 2.3 Hz, 1 H), 7.58 (d, J = 2.3 Hz, 1 H), 8.09 (brs, 1 H), 8. 81 (s, 1 H).
ESI-MS: m / z = 538 (M + H) ⁺ .

Example 111 (R) -N- (3-chloro-4-(((S) -1- (3,5-dimethylphenyl) pyrrolidin-3-yl) oxy) phenyl) -1- (2- Synthesis of Cyanoacetyl) piperidine-2-carboxamide:

The title compound was obtained by the same procedure as in Example 109 except that 2-cyanoacetic acid was used instead of 2- (1H-1,2,3-triazol-1-yl) acetic acid, and the title compound (hereinafter referred to as Example 111) Compound (0.101 g, 0.204 mmol, 58%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.63-1.69 (m, 2 H), 1.74-1. 86 (m, 2 H), 1.89-2.00 (m, 1 H) , 2.20-2.36 (m, 9H), 3.37-3.57 (m, 4H), 3.60-3.69 (m, 4H), 4.99-5.03 (m, 1H), 5.18 (brd, J = 5.4 Hz, 1 H), 6.22 (s, 2 H), 6.38 (s, 1 H), 6.88 (d, J = 9.1 Hz, 1 H) , 7.30 (dd, J = 9.1, 2.7 Hz, 1 H), 7.60 (d, J = 2.7 Hz, 1 H), 7.96 (brs, 1 H).
ESI-MS: m / z = 495 (M + H) ^<+> .

Reference Example 147 Synthesis of (S) -3- (2-chloro-4-nitrophenoxy) -1- (3-isopropylphenyl) pyrrolidine:

The title compound (hereinafter, the compound of Reference Example 147) was prepared by the same procedure as Reference Example 143 using 1-bromo-3-isopropylbenzene instead of 1-bromo-3,5-dimethylbenzene .222 g, 0.615 mmol, 69%) were obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (d, J = 6.8 Hz, 6 H), 2.38-2.41 (m, 2 H), 2.81-2.91 (m, 1H), 3.51-3.61 (m, 3H), 3.83 (dd, J = 10.9, 5.0 Hz, 1H), 5.18-5.22 (m, 1H), 6. 43-6.47 (m, 2H), 6.64 (brd, J = 7.7 Hz, 1 H), 7.01 (d, J = 9.1 Hz, 1 H), 7.19 (dd, J = 7) 7, 7.7 Hz, 1 H), 8. 17 (dd, J = 9.1, 2.7 Hz, 1 H), 8.30 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 361 (M + H) ⁺ .

Reference Example 148 Synthesis of (S) -3-chloro-4-((1- (3-isopropylphenyl) pyrrolidin-3-yl) oxy) aniline:

Using the compound of Reference Example 147 instead of the compound of Reference Example 143, and using the same procedure as Reference Example 144 except the above, the title compound (hereinafter, the compound of Reference Example 148) (0.148 g, 0.447 mmol, 73) %) As a pale brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (d, J = 6.9 Hz, 6 H), 2.18-2.21 (m, 1 H), 2.31-2.36 (m, 1H), 2.80 to 2.90 (m, 1H), 3.44 (ddd, J = 8.7, 8.7, 3.2 Hz, 1H), 3.50 to 3.58 (m, 4H) ), 3.63 (dd, J = 11.2, 5.2 Hz, 1 H), 4.94 to 4.93 (m, 1 H), 6.41 to 6.45 (m, 2 H), 6.53 (Dd, J = 8.7, 2.7 Hz, 1 H), 6.59 (brd, J = 7.8 Hz, 1 H), 6.74 (d, J = 2.7 Hz, 1 H), 6.80 ( d, J = 8.7 Hz, 1 H, 7.17 (dd, J = 7.8, 7.8 Hz, 1 H).
ESI-MS: m / z = 331 (M + H) ⁺ .

(Reference Example 149) (R) -2-((3-chloro-4-(((S) -1- (3-isopropylphenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1-carvone Synthesis of acid tert-butyl:

The title compound (hereinafter, the compound of Reference Example 149) (0.230 g, 0.424 mmol, 95) was prepared by using the compound of Reference Example 148 in place of the compound of Reference Example 144 and using the same procedure as in Reference Example 145 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (d, J = 7.2 Hz, 6 H), 1.40 to 1.72 (m, 14 H), 2.24 to 2.35 (m, 3H), 2.82-2.86 (m, 2H), 3.44-3.60 (m, 3H), 3.70 (dd, J = 10.6, 5.2 Hz, 1H), 4. 05-4.08 (m, 1 H), 4.84-4. 86 (m, 1 H), 5.01-5. 05 (m, 1 H), 6.42-6. 44 (m, 2 H), 6.60 (d, J = 7.7 Hz, 1 H), 6. 91 (d, J = 9.1 Hz, 1 H), 7.17 (dd, J = 7.7, 7.7 Hz, 1 H), 7 36 (dd, J = 9.1, 2.7 Hz, 1 H), 7.58 (d, J = 2.7 Hz, 1 H), 8. 14 (s, 1 H).
ESI-MS: m / z = 542 (M + H) ⁺ .

Example 112 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (3-isopropylphenyl) pyrrolidin-3-yl) oxy) phenyl) piperidine-2- Carboxamide Synthesis:

Using the compound of Reference Example 149 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 112 below) (0.154 g, 0.318 mmol, 75) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (d, J = 6.8 Hz, 6 H), 1.45-1.62 (m, 2 H), 1.70-1. 79 (m, 2H), 1.89-1 to 98 (m, 1H), 2.21 (s, 3H), 2.22 to 2.37 (m, 3H), 2.80 to 2.90 (m, 1H) , 3.16 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3.44-3.59 (m, 3 H), 3.70 (dd, J = 10.6, 5) .2 Hz, 1 H), 3.74-3.79 (m, 1 H), 5.00-5.04 (m, 1 H), 5.25 (brd, J = 5.4 Hz, 1 H), 6.41 −6.45 (m, 2H), 6.60 (d, J = 7.7 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 1 H), 7.17 (dd, J = 7. 7, 7.7 Hz, 1 ), 7.36 (dd, J = 8.6,2.7Hz, 1H), 7.59 (d, J = 2.7Hz, 1H), 8.32 (brs, 1H).
ESI-MS: m / z = 484 (M + H) ⁺ .

Reference Example 150 Synthesis of (S) -3- (2-chloro-4-nitrophenoxy) -1- (3,5-difluorophenyl) pyrrolidine:

Title compound (following, compound of Reference Example 150) in the same manner as in Reference Example 143 using 1-bromo-3,5-difluorobenzene instead of 1-bromo-3,5-dimethylbenzene (0.220 g, 0.620 mmol, 55%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.34-2.47 (m, 2H), 3.46-3.59 (m, 3H), 3.76 (dd, J = 11.1, 4.8 Hz, 1 H), 5.20-5. 23 (m, 1 H), 6.02-6. 10 (m, 2 H), 6.17 (tt, J = 9.1, 2.2 Hz, 1 H ), 7.01 (d, J = 9.1 Hz, 1 H), 8.18 (dd, J = 9.1, 2.7 Hz, 1 H), 8.32 (d, J = 2.7 Hz, 1 H) .
ESI-MS: m / z = 355 (M + H) ⁺ .

(Reference Example 151) Synthesis of (S) -3-chloro-4-((1- (3,5-difluorophenyl) pyrrolidin-3-yl) oxy) aniline:

The title compound (hereinafter, the compound of Reference Example 151) (0.141 g, 0.434 mmol, 70) was prepared by using the compound of Reference Example 150 instead of the compound of Reference Example 143 and using the same procedure as in Reference Example 144 except the above. %) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14-2.23 (m, 1 H), 2.33-2.40 (m, 1 H), 3.39 (ddd, J = 8.8, 8.8, 2.7 Hz, 1 H), 3.47 (ddd, J = 11.2, 1.6, 1.6 Hz, 1 H), 3.52 (d, J = 4.5 Hz, 1 H), 3 .54-3.58 (m, 3H), 4.89-4.92 (m, 1H), 6.00-6.07 (m, 2H), 6.12 (tt, J = 9.3, 2.2 Hz, 1 H), 6.54 (dd, J = 8.6, 2.7 Hz, 1 H), 6.73 (d, J = 2.7 Hz, 1 H), 6.80 (d, J = 8 .6 Hz, 1 H).
ESI-MS: m / z = 325 (M + H) ⁺ .

(Reference Example 152) (R) -2-((3-Chloro-4-(((S) -1- (3,5-difluorophenyl) pyrrolidin-3-yl) oxy) phenyl) carbamoyl) piperidine-1 Synthesis of tert-butyl carboxylic acid:

The title compound (hereinafter, the compound of Reference Example 152) (0.206 g, 0.384 mmol, 89) was prepared by using the compound of Reference Example 151 instead of the compound of Reference Example 144 and using the same procedure as in Reference Example 145 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.49 (m, 2H), 1.52 (s, 9H), 1.64-1.69 (m, 3H), 2.20 -2.29 (m, 1 H), 2.30-2.41 (m, 2 H), 2.78-2.86 (m, 1 H), 3.42 (ddd, J = 8.8, 8. 8, 2.7 Hz, 1 H), 3.47 (brd, J = 11.3 Hz, 1 H), 3.55 (ddd, J = 9.3, 9.3, 6.8 Hz, 1 H), 3.61 (Dd, J = 11.1, 4.8 Hz, 1 H), 4.01-4.12 (m, 1 H), 4.83-4. 87 (m, 1 H), 5.01-5. 04 ( m, 1 H), 6.00-6.07 (m, 2 H), 6. 13 (tt, J = 9.3, 2.2 Hz, 1 H), 6. 90 (d, J = 8.6 Hz, 1 H ), 7.36 (dd J = 8.6,2.7Hz, 1H), 7.61 (d, J = 2.7Hz, 1H), 8.21 (brs, 1H).
ESI-MS: m / z = 558 (M + Na) ⁺ .

Example 113 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (3,5-difluorophenyl) pyrrolidin-3-yl) oxy) phenyl) piperidine- Synthesis of 2-carboxamide:

Using the compound of Reference Example 152 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 113 below) (0.0783 g, 0.164 mmol, 85) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.64-1.48 (m, 2 H), 1.71-1. 79 (m, 2 H), 1.89-1. 98 (m, 1 H) , 2.17-2.30 (m, 5 H), 2.34-2. 40 (m, 1 H), 3. 16 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3.41 (ddd, J = 8.8, 8.8, 2.7 Hz, 1 H), 3.47 (brd, J = 10.9 Hz, 1 H), 3.52-3.62 (m, 2 H) , 3.74-3.79 (m, 1 H), 5.00-5.04 (m, 1 H), 5.25 (brd, J = 5.0 Hz, 1 H), 6.00-6.07 (m. m, 2H), 6.13 (tt, J = 9.1, 2.2 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 1 H), 7.36 (dd, J = 8.6) , 2.7 Hz, H), 7.61 (d, J = 2.7Hz, 1H), 8.37 (brs, 1H).
ESI-MS: m / z = 500 (M + Na) ⁺ .

Reference Example 153 Synthesis of (S) -3- (2-chloro-4-nitrophenoxy) -1- (3-methyl-4- (trifluoromethoxy) phenyl) pyrrolidine:

Using 4-bromo-2-methyl-1- (trifluoromethoxy) benzene instead of 1-bromo-3,5-dimethylbenzene and following the same procedure as Reference Example 143 except for using the title compound (hereinafter referred to as The compound of Reference Example 153 (0.487 g, 1.17 mmol, 65%) was obtained as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.28 (s, 3 H), 2.38-2.43 (m, 2 H), 3.47-3. 59 (m, 3 H), 3.80 (Dd, J = 11.1, 4.8 Hz, 1 H), 5.19-5.22 (m, 1 H), 6.37-6. 41 (m, 2 H), 7.01 (d, J = 9.1 Hz, 1 H), 7.08 (brd, J = 8.6 Hz, 1 H), 8. 18 (dd, J = 9.1, 2.7 Hz, 1 H), 8.31 (d, J = 2) .7 Hz, 1 H).
ESI-MS: m / z = 417 (M + H) ⁺ .

Reference Example 154 Synthesis of (S) -3-chloro-4-((1- (3-methyl-4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) oxy) aniline:

The title compound (hereinafter, the compound of Reference Example 154) (0.373 g, 0.964 mmol, 83) was prepared by using the compound of Reference Example 153 instead of the compound of Reference Example 143 and using the same procedure as in Reference Example 144 except the above. %) As a brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.17-2.21 (m, 1 H), 2.27 (s, 3 H), 2.32-2.37 (m, 1 H), 3.40 (Ddd, J = 8.6, 8.6, 3.0 Hz, 1 H), 3.47-3. 60 (m, 5 H), 4.89-4.93 (m, 1 H), 6.35 6.37 (m, 2 H), 6.54 (dd, J = 8.7, 2.7 Hz, 1 H), 6. 74 (d, J = 2.7 Hz, 1 H), 6. 80 (d, J = 8.7 Hz, 1 H), 7.05 (dd, J = 8.7, 1.4 Hz, 1 H).
ESI-MS: m / z = 387 (M + H) ⁺ .

(Reference Example 155) (R) -2-((3-chloro-4-(((S) -1- (3-methyl-4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) oxy) phenyl Synthesis of tert-butyl)) carbamoyl) piperidine-1-carboxylate:

The title compound (hereinafter, the compound of Reference Example 155) (0.525 g, 0.878 mmol, 91) was prepared by using the compound of Reference Example 154 instead of the compound of Reference Example 144 and using the same procedure as in Reference Example 145 except the above. %) As a brown solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.49 (m, 2H), 1.52 (s, 9H), 1.64-1.67 (m, 3H), 2.20 -2.39 (m, 6 H), 2.83 (ddd, J = 13.2, 13.2, 2.4 Hz, 1 H), 3.43 (ddd, J = 8.6, 8.6, 2 .9 Hz, 1 H), 3.48 (brd, J = 1 1.0 Hz, 1 H), 3.55 (ddd, J = 9.0, 9.0, 6.7 Hz, 1 H), 3.65 (dd, J) J = 11.0, 5.0 Hz, 1 H), 4.04-4. 08 (m, 1 H), 4.84-4. 86 (m, 1 H), 5.01-5. 04 (m, 1 H) ), 6.34-6.38 (m, 2H), 6.90 (d, J = 8.7 Hz, 1 H), 7.06 (d, J = 8.7 Hz, 1 H), 7.35 (dd , J = 8.7 2.7Hz, 1H), 7.59 (d, J = 2.7Hz, 1H), 8.19 (brs, 1H).
ESI-MS: m / z = 598 (M + H) ^<+> .

Example 114 (R) -1-Acetyl-N- (3-chloro-4-(((S) -1- (3-methyl-4- (trifluoromethoxy) phenyl) pyrrolidin-3-yl) Synthesis of oxy) phenyl) piperidine-2-carboxamide:

Using the compound of Reference Example 155 instead of the compound of Reference Example 104, and using the same procedure as Example 87 except the above, the title compound (the compound of Example 114 below) (0.0580 g, 0.107 mmol, 54) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.57 (m, 2 H), 1.73-1. 76 (m, 2 H), 1.89-2.00 (m, 1 H) , 2.21 (s, 3 H), 2.22-2.29 (m, 5 H), 2.33-2.38 (m, 1 H), 3.16 (ddd, J = 13.2, 13.3. 2, 2.8 Hz, 1 H), 3.43 (ddd, J = 8.6, 8.6, 3.2 Hz, 1 H), 3.48 (brd, J = 11.3 Hz, 1 H), 3.54 (Ddd, J = 9.1, 9.1, 6.8 Hz, 1 H), 3.65 (dd, J = 10.9, 5.0 Hz, 1 H), 3.74-3. 79 (m, 1 H) ), 5.01-5.04 (m, 1 H), 5.25 (brd, J = 5.9 Hz, 1 H), 6.34-6. 38 (m, 2 H), 6.88 (d, J) = 9.1 Hz 1H), 7.06 (brd, J = 7.7 Hz, 1 H), 7. 35 (dd, J = 9.1, 2.7 Hz, 1 H), 7.59 (d, J = 2.7 Hz, 1 H) ), 8.34 (brs, 1 H).
ESI-MS: m / z = 540 (M + H) ⁺ .

(Reference Example 156) Synthesis of 1- (3,5-dimethylphenyl) pyrrolidin-3-ol:

The pyrrolidin-3-ol hydrochloride (2.00 g, 16.2 mmol) and tert-butyloxy sodium (4.36 g, 38.8 mmol) are suspended in toluene (40.5 mL), 1-bromo-3,5- Dimethylbenzene (3.29 g, 17.8 mmol), 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (1.51 g, 2.43 mmol) and tris (dibenzylideneacetone) dipalladium (0 ) (0.741 g, 0.809 mmol) was added at room temperature. After stirring at 120 ° C. for 14 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 98/2 to 70/30), and the title compound (hereinafter, the compound of Reference Example 156) (2.10 g, 11.0 mmol, 68) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.01-2.07 (m, 1 H), 2.11-2. 20 (m, 1 H), 2.28 (s, 6 H), 3.26 (Brd, J = 10.4 Hz, 1 H), 3.33 (ddd, J = 9.2, 9.2, 3.6 Hz, 1 H), 3.45-3.52 (m, 2 H); 55-4.59 (m, 1 H), 6.22 (s, 2 H), 6. 37 (s, 1 H).
ESI-MS: m / z = 192 (M + H) ⁺ .

Reference Example 157 Synthesis of 1- (3,5-dimethylphenyl) pyrrolidin-3-one:

The compound of Reference Example 156 (1.50 g, 7.84 mmol) was dissolved in dichloromethane (26.1 mL), and dried molecular sieves 4A (1.50 g) was added at room temperature. Subsequently, N-methylmorpholine N-oxide (1.38 g, 11.8 mmol) and tetrapropylammonium perruthenate (0.276 g, 0.784 mmol) were added at 0 ° C. After stirring for 30 minutes at room temperature, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 98/2 to 80/20) to give the title compound (hereinafter referred to as the compound of Reference Example 157) (0.778 g, 4.11 mmol, 52) %) As an orange solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.31 (6 H, s), 2.71 (t, J = 7.2 Hz, 2 H), 3.65-3.69 (m, 4 H), 6 31 (s, 2 H), 6.51 (s, 1 H).
ESI-MS: m / z = 190 (M + H) ⁺ .

(Reference Example 158) Synthesis of 1- (3,5-dimethylphenyl) -3-ethynylpyrrolidin-3-ol:

The compound of Reference Example 157 (0. 100 g, 0.528 mmol) is dissolved in THF (5.28 mL), and ethynyl magnesium bromide-THF solution (0.5 M, 1.58 mL, 0.793 mmol) is added at -20 ° C. The After stirring for 30 minutes at the same temperature, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 70/30), and the title compound (hereinafter, the compound of Reference Example 158) (0.0870 g, 0.404 mmol, 76) %) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.17 (s, 1 H), 2.27-2.36 (m, 8 H), 2.57 (s, 1 H), 3.41-3. 54 (M, 3 H), 3.66 (d, J = 10.4 Hz, 1 H), 6. 19 (s, 2 H), 6. 39 (s, 1 H).
ESI-MS: m / z = 216 (M + H) ⁺ .

Reference Example 159 Synthesis of 3- (2-chloro-4-nitrophenoxy) -1- (3,5-dimethylphenyl) -3-ethynylpyrrolidine:

The compound of Reference Example 158 (0.109 g, 0.506 mmol) was dissolved in DMF (1.01 mL), and sodium hydride (60 wt% mineral oil dispersion, 0.0223 g, 0.557 mmol) was added at 0 ° C. . After stirring for 20 minutes at the same temperature, 2-chloro-1-fluoro-4-nitrobenzene (0.0888 g, 0.506 mmol) was added at the same temperature. After stirring at room temperature for 2 hours, saturated aqueous ammonium chloride solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5-80 / 20), and the title compound (hereinafter, the compound of Reference Example 159) (0.157 g, 0.423 mmol, 84) %) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.27 (s, 6 H), 2. 60 (ddd, J = 13.6, 8.8, 8.8 Hz, 1 H), 2.78 (ddd, Jd) J = 13.6, 6.0, 4.4 Hz, 1 H), 2.84 (s, 1 H), 3.54-3. 58 (m, 2 H), 3. 90 (s, 2 H), 6. 19 (s, 2 H), 6.41 (s, 1 H), 7.63 (d, J = 9.1 Hz, 1 H), 8. 16 (dd, J = 9.1, 2.7 Hz, 1 H), 8.28 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 371 (M + H) ⁺ .

(Reference Example 160) Synthesis of 3-chloro-4-((1- (3,5-dimethylphenyl) -3-ethynylpyrrolidin-3-yl) oxy) aniline:

The compound of Reference Example 159 (0.157 g, 0.423 mmol) is dissolved in THF (1.84 mL), ethanol (3.65 mL), water (1.84 mL), iron powder (0.0946 g, 1.69 mmol) And acetic acid (0.242 mL, 4.23 mmol) were added at room temperature. After stirring at 50 ° C. for 2 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 93/7 to 70/30) to give the title compound (hereinafter referred to as the compound of Reference Example 160) (0.120 g, 0.352 mmol, 83) %) As a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.27 (s, 6 H), 2.42 (ddd, J = 13.2, 8.4, 8.4 Hz, 1 H), 2.62-2. 69 (m, 2H), 3.48 (ddd, J = 8.4, 8.4, 4.4 Hz, 1 H), 3.56 (brs, 2 H), 3.61 (ddd, J = 8.4 , 8.4, 6.8 Hz, 1 H), 3.69 (d, J = 10.4 Hz, 1 H), 3.77 (d, J = 10.4 Hz, 1 H), 6.16 (s, 2 H) , 6.37 (s, 1 H), 6.52 (dd, J = 8.6, 2.7 Hz, 1 H), 6.69 (d, J = 2.7 Hz, 1 H), 7. 34 (d, J = 8.6 Hz, 1 H).
ESI-MS: m / z = 341 (M + H) ^<+> .

Reference Example 161 Synthesis of 8-chloro-1 ′-(3,5-dimethylphenyl) spiro [chromene-2,3′-pyrrolidine] -6-amine:

The compound of Reference Example 160 (0.100 g, 0.293 mmol) was dissolved in o-xylene (5.86 mL) and stirred at 145 ° C. for 3.5 hours. The reaction solution is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 60/40) to obtain the title compound (hereinafter, a compound of Reference Example 161) (0. 1). 0596 g (0.175 mmol, 60%) were obtained as a brown oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.97 (ddd, J = 13.6, 10.0, 8.8 Hz, 1 H), 2.27 (s, 6 H), 2.45-2. 51 (m, 1 H), 3.43-3. 50 (m, 4 H), 3. 60 (ddd, J = 10.0, 10.0, 6.4 Hz, 1 H), 3.69 (dd, J = 11.2, 1.6 Hz, 1 H), 5. 80 (d, J = 9.5 Hz, 1 H), 6. 20 (s, 2 H), 6.3 1 (d, J = 2.7 Hz, 1 H) , 6.37 (s, 1 H), 6. 39 (d, J = 9.5 Hz, 1 H), 6.56 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 341 (M + H) ^<+> .

(Reference Example 162) (2R) -2-((8-Chloro-1 '-(3,5-dimethylphenyl) spiro [chromene-2,3'-pyrrolidine] -6-yl) carbamoyl) piperidine-1- ( Synthesis of tert-butyl carboxylic acid:

The compound of Reference Example 161 (0.100 g, 0.293 mmol) was dissolved in DMF (2.93 mL), diisopropylethylamine (0.0666 mL, 0.381 mmol), (R) -1- (tert-butoxycarbonyl)- 2-Piperidinecarboxylic acid (0.0740 g, 0.323 mmol) and HATU (0.134 g, 0.352 mmol) were added at 0 ° C. After stirring at room temperature for 17 hours, water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 90/10 to 70/30), and the title compound (hereinafter, the compound of Reference Example 162) (0.0991 g, 0.179 mmol, 61%) Was obtained as a brown solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.70 (m, 13 H), 2.00 (ddd, J = 13.2, 6.4, 6.4 Hz, 1 H), 27-2.35 (m, 8 H), 2.48 (dd, J = 13.2, 6.4 Hz, 1 H), 2.78-2.85 (m, 1 H), 3.45-3.51 (M, 2H), 3.61 (ddd, J = 9.6, 9.6, 6.4 Hz, 1 H), 3.70 (brd, J = 10.8 Hz, 1 H), 3.99-4. 14 (m, 1 H), 4.82-4. 87 (m, 1 H), 5. 83 (d, J = 10.0 Hz, 1 H), 6.20 (s, 2 H), 6.38 (s, 1H), 6.45 (d, J = 10.0 Hz, 1 H), 7.22 to 7.23 (m, 1 H), 7.26 to 7.28 (m, 1 H), 8.11 (brs, 1H).
ESI-MS: m / z = 552 (M + H) ⁺ .

Example 115 (2R) -1-Acetyl-N- (8-chloro-1 ′-(3,5-dimethylphenyl) spiro [chromene-2,3′-pyrrolidine] -6-yl) piperidine-2 -Synthesis of carboxamide:

The compound of Reference Example 162 (0.0991 g, 0.179 mmol) was dissolved in dichloromethane (1.80 mL), and trifluoroacetic acid (0.449 mL, 5.83 mmol) was added at 0 ° C. After stirring at room temperature for 1.5 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product was dissolved in dichloromethane (1.79 mL) and triethylamine (0.0325 mL, 0.233 mmol) and acetic anhydride (0.0203 mL, 0.215 mmol) were added at 0 ° C. After stirring at room temperature for 16 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform / ethyl acetate = 94/6 to 75/25) to give the title compound (compound of Example 115 below) (0.0745 g, 0.151 mmol, 84%) Was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.60 (m, 2 H), 1.70 to 1. 79 (m, 2 H), 1.89 to 2. 04 (m, 2 H) , 2.21 (s, 3 H), 2.24-2.30 (m, 7 H), 2.44-2.50 (m, 1 H), 3.11-3.18 (m, 1 H), 3 .44-3.51 (m, 2H), 3.61 (ddd, J = 9.2, 9.2, 6.4 Hz, 1 H), 3.70 (brd, J = 10.4 Hz, 1 H), 3.73-3.80 (m, 1 H), 5.22-5. 26 (m, 1 H), 5.82 (d, J = 10.0 Hz, 1 H), 6.20 (s, 2 H), 6.37 (s, 1 H), 6.44 (d, J = 10.0 Hz, 1 H), 7.16-7.20 (m, 1 H), 7.31-7. 35 (m, 1 H), 8.28 (s, 1 H)
ESI-MS: m / z = 494 (M + H) ^<+> .

Example 116 (2R) -1-Acetyl-N- (8-chloro-1 ′-(3,5-dimethylphenyl) spiro [chroman-2,3′-pyrrolidine] -6-yl) piperidine-2 -Synthesis of carboxamide:

The compound of Example 115 (0.0487 g, 0.0986 mmol) was dissolved in ethanol (1.97 mL) and palladium-carbon (5 wt%, 0.00974 g) was added at room temperature. After stirring under the hydrogen atmosphere at the same temperature for 9 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 10/90) to give the title compound (compound of Example 116 below) (0.0429 g, 0.0865 mmol, 88%) as a pale brown solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 to 1.56 (m, 2 H), 1.70-1. 79 (m, 2 H), 1.88-2.12 (m, 4 H) , 2.21 (s, 3 H), 2.25-2.31 (m, 8 H), 2.87 (dd, J = 6.4, 6.4 Hz, 2 H), 3.12-3. m, 1 H), 3.41-3. 52 (m, 3 H), 3.57 (ddd, J = 9.2, 9.2, 6.4 Hz, 1 H), 3.73-3. 79 (m , 1H), 5.23-5.26 (m, 1H), 6.19 (s, 2H), 6.37 (s, 1H), 7.23 (d, J = 2.3 Hz, 1H), 7.32 (d, J = 2.3 Hz, 1 H), 8.22 (s, 1 H).
ESI-MS: m / z = 496 (M + H) ^<+> .

Reference Example 163 Synthesis of 1- (o-tolyl) piperidin-4-one:

Suspend 1,4-dioxa-8-azaspiro [4.5] decane (2.00 g, 14.0 mmol) and tert-butyloxy potassium (2.19 g, 19.6 mmol) in toluene (34.9 mL), 1-bromo-2-methylbenzene (2.63 g, 15.4 mmol), 2,2'-bis (diphenylphosphino) -1,1'-binaphthyl (0.261 g, 0.419 mmol) and tris (dibenzylidene) Acetone) dipalladium (0) (0.128 g, 0.140 mmol) was added at room temperature. After stirring at 100 ° C. for 20 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product was dissolved in THF (14.0 mL) and water (14.0 mL) and acetic acid (42.3 mL) were added at room temperature. After stirring at 50 ° C. for 120 hours, the reaction solution was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized with ethyl acetate to give the title compound (hereinafter, the compound of Reference Example 163) (1.16 g, 6.13 mmol, 44%) as an orange solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.39 (s, 3 H), 2.61 (t, J = 5.9 Hz, 4 H), 3.22 (t, J = 5.9 Hz, 4 H) , 7.02-7.05 (m, 2H), 7.18 (ddd, J = 7.7, 7.7, 1.2 Hz, 1 H), 7.23 (d, J = 7.7 Hz, 1 H) ),
ESI-MS: m / z = 190 (M + H) ⁺ .

Reference Example 164 Synthesis of 4-ethynyl-1- (o-tolyl) piperidin-4-ol:

The compound of Reference Example 163 (0.500 g, 2.64 mmol) is dissolved in THF (26.0 mL), and ethynyl magnesium bromide-THF solution (0.5 M, 7.92 mL, 3.96 mmol) is added at -20 ° C. The After stirring for 30 minutes at the same temperature, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5-80 / 20) to give the title compound (hereinafter, the compound of Reference Example 164) (0.441 g, 2.05 mmol, 78) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.95 to 2.01 (m, 2 H), 2.06 to 2.12 (m, 2 H), 2.30 (s, 3 H), 2.57 (S, 1H), 2.90-2.96 (m, 2H), 3.04-3.09 (m, 2H), 6.98 (dd, J = 7.7, 7.7 Hz, 1H) , 7.05 (d, J = 7.7 Hz, 1 H), 7.14-7. 19 (m, 2 H).
ESI-MS: m / z = 216 (M + H) ⁺ .

Reference Example 165 Synthesis of 4- (2-chloro-4-nitrophenoxy) -4-ethynyl-1- (o-tolyl) piperidine:

The compound of Reference Example 164 (0.441 g, 2.05 mmol) was dissolved in DMF (4.10 mL), and sodium hydride (60% by weight mineral oil dispersion, 0.0900 g, 2.25 mmol) was added at 0 ° C. . After stirring for 20 minutes at the same temperature, 2-chloro-1-fluoro-4-nitrobenzene (0.360 g, 2.05 mmol) was added at the same temperature. After stirring at room temperature for 1 hour, saturated aqueous ammonium chloride solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 98/2 to 90/10) to give the title compound (hereinafter, the compound of Reference Example 165) (0.471 g, 1.27 mmol, 62) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.31 (s, 3 H), 2.35-2.42 (m, 4 H), 2.87 (s, 1 H), 2.95-3.01 (M, 2H), 3.08-3. 13 (m, 2H), 7.01 (ddd, J = 7.7, 7.7, 1.1 Hz, 1 H), 7.06 (d, J = 7.7 Hz, 1 H), 7.16-7.20 (m, 2 H), 7.82 (d, J = 9.1 Hz, 1 H), 8.13 (dd, J = 9.1, 2.7 Hz , 1 H), 8.33 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 371 (M + H) ⁺ .

Reference Example 166 Synthesis of 3-chloro-4-((4-ethynyl-1- (o-tolyl) piperidin-4-yl) oxy) aniline:

The compound of Reference Example 165 (0.450 g, 1.21 mmol) is dissolved in THF (3.03 mL), ethanol (6.07 mL), water (3.03 mL), iron powder (0.271 g, 4.85 mmol) And acetic acid (0.695 mL, 12.1 mmol) were added at room temperature. After stirring at 50 ° C. for 3 hours, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. To the obtained residue was added saturated aqueous sodium hydrogen carbonate solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 94/6 to 75/25), and the title compound (hereinafter, the compound of Reference Example 166) (0.408 g, 1.20 mmol, 99) %) As a pale orange solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14-2.20 (m, 2H), 2.26-2.31 (m, 5H), 2.68 (s, 1H), 2.90 -2.96 (m, 2H), 3.10-3.16 (m, 2H), 3.56 (brs, 2H), 6.52 (dd, J = 8.8, 2.8 Hz, 1H) , 6.73 (d, J = 2.8 Hz, 1 H), 6.98 (dd, J = 7.7 Hz, 1 H), 7.07 (d, J = 7.7 Hz, 1 H), 7.14 7.19 (m, 2H), 7.40 (d, J = 8.8 Hz, 1 H).
ESI-MS: m / z = 341 (M + H) ^<+> .

(Reference Example 167) Synthesis of 8-chloro-1 '-(o-tolyl) spiro [chromene-2,4'-piperidine] -6-amine:

The compound of Reference Example 166 (0.408 g, 1.20 mmol) was dissolved in o-xylene (23.9 mL) and stirred at 145 ° C. for 8 hours. The reaction solution is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 70/30) to obtain the title compound (hereinafter, a compound of Reference Example 167) (0. 1). 307 g, 0.901 mmol, 75%) were obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.81-1.88 (m, 2H), 2.09-2.15 (m, 2H), 2.31 (s, 3H), 2.89 −2.93 (m, 2 H), 3.23 (ddd, J = 12.0, 12.0, 1.6 Hz, 2 H), 3.43 (brs, 2 H), 5.71 (d, J = 10.0 Hz, 1 H), 6.30 (d, J = 2.7 Hz, 1 H), 6.31 (d, J = 10.0 Hz, 1 H), 6.58 (d, J = 2.7 Hz, 1 H ), 6.98 (ddd, J = 7.2, 7.2, 1.2 Hz, 1 H), 7.12-7.14 (m, 1 H), 7.17-7.19 (m, 2 H) .
ESI-MS: m / z = 341 (M + H) ^<+> .

(Reference Example 168) (R) -2-((8-Chloro-1 '-(o-tolyl) spiro [chromene-2,4'-piperidine] -6-yl) carbamoyl) piperidine-1-carboxylic acid tert Synthesis of -butyl:

The compound of Reference Example 167 (0.207 g, 0.607 mmol) was dissolved in DMF (6.07 mL), diisopropylethylamine (0.138 mL, 0.790 mmol), (R) -1- (tert-butoxycarbonyl)- 2-Piperidinecarboxylic acid (0.153 g, 0.668 mmol) and HATU (0.277 g, 0.729 mmol) were added at 0 ° C. After stirring at room temperature for 22 hours, water was added to the reaction solution, and the aqueous layer was extracted with a mixed solvent of n-hexane / ethyl acetate = 80/20 (V / V). The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 94/6 to 75/25) to give the title compound (hereinafter, the compound of Reference Example 168) (0.329 g, 0.596 mmol, 98) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41-1.72 (m, 14 H), 1.83-1. 91 (m, 2 H), 2. 12 (brd, J = 12.7 Hz, 2H), 2.27-2.37 (m, 4H), 2.78-2.85 (m, 1H), 2.92 (ddd, J = 12.0.3.2, 3.2 Hz, 2H ), 3.23 (ddd, J = 12.0, 12.0, 1.6 Hz, 2 H), 3.99-4.14 (m, 1 H), 4.82-4. 88 (m, 1 H) , 5.73 (d, J = 9.5 Hz, 1 H), 6.37 (d, J = 9.5 Hz, 1 H), 6.99 (ddd, J = 7.2, 7.2, 0.8 Hz , 1H), 7.13 (d, J = 7.2 Hz, 1 H), 7.18-7.21 (m, 3 H), 7.33 (d, J = 1.8 Hz, 1 H), 8.11 (Brs, H).
ESI-MS: m / z = 552 (M + H) ⁺ .

Example 117 (R) -1-Acetyl-N- (8-chloro-1 ′-(o-tolyl) spiro [chromene-2,4′-piperidine] -6-yl) piperidine-2-carboxamide Synthesis:

The compound of Reference Example 168 (42.1 g, 76.2 mmol) was dissolved in dichloromethane (800 mL), and trifluoroacetic acid (200 mL, 2.60 mol) was added at 0 ° C. After stirring for 0.5 hours at room temperature, the reaction solution was added to saturated aqueous sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product was dissolved in dichloromethane (240 mL) and triethylamine (13.8 mL, 99.1 mmol) and acetic anhydride (8.63 mL, 91.4 mmol) were added at 0 ° C. After stirring at room temperature for 18 hours, to the reaction solution was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform / methanol = 100/0 to 80/20), and recrystallized from ethyl acetate / heptane to give the title compound (compound of Example 117 below) (24) .2 g, 49.0 mmol, 64%) were obtained as white crystals.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.60 (m, 2 H), 1. 70 1. 78 (m, 2 H), 1.8 4 1. 98 (m, 3 H) , 2.09-2.14 (m, 2 H), 2.21 (s, 3 H), 2.24-2.30 (m, 1 H), 2.31 (s, 3 H), 2.89-2 .94 (m, 2H), 3.12-3.26 (m, 3H), 3.73-3.79 (m, 1H), 5.23-5.25 (m, 1H), 5.72 (D, J = 10.0 Hz, 1 H), 6.35 (d, J = 10.0 Hz, 1 H), 6.98 (ddd, J = 7.2, 7.2, 1.2 Hz, 1 H), 7.12-7.19 (m, 4H), 7.37 (d, J = 2.3 Hz, 1 H), 8.26 (brs, 1 H).
ESI-MS: m / z = 494 (M + H) ^<+> .

Example 118 (R) -1-Acetyl-N- (8-chloro-1 ′-(o-tolyl) spiro [chroman-2,4′-piperidine] -6-yl) piperidine-2-carboxamide Synthesis:

The compound of Example 117 (0.110 g, 0.223 mmol) was dissolved in ethanol (4.45 mL) and palladium-carbon (5 wt%, 0.0220 g) was added at room temperature. After stirring for 9 hours under a hydrogen atmosphere, the reaction solution was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 20/80) to give the title compound (compound of Example 118 below) (0.0836 g, 0.169 mmol, 76) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 to 1.56 (m, 2 H), 1.73-1. 83 (m, 4 H), 1.86 to 1. 89 (m, 2 H) , 1.90-1.94 (m, 3 H), 2. 20 (s, 3 H), 2.24-2. 30 (m, 1 H), 2.31 (s, 3 H), 2.79-2 .82 (m, 2H), 2.88-2 .95 (m, 2H), 3.11-3.19 (m, 3H), 3.72-3.79 (m, 1H), 5.23 -5.26 (m, 1 H), 6.98 (ddd, J = 7.7, 7.7, 1.2 Hz, 1 H), 7.11 (d, J = 7.7 Hz, 1 H), 7. 17-7.20 (m, 3H), 7.36 (d, J = 2.4 Hz, 1 H), 8.21 (brs, 1 H).
ESI-MS: m / z = 496 (M + H) ^<+> .

Reference Example 169 Synthesis of 1- (m-tolyl) piperidin-4-one:

The title compound (following, compound of Reference Example 169) (1.15 g) was prepared according to the same procedure as in Reference Example 163 except for using 1-bromo-3-methylbenzene instead of 1-bromo-2-methylbenzene. , 6.08 mmol, 44%) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.34 (s, 3 H), 2.55 (t, J = 5.9 Hz, 4 H), _3. 60 (t, J = 5.9 Hz, 4 H) , 6.72 (d, J = 7.7 Hz, 1 H), 6.79-6.81 (m, 2 H), 7.19 (dd, J = 7.7, 7, 7 Hz, 1 H).
ESI-MS: m / z = 190 (M + H) ⁺ .

Reference Example 170 Synthesis of 4-ethynyl-1- (m-tolyl) piperidin-4-ol:

The title compound (hereinafter, the compound of Reference Example 170) (0.840 g, 3.90 mmol, 64) was prepared by using the compound of Reference Example 169 instead of the compound of Reference Example 163 and using the same procedure as in Reference Example 164 except the above. %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90-1.97 (m, 2 H), 2.02 (s, 1 H), 2.03-2.09 (m, 2 H), 2.31 (S, 3 H), 2.5 5 (s, 1 H), 3. 12-3. 18 (m, 2 H), 3. 46-3. 52 (m, 2 H), 6. 67 (d, J = 7) 2 Hz, 1 H), 6.75-6. 79 (m, 2 H), 7. 15 (dd, J = 7.2, 7.2 Hz, 1 H).
ESI-MS: m / z = 216 (M + H) ⁺ .

Reference Example 171 Synthesis of 4- (2-chloro-4-nitrophenoxy) -4-ethynyl-1- (m-tolyl) piperidine:

Using the compound of Reference Example 170 instead of the compound of Reference Example 164, and using the same procedure as Reference Example 165 except the above, the title compound (the compound of Reference Example 171) (0.763 g, 2.06 mmol, 53) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.28-2.39 (m, 7 H), 2.84 (s, 1 H), 3.27-3. 33 (m, 2 H), 3.37 -3.44 (m, 2 H), 6.71 (d, J = 7.7 Hz, 1 H), 6.75-6. 77 (m, 2 H), 7.14-7. 19 (m, 1 H) , 7.80 (d, J = 9.1 Hz, 1 H), 8.12 (dd, J = 9.1, 2.7 Hz, 1 H), 8.31 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 371 (M + H) ⁺ .

Reference Example 172 Synthesis of 3-chloro-4-((4-ethynyl-1- (m-tolyl) piperidin-4-yl) oxy) aniline:

The title compound (hereinafter, the compound of Reference Example 172) (0.660 g, 1.94 mmol, 94) was prepared by using the compound of Reference Example 171 instead of the compound of Reference Example 165 and using the same procedure as in Reference Example 166 except the above. %) As a pale red solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.13-2.19 (m, 2H), 2.22-2.29 (m, 2H), 2.31 (s, 3H), 2.65 (S, 1 H), 3.11-3. 17 (m, 2 H), 3.51-3. 56 (m, 4 H), 6.51 (dd, J = 8.8, 2.8 Hz, 1 H) , 6.68 (d, J = 7.6 Hz, 1 H), 6.72 (d, J = 2.8 Hz, 1 H), 6.75-6.77 (m, 2 H), 7.15 (dd, J = 7.6, 7.6 Hz, 1 H, 7.38 (d, J = 8.8 Hz, 1 H).
ESI-MS: m / z = 341 (M + H) ^<+> .

Reference Example 173 Synthesis of 8-chloro-1 ′-(m-tolyl) spiro [chromene-2,4′-piperidine] -6-amine:

The title compound (hereinafter, the compound of Reference Example 173) (0.436 g, 1.28 mmol, 66) was prepared by using the compound of Reference Example 172 instead of the compound of Reference Example 166 and using the same procedure as in Reference Example 167 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.77-1.84 (m, 2H), 2.07-2.12 (m, 2H), 2.33 (s, 3H), 3.30 -3.37 (m, 2H), 3.42 (brs, 2H), 3.45-3. 50 (m, 2H), 5.64 (d, J = 10.0 Hz, 1H), 6.29 -6.31 (m, 2H), 6.57 (d, J = 2.7 Hz, 1 H), 6.67 (d, J = 7.7 Hz, 1 H), 6.78-6.81 (m, 2H), 7.14-7.18 (m, 1H).
ESI-MS: m / z = 341 (M + H) ^<+> .

(Reference Example 174) (R) -2-((8-Chloro-1 '-(m-tolyl) spiro [chromene-2,4'-piperidine] -6-yl) carbamoyl) piperidine-1-carboxylic acid tert Synthesis of -butyl:

The title compound (hereinafter, the compound of Reference Example 174) (0.541 g, 0.980 mmol, 99) was prepared by using the compound of Reference Example 173 instead of the compound of Reference Example 167 and using the same procedure as in Reference Example 168 except the above. %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41-1.71 (m, 12H), 1.79-1.87 (m, 2H), 2.07-2.12 (m, 2H) , 2.28-2.37 (m, 4H), 2.79-2.85 (m, 1H), 3.30-3.36 (m, 2H), 3.46-3.51 (m, 2H), 3.99-4.14 (m, 3H), 4.83-4.86 (m, 1H), 5.66 (d, J = 10.0 Hz, 1H), 6.36 (d, J) J = 10.0 Hz, 1 H), 6.68 (d, J = 7.2 Hz, 1 H), 6.77-6.81 (m, 2 H), 7.14-7. 18 (m, 2 H), 7.31 (d, J = 2.3 Hz, 1 H), 8.09 (brs, 1 H).
ESI-MS: m / z = 552 (M + H) ⁺ .

Example 119 (R) -1-Acetyl-N- (8-chloro-1 ′-(m-tolyl) spiro [chromene-2,4′-piperidine] -6-yl) piperidine-2-carboxamide Synthesis:

Using the compound of Reference Example 174 instead of the compound of Reference Example 168, and using the same procedure as Example 117 except the above, the title compound (the compound of Example 119 below) (0.438 g, 0.887 mmol, 90) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.52-1.60 (m, 2 H), 1.71-1. 86 (m, 4 H), 1.88-2.01 (m, 1 H) , 2.06-2.12 (m, 2H), 2.21 (s, 3H), 2.24-2.30 (m, 1H), 2.33 (s, 3H), 3.11-3. .19 (m, 1 H), 3.29-3. 36 (m, 2 H), 3.45-3. 50 (m, 2 H), 3. 73-3. 79 (m, 1 H), 5.23 −5.25 (m, 1 H), 5.65 (d, J = 10.0 Hz, 1 H), 6.34 (d, J = 1.0 Hz, 1 H), 6.68 (d, J = 7. 2 Hz, 1 H), 6.78-6.81 (m, 2 H), 7.13-7. 18 (m, 2 H), 7. 36 (d, J = 2.7 Hz, 1 H), 8. 26 ( s, 1 H).
ESI-MS: m / z = 494 (M + H) ^<+> .

Reference Example 175 Synthesis of 1- (p-tolyl) piperidin-4-one:

The title compound (hereinafter, the compound of Reference Example 175) (2.25 g) was prepared according to the same procedure as in Reference Example 163 except for using 1-bromo-4-methylbenzene instead of 1-bromo-2-methylbenzene. , 11.9 mmol, 85%) as a yellow oil.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.29 (s, 3 H), 2.55 (t, J = 6.1 Hz, 4 H), 3.55 (t, J = 6.1 Hz, 4 H) , 6.91 (d, J = 8.2 Hz, 2 H), 7.11 (d, J = 8.2 Hz, 2 H).
ESI-MS: m / z = 190 (M + H) ⁺ .

Reference Example 176 Synthesis of 4-ethynyl-1- (p-tolyl) piperidin-4-ol:

The title compound (hereinafter, the compound of Reference Example 176) (1.51 g, 7.01 mmol, 59) was prepared by using the compound of Reference Example 175 instead of the compound of Reference Example 163 and using the same procedure as in Reference Example 164 except the above. %) As a pale red solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.91-1.98 (m, 2 H), 2.01 (brs, 1 H), 2.03-2.10 (m, 2 H), 2.27 (S, 3H), 2.54 (s, 1H), 3.08-3.14 (m, 2H), 3.40-3.46 (m, 2H), 6.87 (d, J = 8) 6 Hz, 2 H), 7.07 (d, J = 8.6 Hz, 2 H).
ESI-MS: m / z = 216 (M + H) ⁺ .

Reference Example 177 Synthesis of 4- (2-chloro-4-nitrophenoxy) -4-ethynyl-1- (p-tolyl) piperidine:

The title compound (hereinafter, the compound of Reference Example 177) (1.97 g, 5.31 mmol, 76) was prepared by using the compound of Reference Example 176 instead of the compound of Reference Example 164 and using the same procedure as in Reference Example 165 except the above. %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.28 (s, 3 H), 2.29-2.40 (m, 4 H), 2.84 (s, 1 H), 3.22-3. 28 (M, 2 H), 3.33-3. 39 (m, 2 H), 6. 87 (d, J = 8.6 Hz, 2 H), 7.09 (d, J = 8.6 Hz, 2 H), 7 80 (d, J = 9.1 Hz, 1 H), 8.12 (dd, J = 9.1, 2.7 Hz, 1 H), 8.31 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 371 (M + H) ⁺ .

Reference Example 178 Synthesis of 3-chloro-4-((4-ethynyl-1- (p-tolyl) piperidin-4-yl) oxy) aniline:

The title compound (hereinafter, the compound of Reference Example 178) (1.43 g, 4.20 mmol, 98) was prepared by using the compound of Reference Example 177 instead of the compound of Reference Example 165 and using the same procedure as in Reference Example 166 except the above. %) As a yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.13-2.19 (m, 2H), 2.23-2.29 (m, 5 H), 2.65 (s, 1 H), 3.07 -3. 14 (m, 2H), 3.46-3.51 (m, 2H), 3.56 (brs, 2H), 6.51 (dd, J = 8.6, 2.7 Hz, 1H) , 6.72 (d, J = 2.7 Hz, 1 H), 6.87 (d, J = 8.6 Hz, 2 H), 7.07 (d, J = 8.6 Hz, 2 H), 7.39 ( d, J = 8.6 Hz, 1 H).
ESI-MS: m / z = 341 (M + H) ^<+> .

Reference Example 179 Synthesis of 8-chloro-1 ′-(p-tolyl) spiro [chromene-2,4′-piperidine] -6-amine:

Using the compound of Reference Example 178 instead of the compound of Reference Example 166, and using the same procedure as Reference Example 167 except the above, the title compound (compound of Reference Example 179 below) (1.05 g, 3.08 mmol, 73) %) As a pale yellow solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.78 to 1.86 (m, 2 H), 2.07 to 2.12 (m, 2 H), 2.28 (s, 3 H), 3.26 -3.33 (m, 2H), 3.38-3.44 (m, 4H), 5.64 (d, J = 10.0 Hz, 1 H), 6.28-6.31 (m, 2 H) , 6.56 (d, J = 2.7 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 2 H), 7.08 (d, J = 8.6 Hz, 2 H).
ESI-MS: m / z = 341 (M + H) ^<+> .

(Reference Example 180) (R) -2-((8-Chloro-1 '-(p-tolyl) spiro [chromene-2,4'-piperidine] -6-yl) carbamoyl) piperidine-1-carboxylic acid tert Synthesis of -butyl:

Using the compound of Reference Example 179 instead of the compound of Reference Example 167, and according to the same procedure as Reference Example 168 except the above, the title compound (hereinafter, the compound of Reference Example 180) (0.759 g, 1.37 mmol, 94) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41-1.72 (m, 14 H), 1.81-1. 88 (m, 2 H), 2.07-2.13 (m, 2 H) , 2.28 (s, 3 H), 2.30-2.36 (m, 1 H), 2.77-2.85 (m, 1 H), 3.26-3. 33 (m, 2 H), 3 .39-3.45 (m, 2H), 4.02-4.10 (m, 1H), 4.82-4.85 (m, 1H), 5.66 (d, J = 10.0 Hz, 1H), 6.36 (d, J = 10.0 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 2 H), 7.09 (d, J = 8.6 Hz, 2 H), 7. 17 (d, J = 2.7 Hz, 1 H), 7.31 (d, J = 2.7 Hz, 1 H), 8.07 (brs, 1 H).
ESI-MS: m / z = 552 (M + H) ⁺ .

Example 120 (R) -1-Acetyl-N- (8-chloro-1 ′-(p-tolyl) spiro [chromene-2,4′-piperidine] -6-yl) piperidine-2-carboxamide Synthesis:

Using the compound of Reference Example 180 instead of the compound of Reference Example 168, and using the same procedure as Example 117 except the above, the title compound (the compound of Example 120 below) (0.631 g, 1.28 mmol, 93) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44-1.62 (m, 2H), 1.69-1.79 (m, 2H), 1.80-1.88 (m, 2H) , 1.89-2.01 (m, 1 H), 2.07-2.12 (m, 2 H), 2.21 (s, 3 H), 2.23-2.28 (m, 4 H), 3 .11-3.18 (m, 1H), 3.26-3.32 (m, 2H), 3.38-3.44 (m, 2H), 3.73-3.79 (m, 1H) , 5.23-5.25 (m, 1 H), 5.65 (d, J = 10.0 Hz, 1 H), 6.34 (d, J = 10.0 Hz, 1 H), 6.91 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2 H), 7.13 (d, J = 2.3 Hz, 1 H), 7.36 (d, J = 2.3 Hz , 1H), 8.26 (s, H).
ESI-MS: m / z = 494 (M + H) ^<+> .

(Reference Example 181) Synthesis of tert-butyl 4-ethynyl-4-hydroxypiperidine-1-carboxylic acid:

After cooling an ethynyl magnesium bromide-THF solution (0.5 M, 65.2 mL, 32.6 mmol) to −20 ° C., tert-butyl 4-oxopiperidine-1-carboxylic acid dissolved in THF (50 mL) (5. 00 g (25.1 mmol) was added dropwise at the same temperature. After stirring at the same temperature for 1 hour, a saturated aqueous ammonium chloride solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 70/30), and the title compound (hereinafter, the compound of Reference Example 181) (2.89 g, 12.8 mmol, 51) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 (s, 9 H), 1.68-1.75 (m, 2 H), 1.87-1. 93 (m, 2 H), 2.01 (Brs, 1 H), 2.54 (s, 1 H), 3.24-3. 30 (m, 2 H), 3.71-3. 84 (m, 2 H).

Reference Example 182 Synthesis of tert-butyl 4- (2-chloro-4-cyanophenoxy) -4-ethynylpiperidine-1-carboxylate:

The compound of Reference Example 181 (2.89 g, 12.8 mmol) was dissolved in DMF (25.7 mL), and sodium hydride (60 wt% mineral oil dispersion, 0.564 g, 14.1 mmol) was added at 0 ° C. . After stirring for 30 minutes at the same temperature, 3-chloro-4-fluoro-benzonitrile (2.00 g, 12.8 mmol) was added at the same temperature. After stirring at room temperature for 1 hour, saturated aqueous ammonium chloride solution was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 70/30) to give the title compound (compound of Reference Example 182 below) (3.42 g, 9.48 mmol, 74%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 (s, 9 H), 2.06-2.18 (m, 4 H), 2.82 (s, 1 H), 3.48-3. 55 (M, 2H), 3.58-3.65 (m, 2H), 7. 50 (dd, J = 8.6, 2.3 Hz, 1 H), 7.69 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1 H).
ESI-MS: m / z = 359 (M-H) ^- .

Reference Example 183 Synthesis of tert-butyl 8-chloro-6-cyanospiro [chromene-2,4′-piperidine] -1′-carboxylate:

The compound of Reference Example 182 (3.42 g, 9.48 mmol) was dissolved in o-xylene (94.8 mL) and stirred at 145 ° C. for 16 hours. The reaction solution was added with n-hexane and extracted with acetonitrile. The acetonitrile layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography (n-hexane / ethyl acetate = 96/4 to 75/25), recrystallized with dichloromethane, and the title compound (hereinafter referred to as the compound of Reference Example 183) (2. 16 g, 5.99 mmol, 64%) were obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (s, 9 H), 1.61-1.68 (m, 2 H), 1.95-2.03 (m, 2 H), 3.23 -3.37 (m, 2H), 3.86-4.05 (m, 2H), 5.69 (d, J = 10.0 Hz, 1 H), 6.37 (d, J = 10.0 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1 H), 7.49 (d, J = 1.8 Hz, 1 H).
ESI-MS: m / z = 359 (M-H) ^- .

Reference Example 184 Synthesis of 8-Chlorospiro [chromene-2,4′-piperidine] -6-carbonitrile:

The compound of Reference Example 183 (1.80 g, 4.99 mmol) was dissolved in dichloromethane (49.9 mL), and trifluoroacetic acid (12.5 mL, 162 mmol) was added at 0 ° C. After stirring at room temperature for 1.5 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound (hereinafter, the compound of Reference Example 184) (1.23 g, 4.72 mmol, 95%) as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.64-1.72 (m, 2 H), 1.97-2.02 (m, 2 H), 2.87-2.92 (m, 2 H) , 3.14-3.21 (m, 2 H), 5. 74 (d, J = 10.0 Hz, 1 H), 6.33 (d, J = 10.0 Hz, 1 H), 7.17 (d, J) J = 1.8 Hz, 1 H), 7.48 (d, J = 1.8 Hz, 1 H).
ESI-MS: m / z = 261 (M + H) ⁺ .

Reference Example 185 Synthesis of 8-chloro-1′-phenylspiro [chromene-2,4′-piperidine] -6-carbonitrile:

The compound of Reference Example 184 (0.200 g, 0.767 mmol) and tert-butyloxysodium (0.103 g, 1.07 mmol) were suspended in toluene (1.92 mL), and bromobenzene (0.132 g, 0.844 mmol). ), 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl (0.0143 g, 0.0230 mmol) and tris (dibenzylideneacetone) dipalladium (0) (0.00702 g, 0.00767 mmol) Was added at room temperature. After stirring at 100 ° C. for 17 hours, distilled water was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 70/30) to give the title compound (compound of Reference Example 185 below) (0.175 g, 0.520 mmol, 68%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.87-1.94 (m, 2H), 2.10-2.16 (m, 2H), 3.30-3.37 (m, 2H) , 3.50-3.54 (m, 2H), 5.74 (d, J = 10.0 Hz, 1 H), 6.38 (d, J = 10.0 Hz, 1 H), 6.86-6. 90 (m, 1 H), 6.99 (d, J = 8.6 Hz, 2 H), 7. 19 (d, J = 2.3 Hz, 1 H), 7. 29 (dd, J = 8. 6, 7 2 Hz, 2 H), 7.49 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 337 (M + H) ⁺ .

(Reference Example 186) Synthesis of tert-butyl (8-chloro-1'-phenylspiro [chromene-2,4'-piperidine] -6-yl) carboxylic acid:

The compound of Reference Example 185 (0.175 g, 0.520 mmol) was suspended in toluene (5.20 mL), and methanol (5.20 mL) and sodium hydroxide (0.416 g, 10.4 mmol) were added at room temperature. After stirring at 65 ° C. for 19 hours, 1 M hydrochloric acid was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product was suspended in tert-butanol (26.0 mL) and triethylamine (0.109 mL, 0.780 mmol) and diphenylphosphoryl azide (0.157 g, 0.572 mmol) were added at room temperature. After stirring for 17 hours at 80 ° C., the reaction solution was diluted with THF, 1M aqueous sodium hydroxide solution was added, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 50/50) to give the title compound (hereinafter, the compound of Reference Example 186) (0.0298 g, 0.0700 mmol, 13%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.51 (s, 9 H), 1.79-1.87 (m, 2 H), 2.08-2.13 (m, 2 H), 3.31 -3.38 (m, 2H), 3.47-3.51 (m, 2H), 5.65 (d, J = 10.0 Hz, 1 H), 6.29 (brs, 1 H), 6.36 (D, J = 10.0 Hz, 1 H), 6.82-6.87 (m, 1 H), 6.98-7.03 (m, 3 H), 7.16 (d, J = 2.3 Hz, 1H), 7.25-7.30 (m, 2H).
ESI-MS: m / z = 427 (M + H) ⁺ .

Reference Example 187 Synthesis of tert-butyl (R) -2-((8-chloro-1′-phenylspiro [chromene-2,4′-piperidine] -6-yl) carbamoyl) piperidine-1-carboxylic acid :

The compound of Reference Example 186 (0.0298 g, 0.0700 mmol) was dissolved in dichloromethane (0.700 mL), and trifluoroacetic acid (0.174 mL, 2.26 mmol) was added at 0 ° C. After stirring at room temperature for 1.5 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product is dissolved in DMF (0.700 mL), diisopropylethylamine (0.0159 mL, 0.0910 mmol), (R) -1- (tert-butoxycarbonyl) -2-piperidine carboxylic acid (0.0177 g) , 0.0770 mmol) and HATU (0.0319 g, 0.0840 mmol) were added at 0 ° C. After stirring at room temperature for 19 hours, water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 60/40), and the title compound (compound of reference example 187 below) (0.0340 g, 0.0632 mmol, 90) %) As a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.72 (m, 14H), 1.80-1.87 (m, 2H), 2.08-2.13 (m, 2H) , 2.27-2.36 (m, 1 H), 2.80-2.87 (m, 1 H), 3.31-3.38 (m, 2 H), 3.47-3. 52 (m, 2) 2H), 3.98-4.14 (m, 1H), 4.83-4.85 (m, 1H), 5.66 (d, J = 10.0 Hz, 1H), 6.36 (d, J = 10.0 Hz, 1 H), 6.84-6.87 (m, 1 H), 6.99 (d, J = 8.6 Hz, 2 H), 7.17 (d, J = 2.7 Hz, 1 H ), 7.26-7.32 (m, 3 H), 8.09 (brs, 1 H).
ESI-MS: m / z = 538 (M + H) ⁺ .

Example 121 Synthesis of (R) -1-acetyl-N- (8-chloro-1′-phenylspiro [chromene-2,4′-piperidine] -6-yl) piperidine-2-carboxamide:

The compound of Reference Example 187 (0.0328 g, 0.0610 mmol) was dissolved in dichloromethane (0.610 mL), and trifluoroacetic acid (0.152 mL, 1.97 mmol) was added at 0 ° C. After stirring at room temperature for 1.5 hours, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product was dissolved in dichloromethane (0.610 mL) and triethylamine (0.0111 mL, 0.0793 mmol) and acetic anhydride (0.00691 mL, 0.0732 mmol) were added at 0 ° C. After stirring for 4 hours at room temperature, saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 20/80) to give the title compound (compound of Example 121 below) (0.0272 g, 0.0567 mmol, 93%) was obtained as a white solid.
¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 to 1.57 (m, 2 H), 1.70 to 1.87 (m, 4 H), 1.89 to 2. 01 (m, 1 H) , 2.08-2.12 (m, 2H), 2.20 (s, 3H), 2.23-2.30 (m, 1H), 3.13-3.20 (m, 1H), 3 .31-3.37 (m, 2 H), 3.46-3.51 (m, 2 H), 3.73-3. 79 (m, 1 H), 5.23-5.25 (m, 1 H) , 5.65 (d, J = 10.0 Hz, 1 H), 6.34 (d, J = 10.0 Hz, 1 H), 6.83-6.87 (m, 1 H), 6.99 (d, J) J = 8.6 Hz, 2 H), 7. 13 (d, J = 2.7 Hz, 1 H), 7.25-7. 29 (m, 2 H), 7. 36 (d, J = 2.3 Hz, 1 H) ), 8.30 (s, 1 H)
ESI-MS: m / z = 480 (M + H) ⁺ .

(Example 122) RORγ-coactivator binding inhibitory action:
Cyclic amine derivative (I), stereoisomer or hydrate thereof, or pharmacologically acceptable thereof for binding of RORγ ligand binding domain (hereinafter RORγ-LBD) to coactivator the inhibitory effect of the salt, was assessed using a time-resolved fluorescence energy transfer LanthaScreen ^TM TR-FRET of (TR-FRET) invitrogen, Inc. using retinoid-Related Orphan Receptor (ROR) gamma Coactivator Assay kit.

The test compound was dissolved in DMSO and then diluted with a 5 mmol / L DTT-containing TR-FRET Coregulator Buffer D (invitogen) to a final DMSO concentration of 1%. To each well of a 384 well black plate (Corning), 4 nmol / L GST-fused RORγ-LBD (invitogen) diluted with the above buffer and a test compound were added. A test compound-free and GST-fused RORγ-LBD-free (background), and a test compound-free and GST-fused RORγ-LBD-added (control) wells were provided. Next, 150 nmol / L Flurescein-labeled TRAP220 / DRIP-2 (invitogen) diluted with the above buffer and 32 nmol / L terbium-labeled anti-GST antibody (invitogen) were added to each well. After incubating the plate at room temperature for 16 to 24 hours, the fluorescence at 495 nm and 520 nm when excited at 320 nm was measured for each well, and the Ratio (fluorescence at 520 nm / fluorescence at 495 nm) was calculated.

Fold change at the time of test compound addition (Ratio at the time of test compound addition / Ratio of background), Fold change of control (Ratio of control / Ratio of background), and Fold change of background (Ratio of background / background) After calculating the ratio of the ground, the binding inhibition rate of RORγ-LBD and the coactivator (hereinafter, RORγ-coactivator binding inhibition rate) (%) was calculated from the following formula 1.

RORγ-coactivator binding inhibition rate (%) = (1 − ((Fold change upon addition of test compound) − (Fold change)) / ((Fold change) − (Fold change) )) × 100 ... Formula 1

The RORγ-coactivator binding inhibition rate (%) at 33 μmol / L of the test compound is shown in Tables 2-1 to 2-3.

From this result, cyclic amine derivative (I), its stereoisomer or hydrate thereof, or pharmacologically acceptable salts thereof significantly inhibit the binding of RORγ-LBD to coactivator. It became clear.

(Example 123) IL-17 production inhibitory action in mouse splenocytes:
Inhibitory action of cyclic amine derivative (I), its stereoisomer or hydrates thereof, or their pharmacologically acceptable salts on IL-23 production by IL-23 stimulation using mouse splenocytes , The Journal of Biological Chemistry, 2003, 278, No. 3, p. The method described in 1910-1914 was partially modified and evaluated.

A single cell suspension was prepared from the spleen of a C57BL / 6J mouse (male, 6 to 26 weeks old) (Nihon Charles River Co., Ltd.), and splenocytes were prepared using Histopaque-1083 (Sigma). The culture medium is RPMI 1640 medium (Gibco), 10% FBS (Gibco), 50 U / mL penicillin, 50 μg / mL streptomycin (Gibco), 50 μmol / L 2-mercaptoethanol (Gibco) and 100 U / mL human IL- 2 (Cell Science Research Institute, Inc.) was added and used. The test compound was dissolved in DMSO and then diluted to a final concentration of 0.1% in culture medium. Splenocytes (3 × 10 ⁵ cells / well) prepared in culture medium are seeded in wells of a 96 well flat bottom plate (Corning Co.), and a test compound and 10 ng / mL of human IL-23 (R & D systems) are added. The cells were cultured at 37 ° C. and 5% CO ₂ for 3 days. In addition, a human IL-23 non-added and a test compound non-added, and a human IL-23 added and test compound non-added well were provided. After completion of the culture, the culture supernatant was collected, and the amount of IL-17 produced in the supernatant was quantified by ELISA (R & D systems).

The IL-17 production inhibition rate (%) was calculated from the following formula 2.

IL-17 production suppression rate (%) = (1- ((IL-23 production amount with addition of IL-23 and test compound))-(IL-17 production amount without IL-23 addition and without test compound) )) / ((The amount of IL-17 produced with addition of IL-23 and no test compound)-(the amount of IL-17 produced without addition of IL-23 and no test compound))) × 100 ··· Formula 2

The inhibition ratio (%) of IL-17 production at 5 μmol / L of the test compound is shown in Tables 3-1 to 3-3.

From this result, it was revealed that cyclic amine derivative (I), its stereoisomer or hydrates thereof, or their pharmacologically acceptable salts suppress IL-17 production.

Example 124 Suppressive Effect on Imiquimod-Induced Mouse Psoriasis Model:
Cyclic amine derivative (I), its stereoisomer or these hydrates, or their pharmacologically acceptable salts thereof in the imiquimod-induced mouse psoriasis model, using an increase in thickness of the auricle as an indicator of symptom deterioration The action was evaluated. The imiquimod-induced mouse psoriasis model was prepared by partially modifying the method of Schaper et al. (The Journal of Dermatological Science, 2013, 71, No. 1, p. 29-36).

BALB / c mice (male, 7 weeks old) (Nihon Charles River Co., Ltd.) were used at 8 weeks of age after preliminary breeding. In order to induce psoriasis-like symptoms, 5 mg of Becelna cream was applied once a day on the outside of the left and right auricle of the mouse for 8 days from the first day of imiquimod administration (hereinafter, induction day) to 7 days after induction. (Imikimod dose 0.5 mg / body / day).

The test compound was administered at a dose of 10 mg / kg once a day to the mice for 5 days from the 3rd day to the 7th day after induction. As test compounds, the compound of Example 46, the compound of Example 74, the compound of Example 109 and the compound of Example 117 were used. The compound of Example 46, the compound of Example 74, the compound of Example 109, and the compound of Example 117 were suspended in 0.5 w / v% methylcellulose solution and orally administered. The group to which the compound of Example 46 was administered to mice, the group to which the compound of Example 46 was administered, the group to which the compound of Example 74 was administered, the group to which the compound of Example 74 was administered, the group to which the compound of Example 109 was administered The compound administration group of Example 109 and the group to which the compound of Example 117 was administered were used as the compound administration group of Example 117. The vehicle administration group was similarly administered the solvent (0.5 w / v% methylcellulose solution) of each test compound.

On the day of induction, the thickness of the left and right auricles before (immune) administration of imiquimod and the thickness of the left and right auricles on day 8 after induction were measured using a digital micrometer (Mitsutoyo). The average thickness of the left and right auricles was taken as the auricle thickness, and the change (the auricular thickness on the 8th day after induction-the auricular thickness before the induction) was used as an index for drug efficacy evaluation.

The results are shown in FIG. 1, FIG. 2, FIG. 3 and FIG. The vertical axis represents the change in ear thickness (mm) (mean value ± standard error, n = 6). The “solvent” on the horizontal axis represents a solvent administration group, the “compound of Example 46” represents a compound administration group of Example 46, and the “compound of Example 74” represents a compound administration group of Example 74. Indicate “the compound of Example 109” indicates the compound administration group of Example 109, and “the compound of Example 117” indicates the compound administration group of Example 117. * Indicates statistically significant (*: P <0.05) in comparison with the vehicle administration group (Student's t-test).

Due to imiquimod induction, the auricle thickness at day 8 after induction in the solvent administration group increased by 0.25 mm to 0.27 mm relative to the auricle thickness before induction. The increase in the auricle thickness was statistically significantly suppressed by the administration of the compound of Example 46, the compound of Example 74, the compound of Example 109, or the compound of Example 117.

From these results, it is clear that the cyclic amine derivative (I), its stereoisomer or hydrates thereof, or their pharmacologically acceptable salts show a remarkable symptom suppressing effect on psoriasis. became.

Example 125 Symptom Suppressive Effect on Mouse Experimental Autoimmune Encephalomyelitis Model:
Cyclic amine derivative (I), its stereoisomer or their hydrates, or their pharmacologically acceptable in mouse experimental autoimmune encephalomyelitis model, using an increase in neurological symptom score as an indicator of symptom deterioration The effect of the salt was evaluated. A mouse experimental autoimmune encephalomyelitis model was created by partially modifying the method of Hindinger et al. (Journal of Neuroscience Research, 2006, 84, p. 1225-1234).

MOB 35-55 administration solution in which equal amounts of PBS solution containing partially synthesized peptide (MOG 35-55; CS Bio) of myelin oligodendrocyte glycoprotein prepared to a concentration of 4 mg / mL and complete adjuvant of Freund were mixed, C57BL A total of 0.1 mL (one-sided 0.05 mL) was inoculated intradermally on both flanks of 6J mice (male, 10 weeks old) (Charles River Japan Ltd.). Furthermore, on the day and two days after the inoculation of the MOG 35-55 administration solution, 200 μL of pertussis toxin (Sigma) adjusted to a concentration of 1 μg / mL was administered intraperitoneally to mice.

After inoculation of the MOG 35-55 administration solution, the test compound was administered to mice. The compound of Example 74 was used as a test compound. The compound of Example 74 was suspended in a 0.5 w / v% methylcellulose solution, and orally administered once daily at a dose of 1 mg / kg from 13 days after the inoculation of the MOG 35-55 administration solution on consecutive days. The group to which the compound of Example 74 was administered to mice was taken as the compound administration group of Example 74. The vehicle administration group was similarly administered the solvent (0.5 w / v% methylcellulose solution) of each test compound.

After inoculation of the MOG 35-55 administration solution, scoring the neurological symptom score of the group to which the test compound was administered and the corresponding solvent administration group (0: normal, 1: tail relaxation or hindlimb weakness, 2: tail relaxation and hindlimb weakness, 3: Partial limb paralysis, 4: Complete paralysis of hind limbs, 5: Death condition). As a scoring method, the method described in Current Protocols in Immunology (John Wiley & Sons. Inc, 2000, p.15.1.1-15.1.20) was used.

The results are shown in FIG. The vertical axis represents a neurological symptom score (mean value ± standard error, n = 10). The “solvent” on the horizontal axis represents a solvent administration group, and the “compound of Example 74” represents a compound administration group of Example 74. FIG. 5 shows the neurological symptom score 29 days after inoculation of the MOG 35-55 administration solution. * Indicates statistical significance in comparison with vehicle administration group (Wilcoxon test) (*: P <0.05).

Inoculation of the MOG 35-55 administration solution increased the neurological symptom score of the solvent administration group to 2.1. The elevation of the neurological symptom score was statistically significantly suppressed by the administration of the compound of Example 74.

From this result, it is shown that cyclic amine derivative (I), its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof exhibits a remarkable symptom suppressing effect on multiple sclerosis. It became clear.

Example 126 Suppressive Effect on DNFB Induced Mouse Allergic Dermatitis Model:
Cyclic amine derivative (I), its stereoisomer or their hydrates, or their pharmacologically acceptable in the DNFB-induced mouse allergic dermatitis model, using an increase in ear swelling as an indicator of symptom deterioration The effect of salt was evaluated. The DNFB-induced mouse allergic dermatitis model was prepared by partially modifying the method of Curzytek et al. (Pharmacological Reports, 2013, 65, p. 1237-1246).

BALB / c mice (female, 6 weeks old) (Nihon Charles River Co., Ltd.) were used at 7 or 8 weeks old after preliminary breeding. The back of the mouse was coated with 25 μL of 0.5 v / v% DNFB solution dissolved in acetone: olive oil (4: 1). The same operation was repeated the next day to sensitize the mouse. Four days after sensitization, 10 μL each of 0.2 v / v% DNFB solution dissolved in acetone: olive oil (4: 1) was applied to both sides of the right auricle of sensitized mice to induce inflammation.

One hour prior to challenge, mice were dosed with the test compound at a dose of 10 mg / kg. As test compounds, the compound of Example 46, the compound of Example 74, the compound of Example 109 and the compound of Example 117 were used. The compound of Example 46, the compound of Example 74, the compound of Example 109, and the compound of Example 117 were suspended in 0.5 w / v% methylcellulose solution and orally administered. The group to which the compound of Example 46 was administered to mice, the group to which the compound of Example 46 was administered, the group to which the compound of Example 74 was administered, the group to which the compound of Example 74 was administered, the group to which the compound of Example 109 was administered The compound administration group of Example 109 and the group to which the compound of Example 117 was administered were used as the compound administration group of Example 117. The vehicle administration group was similarly administered the solvent (0.5 w / v% methylcellulose solution) of the test compound.

The thickness of the right auricle before application of the DNFB solution on the day of induction (before induction) and the thickness of the right auricle 24 hours after induction were measured using a digital micrometer (Mitutoyo). The swelling rate of the auricle was calculated by the following equation 3 and was used as an index of drug efficacy evaluation.

Auricle swelling rate (%) = ((thickness of right auricle 24 hours after induction)-(thickness of right auricle before induction)) / Thickness of right auricle before induction × 100 ··· Formula 3

The results are shown in FIG. 6, FIG. 7, FIG. 8 and FIG. The vertical axis shows ear swelling rate (%) (mean value ± standard error, n = 6 to 7). The “solvent” on the horizontal axis represents a solvent administration group, the “compound of Example 46” represents a compound administration group of Example 46, and the “compound of Example 74” represents a compound administration group of Example 74. Indicate “the compound of Example 109” indicates the compound administration group of Example 109, and “the compound of Example 117” indicates the compound administration group of Example 117. * Indicates statistically significant (*: P <0.05) in comparison with the vehicle administration group (Student's t-test).

Auricle application of the DNFB solution increased the auricle swelling rate of the solvent administration group by 30.9% to 41.6%. The increase in the auricular swelling rate was statistically significantly suppressed by the administration of the compound of Example 46, the compound of Example 74, the compound of Example 109, or the compound of Example 117.

From this result, cyclic amine derivative (I), its stereoisomer or hydrates thereof, or pharmacologically acceptable salts thereof are significant against allergic dermatitis, particularly contact dermatitis. It became clear to show the symptom suppression effect.

Example 127 Suppressive Effect on Oxazolone-Induced Mouse Atopic Dermatitis Model:
Cyclic amine derivative (I), its stereoisomer or their hydrates, or their pharmacologically acceptable in oxazolone-induced mouse atopic dermatitis model, using an increase in thickness of the auricle as an indicator of symptom deterioration The effect of salt was evaluated. An oxazolone-induced mouse atopic dermatitis model was prepared by partially modifying the method of Nakajima et al. (Journal of Investigative Dermatology, 2014, 134, p. 2122-2130).

BALB / c mice (female, 7 weeks old) (Nihon Charles River Co., Ltd.) were used at 8 weeks of age after preliminary breeding. The mouse was sensitized by applying 25 μL of a 3 w / v% oxazolone solution in ethanol to the back of the mouse. 10 μL each of a 0.6 w / v% oxazolone solution dissolved in ethanol was applied to both sides of the right auricle of sensitized mice every other day from 5 days to 13 days after sensitization to induce inflammation.

The test compound was administered once daily at a dose of 10 mg / kg to mice for 15 days from the day of sensitization to 14 days after sensitization. As test compounds, the compound of Example 46, the compound of Example 74, the compound of Example 109 and the compound of Example 117 were used. The compound of Example 46, the compound of Example 74, the compound of Example 109, and the compound of Example 117 were suspended in a 0.5 w / v% methylcellulose solution and orally administered. The group to which the compound of Example 46 was administered to mice, the group to which the compound of Example 46 was administered, the group to which the compound of Example 74 was administered, the group to which the compound of Example 74 was administered, the group to which the compound of Example 109 was administered The compound administration group of Example 109 and the group to which the compound of Example 117 was administered were used as the compound administration group of Example 117. The vehicle administration group was similarly administered the solvent (0.5 w / v% methylcellulose solution) of each test compound.

The thickness of the right auricle before application of the oxazolone solution on the day of sensitization (before sensitization) and the thickness of the right auricle the day after the final induction were measured using a digital micrometer (Mitsutoyo). The change in ear thickness (thickness of right ear pinna after the last day of induction-thickness of right ear pinna before sensitization) was used as an index for drug efficacy evaluation.

The results are shown in FIGS. 10, 11, 12 and 13. The vertical axis shows the change in ear thickness (mm) (mean value ± standard error, n = 6 to 7). The “solvent” on the horizontal axis represents a solvent administration group, the “compound of Example 46” represents a compound administration group of Example 46, and the “compound of Example 74” represents a compound administration group of Example 74. Indicate “the compound of Example 109” indicates the compound administration group of Example 109, and “the compound of Example 117” indicates the compound administration group of Example 117. * Indicates statistically significant (*: P <0.05) in comparison with the vehicle administration group (Student's t-test).

The auricle application of the oxazolone solution increased the auricular thickness on the day after the final challenge of the solvent administration group by 0.68 mm to 0.70 mm with respect to the auricular thickness before sensitization. The increase in the auricle thickness was statistically significantly suppressed by the administration of the compound of Example 46, the compound of Example 74, the compound of Example 109, or the compound of Example 117.

From this result, cyclic amine derivative (I), its stereoisomer or their hydrates, or their pharmacologically acceptable salts are remarkable against allergic dermatitis, especially atopic dermatitis. It became clear to show the symptom suppression effect.

The cyclic amine derivative (I) of the present invention, its stereoisomer or hydrates thereof, or their pharmacologically acceptable salts inhibit the function of RORγ because they have excellent RORγ antagonist activity. Thus, it can be used as a medicine for a disease that can be expected to improve the pathological condition or ameliorate the symptoms. In particular, it can be used as an agent for treating or preventing an autoimmune disease such as multiple sclerosis or psoriasis or an allergic disease such as allergic dermatitis such as contact dermatitis or atopic dermatitis.

Claims

Cyclic amine derivatives represented by the following general formula (I), stereoisomers or hydrates thereof, or pharmacologically acceptable salts thereof.

[Wherein, A represents a group represented by the following general formula (II-1), (II-2), (II-3), (II-4) or (II-5)

(Wherein, R 1 is a hydrogen atom, cyano group, hydroxymethyl group, —C (= O) —OR 3 , an alkylsulfonyl group having a carbon number of 1 to 3) having 1 to 3 optional hydrogen atoms; An alkyl group having 1 to 3 carbon atoms (in the alkyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom) and an alkyloxy group having 1 to 3 carbon atoms (the alkyloxy group And the group is an aryl group or a heteroaryl group which may be substituted with a group selected from the group consisting of 1 to 3 arbitrary hydrogen atoms which may be substituted with a halogen atom); R 2 represents a halogen atom, R 3 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and a double line of a solid line and a dotted line represents a single bond or a double bond, and a wavy line represents Represents a bonding point with the general formula (I))
X represents a group represented by —C (= O) — (CH 2 ) n —R 4 or —S (= O) 2 —R 5 ; n represents an integer of 0 to 5; R 4 represents a cyano group, a hydroxy group, -N (R 6 ) R 7 , -NH-C (= Y) -NHR 6 , -NH-S (= O) 2 -NHR 6 , -C (= O) -OR 6 , -C (= O) -NHR 6 , a cyclic ether group having 4 to 6 ring atoms, an alkyl group having 1 to 3 carbon atoms (the alkyl group is an optional hydrogen atom of 1 to 3) And R.sup.5 may be substituted with a halogen atom) or a heteroaryl group in which one or two of the optional hydrogen atoms may be substituted with an alkyl group of 1 to 3 carbon atoms, R 5 R represents an alkyl group having 1 to 3 carbon atoms, R 6 represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (wherein the alkyl group is any of 1 to 3 carbon atoms) Hydrogen atom may be substituted with a halogen atom), and R 7 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an acyl group having 2 to 4 carbon atoms or an alkyl having 1 to 3 carbon atoms Represents a sulfonyl group, and Y represents an oxygen atom, a sulfur atom or = N-CN. ]
In R 1 , one or two optional hydrogen atoms are a fluorine atom, a chlorine atom, a cyano group, a hydroxymethyl group, -C (= O) -OR 3 , an alkylsulfonyl group having 1 to 3 carbon atoms, carbon An alkyl group of 1 to 3 (in the alkyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom) and an alkyloxy group having 1 to 3 carbon atoms (the above The alkyloxy group is a phenyl group which may be substituted by a group selected from the group consisting of one to three arbitrary hydrogen atoms which may be substituted with a fluorine atom or a chlorine atom), A pyridyl group or a pyrimidinyl group,
R 2 is a fluorine atom or a chlorine atom,
R 3 is an alkyl group having 1 to 3 carbon atoms,
n is an integer of 0 to 4 and
R 4 represents a cyano group, a hydroxy group, -N (R 6 ) R 7 , -NH-C (= Y) -NHR 6 , -NH-S (= O) 2 -NHR 6 , -C (= O) -OR 6 , -C (= O) -NHR 6 , oxetan-3-yl group, alkyl group having 1 to 3 carbon atoms (in the alkyl group, one to three arbitrary hydrogen atoms are a fluorine atom or chlorine Optionally substituted by an atom), or a heteroaryl group optionally substituted by one or two hydrogen atoms with a methyl group,
R 6 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (in the alkyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom). 6. The cyclic amine derivative according to item 1, its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof.
R 1 is a methyl group in which one or two optional hydrogen atoms may be substituted with a fluorine atom, a chlorine atom, a cyano group, an isopropyl group, and one or three optional hydrogen atoms. And a phenyl group which may be substituted by a group selected from the group consisting of methoxy group wherein one to three arbitrary hydrogen atoms may be substituted by a fluorine atom,
R 2 is a chlorine atom,
n is an integer of 0 to 3,
R 4 represents a methyl group, a cyano group, -N (R 6 ) R 7 , -NH-C (= Y) -NHR 6 , -NH-S (= O) 2 -NHR 6 , oxetan-3-yl group Or imidazolyl group, pyrazolyl group, triazolyl group, 1,3,4-oxadiazolyl group, tetrazolyl group or pyridyl group, wherein one or two optional hydrogen atoms may be substituted with a methyl group. ,
R 5 is a methyl group,
R 6 is a hydrogen atom or a methyl group,
The cyclic amine derivative according to claim 1, wherein R 7 is a hydrogen atom, a methyl group, an acetyl group or a methylsulfonyl group, a stereoisomer thereof or a hydrate thereof, or a pharmacologically acceptable thereof salt.
R 1 is a group wherein one or two optional hydrogen atoms are selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an isopropyl group, a trifluoromethyl group, a difluoromethoxy group and a trifluoromethoxy group A phenyl group which may be substituted by
R 2 is a chlorine atom,
n is an integer of 0 to 2,
R 4 represents a methyl group, a cyano group, -N (R 6 ) R 7 , -NH-C (= Y) -NHR 6 , -NH-S (= O) 2 -NHR 6 or 1 or 2 Triazolyl group, 1,3,4-oxadiazolyl group or tetrazolyl group, wherein any one hydrogen atom may be substituted with methyl group,
R 5 is a methyl group,
R 6 is a hydrogen atom or a methyl group,
R 7 is a hydrogen atom, a methyl group, an acetyl group or a methylsulfonyl group,
The cyclic amine derivative according to claim 1, wherein Y is an oxygen atom or = N-CN, its stereoisomer or a hydrate thereof, or a pharmacologically acceptable salt thereof.
A medicament comprising the cyclic amine derivative according to any one of claims 1 to 4, its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient.
A retinoid-related orphan comprising the cyclic amine derivative according to any one of claims 1 to 4, its stereoisomer or a hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient Receptor gamma antagonist.
An autoimmune disease comprising the cyclic amine derivative according to any one of claims 1 to 4, its stereoisomer or a hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient Therapeutic or prophylactic agent.
A multiple sclerosis comprising as an active ingredient the cyclic amine derivative according to any one of claims 1 to 4, its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof Or a therapeutic or preventive agent for psoriasis.
An allergic disease containing the cyclic amine derivative according to any one of claims 1 to 4, its stereoisomer or hydrate thereof, or pharmacologically acceptable salt thereof as an active ingredient Therapeutic or prophylactic agent.
An allergic dermatitis comprising, as an active ingredient, the cyclic amine derivative according to any one of claims 1 to 4, its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof. Therapeutic or prophylactic agent.
A contact dermatitis comprising the cyclic amine derivative according to any one of claims 1 to 4, its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient. Or a therapeutic or preventive agent for atopic dermatitis.