TW201910312A - Cyclic amine derivative and pharmaceutical use thereof - Google Patents

Abstract

The present invention addresses the problem of providing a novel compound which has a retinoid-related orphan receptor [gamma] 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 derivatives and their medical uses  

The present invention relates to cyclic amine derivatives and their medical use.

An autoimmune disease is a general term for a disease that causes symptoms due to an excessive immune response to attack normal cells or tissues, and examples thereof include multiple sclerosis, dryness, rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel. Inflammatory bowel disease, ankylosing spondylitis, uveitis or rheumatoid polymyalgia (polymyalgia rheumatica).

The allergic disease is derived from a disease that excessively causes an immune response to a specific antigen, and examples thereof include allergic dermatitis, atopic dermatitis, allergic rhinitis (hay fever), allergic conjunctivitis, allergic gastroenteritis, and bronchi. Bronchial asthma, children with asthma or food allergies.

A wide variety of mechanisms have been proposed for the pathogenesis and progression of autoimmune diseases and allergic diseases, but as one of them, Th17 cells, one of the subgroups of helper T cells, and inflammatory cells produced by them are known. Interleukin IL-17 plays an important role in the onset and progression 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 induces and induces inflammatory mediators, chemokines, metalloprotease, and other inflammatory mediators. Neutral white blood cells are related to the migration. Therefore, it is considered that if the production or function of IL-17 can be inhibited, a strong anti-inflammatory effect can be exerted, and a clinical trial of an anti-IL-17 antibody having various autoimmune diseases as an indication has been carried out.

In recent years, it has been clearly known that the retinoid-associated orphan receptor γ (hereinafter, RORγ), which is a nuclear receptor, is essential for the differentiation and proliferation of Th17 cells and the expression of IL-17. In the case of inhibiting the expression or function of RORγ, it has been shown that differentiation and activation of Th17 cells and production of IL-17 are suppressed (Non-Patent Document 4).

It has been reported that in patients with autoimmune diseases (multiple sclerosis, dryness, systemic lupus erythematosus, etc.), allergic diseases (allergic dermatitis, etc.), the amount of RORγ in peripheral blood mononuclear or skin tissue is A normal person compares and displays a higher value (Non-Patent Documents 5 to 7). It has been reported that in the knockout mouse of RORγ, the morbidity of the experimental autoimmune encephalomyelitis model in the animal model of multiple sclerosis is inhibited, and autoimmune diseases such as colitis are detected. The symptoms of allergic diseases such as symptoms and asthma are suppressed (Non-Patent Documents 3, 8 and 9).

Furthermore, it has been suggested that RORγ is required to function as a transcription factor, and binding of RORγ to a coactivator is necessary (Non-Patent Document 10). Therefore, RORγ antagonists for inhibiting the combination of RORγ and a co-activator are expected to be useful as therapeutic or prophylactic agents for autoimmune diseases.

On the other hand, in the case of RORγ antagonists, N-(5-(N-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) has been reported so far. Phenyl)aminesulfonyl)-4-methylthiazol-2-yl)acetamide (Non-Patent Document 11), 6-(2-chloro-4-methylphenyl)-3-(4- Cyclopropyl-5-(3-neopentylcyclobutyl) a substituted azole derivative including oxazol-3-yl)-5-oxohexanoic acid (Patent Document 1); N-(2-chloro-2'-(trifluoromethoxy)-[1,1' a sulfonylbenzene derivative such as -biphenyl]-4-yl)-2-(4-(methylsulfonyl)phenyl)acetamide (Patent Document 2); but a substituted piperidine Those having a cyclic amine structure such as 2-carbamamine are not disclosed.

Further, as a compound having a cyclic amine structure such as a substituted piperidin-2-carbamide, (S)-1-propenyl-N has been reported as a hepatitis C virus replication inhibitor. -(4'-(2-(())-1-propionylpyrrolidin-2-yl)-1H-imidazol-4-yl)-[1,1'-biphenyl]-4-yl)pyrrole Pyridyl-2-carboxamide, etc. (Patent Document 3), and 2-((4-(4-aminophenyl)sulfanyl)-3-((7-isopropylpyridine [2,3-d]] Pyrimidine-4-yl)amino)phenyl)amine-mercapto)pyrrolidine-1-carboxylic acid (S)-benzyl ester or the like (Patent Document 4), regarding the effect of these compounds on RORγ, has not been revealed Nor has it been implied.

Prior technical literature Patent literature

Patent Document 1 Japanese Patent Laid-Open Publication No. 2012-236822

Patent Document 2 International Publication No. 2013/029338

Patent Document 3 International Publication No. 2011/031934

Patent Document 4 International Publication No. 2010/075376

Non-patent literature

Non-Patent Document 1 Chen et al, International Immunopharmacology, 2011, Vol. 11, p. 536-542

Non-Patent Document 2 Hofmann et al, Current Opinion in Allergy and Clinical Immunology, 2016, Vol. 16, p.451-457

Non-Patent Document 3 Ivanov et al., Cell, 2006, Vol. 126, p. 1121-1133

Non-Patent Document 4 Jetten, Nuclear Receptor Signaling, 2009, Volume 7, e003

Non-Patent Document 5 Hamzaoui et al, Medical Science Monitor, 2011, Vol. 17, p. CR227-234

Non-Patent Document 6 Ma et al, Journal of the European Academy of Dermatology and Venereology, 2014, Vol. 28, p.1079-1086

Non-Patent Document 7 Zhao et al., British Journal of Dermatology, 2009, Vol. 161, p. 1301-1306

Non-Patent Document 8 Leppkes et al., Gastroenterology, 2009, Vol. 136, p. 257-267

Non-Patent Document 9 Jetten et al, The Journal of Immunology, 2007, Vol. 178, p. 3208-3218

Non-Patent Literature 10 Li et al., Molecular Endocrinology, 2010, Vol. 24, p. 923-929

Non-Patent Document 11 Burris et al., Nature, 2011, Vol. 472, p. 491-494

However, in the actual treatment of autoimmune diseases and allergic diseases, steroid agents or immunosuppressive agents that act on the immune system as a whole are used as internal medicines, and the status quo is due to serious side effects such as infectious diseases. There are cases in which most of the effects have to be suspended before sufficient drug effects are observed. Therefore, we are eagerly awaiting the development of new medicines that play an important role in the pathogenesis of autoimmune diseases and allergic diseases.

Therefore, the present invention provides an allergic disease such as autoimmune disease such as multiple sclerosis or dryness, or allergic dermatitis such as contact dermatitis or atopic dermatitis, which is provided with ROR γ antagonist activity. A novel compound for therapeutic or prophylactic effects is intended.

In order to solve the above problems, the inventors of the present invention have intensively studied and found a novel cyclic amine derivative having RORγ antagonist activity, and have completed the present invention.

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

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

(wherein R ¹ represents an aryl group or a heteroaryl group in which one to three arbitrary hydrogen atoms may be substituted with a group selected from the group consisting of a halogen 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 (one or three hydrogen atoms of the alkyl group may be substituted by a halogen atom) and a carbon number of 1 Alkoxy group of ~3 (the alkoxy group may have one to three arbitrary hydrogen atoms which may be substituted by a halogen atom); R ² represents a halogen atom, and R ³ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; The double line of the line and the dotted line indicates a single bond or a double bond, and the wavy line indicates the bond point with the general formula (I); X represents -C(=O)-(CH ₂ ) _n -R ⁴ or -S(= O) _{2 -} R ⁵ , n represents an integer of 0 to 5, and R ⁴ represents a cyano group, a hydroxyl 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 , ring constitutes a cyclic ether group of 4 to 6 atoms, and an alkyl group having 1 to 3 carbon atoms (this Any one or two of the hydrogen atoms of the alkyl group may be substituted by a halogen atom, or one or two hydrogen atoms may be substituted with a carbon number of 1 to 3, and R ⁵ represents a carbon number. alkyl of 1 to 3, R ⁶ represents a hydrogen atom or a carbon atoms of 1 to 3 alkyl group (the alkyl group 1 to 3 of the hydrogen atoms may be substituted by any of halogen atom), R ⁷ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, the carbon atoms or acyl of 2 to 4 carbon atoms, alkylsulfonyl of 1 to 3, Base, Y represents an oxygen atom, a sulfur atom or =N-CN].

The cyclic amine derivative represented by the above formula (I) is preferably a phenyl group or a pyridyl group which may be substituted with a group selected from the group consisting of 1 or 2, wherein any hydrogen atom of R ¹ is one or two. Or pyrimidinyl group: fluorine atom, chlorine atom, cyano group, hydroxymethyl group, -C(=O)-OR ³ , alkylsulfonyl group having 1 to 3 carbon atoms, alkyl group having 1 to 3 carbon atoms Any one or three of the hydrogen atoms of the base group may be substituted by a fluorine atom or a chlorine atom) and an alkoxy group having a carbon number of 1 to 3 (the alkoxy group may have one to three arbitrary hydrogen atoms via a fluorine atom or a chlorine atom is substituted); 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 is a cyano group, a hydroxyl group, and -N(R ⁶ )R ⁷ , -NH-C(=Y)-NHR ⁶ , -NH-S(=O) ₂ -NHR ⁶ , -C(=O)-OR ⁶ , -C(=O)-NHR ⁶ , oxonium-3 a group having an alkyl group having 1 to 3 carbon atoms (the one or three arbitrary hydrogen atoms of the alkyl group may be substituted by a fluorine atom or a chlorine atom), or one or two of any hydrogen atoms may be substituted by a methyl group The heteroaryl group, R ⁶ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (any one hydrogen atom of the alkyl group may be substituted by a fluorine atom or a chlorine atom).

Higher ROR gamma antagonist activity can be expected in this case.

Further, in the cyclic amine derivative represented by the above formula (I), it is more preferred that any one of hydrogen atoms of R ¹ or 2 may be substituted with a phenyl group selected from the group consisting of the following groups: a fluorine atom, a chlorine atom, a cyano group, an isopropyl group, a hydrogen atom which may be substituted by a fluorine atom, and a methoxy group which may be substituted with a fluorine atom by any one of three to three 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 , oxo-3-yl, or one or two of any hydrogen atom which may be substituted with a methyl group, imidazolyl, pyrazolyl, triazolyl, 1,3,4- A oxazolyl, tetrazolyl or pyridyl group, R ⁵ is a methyl group, R ⁶ is a hydrogen atom or a methyl group, and R ⁷ is a hydrogen atom, a methyl group, an ethyl sulfonyl group or a methylsulfonyl group.

In this case, a higher ROR γ antagonist activity can be expected, and an excellent therapeutic effect or a preventive effect of an autoimmune disease such as multiple sclerosis or dryness or an allergic disease such as allergic dermatitis can be expected.

Further, in the cyclic amine derivative represented by the above formula (I), it is further preferred that any one of two or two hydrogen atoms of R ¹ may be substituted with a phenyl group selected from the group consisting of the following groups; : a fluorine atom, a chlorine atom, a methyl group, an isopropyl group, a trifluoromethyl group, a difluoromethoxy group, and a trifluoromethoxy group, R ² is a chlorine atom, n is an integer of 0 to 2, and R ⁴ is a methyl group. , cyano, -N(R ⁶ )R ⁷ , -NH-C(=Y)-NHR ⁶ , -NH-S(=O) ₂ -NHR ⁶ , or any one or two of hydrogen atoms may pass Methyl substituted triazolyl, 1,3,4- A oxazolyl or tetrazolyl 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 ethyl sulfonyl group or a methylsulfonyl group, and Y is an oxygen atom or =N- CN.

In this case, a higher ROR γ antagonist activity can be expected, and an excellent therapeutic effect or a preventive effect of an autoimmune disease such as multiple sclerosis or dryness or an allergic disease such as allergic dermatitis can be expected.

Further, the present invention provides a pharmaceutical and ROR gamma antagonist comprising the cyclic amine derivative represented by the above formula (I), a stereoisomer thereof or a hydrate thereof, or the pharmacologically An acceptable salt is used as an active ingredient.

The above-mentioned medicine is preferably a therapeutic or prophylactic agent for autoimmune diseases or allergic diseases, and more preferably a therapeutic or prophylactic agent for autoimmune diseases, or a therapeutic agent for multiple sclerosis or dryness or The prophylactic agent is more preferably a therapeutic or prophylactic agent for allergic dermatitis, and a therapeutic or prophylactic agent for allergic dermatitis, more preferably in contact with a therapeutic or prophylactic agent for allergic dermatitis. A therapeutic or prophylactic agent for dermatitis or atopic dermatitis.

The cyclic amine derivative of the present invention, a stereoisomer thereof, or a hydrate of the above, or a pharmacologically acceptable salt thereof, can effectively inhibit the function of RORγ by having RORγ antagonist activity, and A therapeutic or prophylactic agent for use as an autoimmune disease or an allergic disease.

Figure 1 is a graph showing the inhibitory effect of the compound of Example 46 on the increase in the thickness of the ear shell in the imiquimod-induced mouse dryness mode.

Figure 2 is a graph showing the inhibitory effect of the compound of Example 74 on the increase in the thickness of the ear shell in the imiquimod-induced dryness mode in mice.

Figure 3 is a graph showing the inhibitory effect of the compound of Example 109 on the increase in the thickness of the ear shell in the imiquimod-induced dryness mode in mice.

Figure 4 is a graph showing the inhibitory effect of the compound of Example 117 on the increase in the thickness of the ear shell in the imiquimod-induced dryness mode in mice.

Fig. 5 is a graph showing the inhibitory effect of the compound of Example 74 on the increase in the neurological symptom score in the experimental autoimmune encephalomyelitis model in mice.

Figure 6 is a graph showing the inhibitory effect of the compound of Example 46 on the increase in the rate of swelling of the ear shell in dinitrofluorobenzene-induced allergic dermatitis mode in mice.

Figure 7 is a graph showing the inhibitory effect of the compound of Example 74 on the increase in the swelling rate of the ear shell in the dinitrofluorobenzene-induced allergic dermatitis mode in mice.

Figure 8 is a graph showing the inhibitory effect of the compound of Example 109 on the increase in the swelling rate of the ear shell in the dinitrofluorobenzene-induced allergic dermatitis mode in mice.

Figure 9 is a graph showing the inhibitory effect of the compound of Example 117 on the increase in the swelling rate of the ear shell in the dinitrofluorobenzene-induced allergic dermatitis mode in mice.

Figure 10 shows the compound of Example 46 for A graph showing the inhibitory effect of oxazolone on the increase in the thickness of the auricle in a mouse model of atopic dermatitis.

Figure 11 shows the compound of Example 74 for A graph showing the inhibitory effect of oxazolinone on the increase in the thickness of the auricle in a mouse model of atopic dermatitis.

Figure 12 shows the compound of Example 109 for A graph showing the inhibitory effect of oxazolinone on the increase in the thickness of the auricle in a mouse model of atopic dermatitis.

Figure 13 shows the compound of Example 117 for A graph showing the inhibitory effect of oxazolinone on the increase in the thickness of the auricle in a mouse model of atopic dermatitis.

Form for implementing the invention

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

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

(wherein R ¹ represents an aryl group or a heteroaryl group in which one to three arbitrary hydrogen atoms may be substituted with a group selected from the group consisting of a halogen 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 (one or three hydrogen atoms of the alkyl group may be substituted by a halogen atom) and a carbon number of 1 Alkoxy group of ~3 (the alkoxy group may have one to three arbitrary hydrogen atoms which may be substituted by a halogen atom); R ² represents a halogen atom, and R ³ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; The double line between the line and the dotted line indicates a single bond or a double bond, the wavy line indicates the bond point with the general formula (I), and X indicates -C(=O)-(CH ₂ ) _n -R ⁴ or -S (= O) _{2 -} R ⁵ , n represents an integer of 0 to 5, and R ⁴ represents a cyano group, a hydroxyl 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 , ring constitutes a cyclic ether group of 4 to 6 atoms, and an alkyl group having 1 to 3 carbon atoms (this Any one or two of the hydrogen atoms of the alkyl group may be substituted by a halogen atom, or one or two hydrogen atoms may be substituted with a carbon number of 1 to 3, and R ⁵ represents a carbon number. alkyl of 1 to 3, R ⁶ represents a hydrogen atom or a carbon atoms of 1 to 3 alkyl group (the alkyl group 1 to 3 of the hydrogen atoms may be substituted by any of halogen atom), R ⁷ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, the carbon atoms or acyl of 2 to 4 carbon atoms, alkylsulfonyl of 1 to 3, Base, Y represents an oxygen atom, a sulfur atom or =N-CN].

The following terms used in this specification are as defined below unless otherwise specified.

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

The "alkyl group having 1 to 3 carbon atoms" means a methyl group, an ethyl group, a propyl group or an isopropyl group.

"Alkyl group having 1 to 3 carbon atoms (any one hydrogen atom of the alkyl group may be substituted by a halogen atom)" means any one to three of the above alkyl groups having 1 to 3 carbon atoms. The group in which the hydrogen atom is independently substituted by the above halogen atom may, for example, be a methyl group, an ethyl group, a propyl group, an isopropyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group or a 2-fluoroethyl group. Base, trifluoroethyl, trichloromethyl or trichloroethyl.

"Alkyl group having 1 to 3 carbon atoms (the alkyl group is one or three of any hydrogen atoms which may be substituted by a fluorine atom or a chlorine atom)" means one to three of the above alkyl groups having 1 to 3 carbon atoms. Any of the hydrogen atom-based groups independently substituted by a fluorine atom or a chlorine atom, and examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a fluoromethyl group, a difluoromethyl group, and a trifluoromethyl group. 2-fluoroethyl, trifluoroethyl, trichloromethyl or trichloroethyl.

The "alkoxy group having 1 to 3 carbon atoms" means a methoxy group, an ethoxy group, a propoxy group or an isopropoxy group.

"Alkoxy group having 1 to 3 carbon atoms (the alkoxy group may be substituted by a halogen atom with any one of 3 to 3)" means 1 to 3 of the above alkoxy group having 1 to 3 carbon atoms. Any one of the hydrogen atom groups independently substituted by the above halogen atom may, for example, be a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a fluoromethoxy group or a difluoromethoxy group. Trifluoromethoxy, 2-fluoroethoxy, trifluoroethoxy, trichloromethoxy or trichloroethoxy.

"Alkoxy group having 1 to 3 carbon atoms (the alkoxy group may be substituted by a fluorine atom or a chlorine atom by any one of 3 to 3)" means the alkoxy group having 1 to 3 carbon atoms as described above. Each of the ~3 arbitrary hydrogen atom groups may be independently substituted by a fluorine atom or a chlorine atom, and examples thereof include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a fluoromethoxy group, and a difluoro group. Methoxy, trifluoromethoxy, 2-fluoroethoxy, trifluoroethoxy, trichloromethoxy or trichloroethoxy.

The "alkylsulfonyl group having 1 to 3 carbon atoms" means a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group or an isopropylsulfonyl group.

The "mercapto group having 2 to 4 carbon atoms" means an ethyl group, a propyl group, a butyl group or a 2-methyl propyl group.

The "ring constitutes a cyclic ether group having 4 to 6 atomic atoms" means oxo-2-yl, oxind-3-yl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydro-2H-pyran- 2-Based, tetrahydro-2H-piperidin-3-yl or tetrahydro-2H-pyran-4-yl.

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

The "heteroaryl group" means a heterocyclic aromatic group each independently containing one to four hetero atoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and examples thereof include a thienyl group and a pyrrolyl group. , furyl, thiazolyl, imidazolyl, Azyl, pyrazolyl, isothiazolyl, iso Azolyl, triazolyl, Diazolyl, tetrazolyl, pyridyl, anthracene Base, pyrimidinyl, pyridyl Base or three base.

"1 to 3 of any hydrogen atom may be substituted with an aryl group selected from the group consisting of a halogen atom, a cyano group, a hydroxymethyl group, -C(=O)-OR ³ , a carbon number of 1~ An alkylsulfonyl group of 3, an alkyl group having 1 to 3 carbon atoms (the alkyl group is one or three of any hydrogen atoms may be substituted by a halogen atom), and an alkoxy group having a carbon number of 1 to 3 (the alkoxy group) Any one of the hydrogen atoms of the base system may be substituted by a halogen atom," meaning that any one of the above-mentioned aryl groups may independently be selected from the group consisting of a halogen atom, a cyano group, and a hydroxy group. Methyl, -C(=O)-OR ³ , the above alkyl sulfonyl group having 1 to 3 carbon atoms, and the above alkyl group having 1 to 3 carbon atoms (the alkyl group is one to three hydrogens) a group in which the atom may be substituted by a halogen atom) and a group of the above-mentioned alkoxy group having 1 to 3 carbon atoms (the alkoxy group is one or three hydrogen atoms which may be substituted by a halogen atom) may be substituted. For example, phenyl, 1-naphthyl, 2-naphthyl, fluorophenyl, difluorophenyl, chlorophenyl, dichlorophenyl, chlorofluorophenyl, bromophenyl, iodophenyl, tolyl, Dimethylphenyl, ethylphenyl, propylphenyl, isopropylphenyl, fluoromethylphenyl, chloromethylphenyl (fluoromethyl)phenyl, (difluoromethyl)phenyl, (trifluoromethyl)phenyl, (2-fluoroethyl)phenyl, (trifluoroethyl)phenyl, (trichloromethyl) Phenyl, (trichloroethyl)phenyl, fluoro(trifluoromethyl)phenyl, chloro(trifluoromethyl)phenyl, methyl(trifluoromethyl)phenyl, methoxyphenyl, Ethoxyphenyl, propoxyphenyl, isopropoxyphenyl, (fluoromethoxy)phenyl, (difluoromethoxy)phenyl, (trifluoromethoxy)phenyl, (2 -fluoroethoxy)phenyl, (trifluoroethoxy)phenyl, (trichloromethoxy)phenyl, (trichloroethoxy)phenyl, fluoromethoxyphenyl, chloromethoxy Phenyl, methoxymethylphenyl, methoxy(trifluoromethyl)phenyl, fluoro(trifluoromethoxy)phenyl, chloro(trifluoromethoxy)phenyl, methyl (trifluoro Methoxy)phenyl, methoxy(trifluoromethoxy)phenyl, (methylsulfonyl)phenyl, (ethylsulfonyl)phenyl, (propylsulfonyl)phenyl, (isopropylsulfonyl)phenyl, cyanophenyl, cyanofluorophenyl, chlorocyanophenyl, cyanomethylphenyl, cyano(trifluoromethyl)phenyl, cyano (three Fluoromethoxy)phenyl, (hydroxymethyl)phenyl, (hydroxycarbonyl)phenyl, (Methoxycarbonyl)phenyl, (ethoxycarbonyl)phenyl, (propoxycarbonyl)phenyl or (isopropoxycarbonyl)phenyl.

"1 to 3 of any hydrogen atom may be substituted with a heteroaryl group selected from the group consisting of a halogen atom, a cyano group, a hydroxymethyl group, -C(=O)-OR ³ , a carbon number of 1 ~3 alkylsulfonyl group, alkyl group having 1 to 3 carbon atoms (the alkyl group is one to three of any hydrogen atom may be substituted by a halogen atom) and an alkoxy group having a carbon number of 1 to 3 (the alkane) Any one of the oxygen radicals may be substituted by a halogen atom," meaning that any one of the above-mentioned heteroaryl groups may independently be selected from a halogen atom and a cyano group. , hydroxymethyl, -C(=O)-OR ³ , the above alkyl sulfonyl group having 1 to 3 carbon atoms, and the above alkyl group having 1 to 3 carbon atoms (the alkyl group is 1 to 3) a group in which any hydrogen atom may be substituted by a halogen atom) and a group of the above-mentioned alkoxy groups having 1 to 3 carbon atoms (the alkoxy group is one or three of any hydrogen atoms may be substituted by a halogen atom) , for example, a thienyl group, a pyrrolyl group, a furyl group, a thiazolyl group, Azolyl, isothiazolyl, iso Azolyl, Diazolyl, pyridyl, anthracene Base, pyrimidinyl, pyridyl , fluorothienyl, chlorothienyl, methylthienyl, dimethylthienyl, ethylthienyl, (trifluoromethyl)thienyl, methoxythienyl, fluoropyrrolyl, chloropyrrolyl, a Pyryryl, dimethylpyrrolyl, ethylpyrrolyl, (trifluoromethyl)pyrrolyl, methoxypyrrolyl, fluorofuranyl, chlorofuranyl, methylfuranyl, dimethylfuranyl, Furyl, (trifluoromethyl)furanyl, methoxyfuranyl, fluorothiazolyl, chlorothiazolyl, methylthiazolyl, dimethylthiazolyl, ethylthiazolyl, (trifluoromethyl)thiazole Base, methoxythiazolyl, fluorine Azolyl, chlorine Azolyl, methyl Azolyl, dimethyl Azolyl, ethyl Azolyl, (trifluoromethyl) Azolyl, methoxy Azyl, fluoroisothiazolyl, chloroisothiazolyl, methylisothiazolyl, dimethylisothiazolyl, ethylisothiazolyl, (trifluoromethyl)isothiazolyl, fluoroiso Azolyl, chlorine Azyl, methyl Azolyl, dimethyliso Azyl, ethyl Azolyl, (trifluoromethyl) Azolyl, methoxy Azolyl, fluorine Diazolyl, chlorine Diazolyl, methyl Diazolyl, ethyl Diazolyl, (trifluoromethyl) Diazolyl, methoxy Diazolyl, fluoropyridyl, difluoropyridyl, chloropyridyl, dichloropyridyl, chlorofluoropyridyl, methylpyridyl, dimethylpyridyl, ethylpyridyl, fluoromethylpyridinyl, chloro Methylpyridyl, (trifluoromethyl)pyridyl, fluoro(trifluoromethyl)pyridyl, chloro(trifluoromethyl)pyridinyl, methyl(trifluoromethyl)pyridinyl, methoxypyridyl , fluoromethoxypyridyl, chloromethoxypyridyl, methoxymethylpyridyl, (trifluoromethoxy)pyridinyl, fluoro(trifluoromethoxy)pyridinyl, chloro(trifluoromethoxy) Pyridyl, methyl (trifluoromethoxy)pyridyl, fluoranthene Chloroquinone Methyl hydrazine Dimethyl hydrazine Base, ethyl hydrazine (trifluoromethyl)anthracene Methoxy oxime (trifluoromethoxy) hydrazine , fluoropyrimidinyl, difluoropyrimidinyl, chloropyrimidinyl, dichloropyrimidinyl, chlorofluoropyrimidinyl, methylpyrimidinyl, dimethylpyrimidinyl, ethylpyrimidinyl, fluoromethylpyrimidinyl, chloromethyl Pyrimidinyl, (trifluoromethyl)pyrimidinyl, fluoro(trifluoromethyl)pyrimidinyl, chloro(trifluoromethyl)pyrimidinyl, methyl(trifluoromethyl)pyrimidinyl, methoxypyrimidinyl, fluoro Methoxypyrimidinyl, chloromethoxypyrimidinyl, methoxymethylpyrimidinyl, (trifluoromethoxy)pyrimidinyl, fluoro(trifluoromethoxy)pyrimidinyl, chloro(trifluoromethoxy) Pyrimidinyl, methyl(trifluoromethoxy)pyrimidinyl, fluoropyridyl Chloropyridine Methylpyr Dimethylpyridyl Ethyl pyridyl (trifluoromethyl)pyridinyl Methoxy pyridine (trifluoromethoxy)pyridinyl base.

"One or two arbitrary hydrogen atoms may be substituted with a phenyl group, a pyridyl group or a pyrimidinyl group selected from the group consisting of 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 (any one or three hydrogen atoms of the alkyl group may be substituted by a fluorine atom or a chlorine atom) and carbon Alkoxy groups of 1 to 3 (the alkoxy group may have one or three arbitrary hydrogen atoms which may be substituted by a fluorine atom or a chlorine atom), and means one or two of a phenyl group, a pyridyl group or a pyrimidyl group. Any of the hydrogen atom systems may be independently selected from the group consisting of an alkylsulfonyl group containing a fluorine atom, a chlorine atom, a cyano group, a hydroxymethyl group, -C(=O)-OR ³ , and the above carbon number 1 to 3, The alkyl group having 1 to 3 carbon atoms (the alkyl group is one to three of any hydrogen atom may be substituted by a fluorine atom or a chlorine atom) and the above alkoxy group having 1 to 3 carbon atoms (the alkoxy group) A group substituted with a group of one to three arbitrary hydrogen atoms which may be substituted by a fluorine atom or a chlorine atom, and examples thereof include a phenyl group, a fluorophenyl group, a difluorophenyl group, a chlorophenyl group, and a dichlorobenzene group. Base, chlorofluorophenyl, tolyl, dimethylphenyl, ethylphenyl, propylphenyl, Propylphenyl, fluoromethylphenyl, chloromethylphenyl, (fluoromethyl)phenyl, (difluoromethyl)phenyl, (trifluoromethyl)phenyl, (2-fluoroethyl) Phenyl, (trifluoroethyl)phenyl, (trichloromethyl)phenyl, (trichloroethyl)phenyl, fluoro(trifluoromethyl)phenyl, chloro(trifluoromethyl)phenyl, Methyl (trifluoromethyl)phenyl, methoxyphenyl, ethoxyphenyl, propoxyphenyl, isopropoxyphenyl, (fluoromethoxy)phenyl, (difluoromethoxy) Phenyl, (trifluoromethoxy)phenyl, (2-fluoroethoxy)phenyl, (trifluoroethoxy)phenyl, (trichloromethoxy)phenyl, (trichloroethane) Oxy)phenyl, fluoromethoxyphenyl, chloromethoxyphenyl, methoxymethylphenyl, methoxy(trifluoromethyl)phenyl, fluoro(trifluoromethoxy)phenyl , chloro(trifluoromethoxy)phenyl, methyl(trifluoromethoxy)phenyl, methoxy(trifluoromethoxy)phenyl, (methylsulfonyl)phenyl, (ethyl Sulfhydryl)phenyl, (propylsulfonyl)phenyl, (isopropylsulfonyl)phenyl, cyanophenyl, cyanofluorophenyl, chlorocyanophenyl, cyanomethylbenzene Base, cyano (trifluoromethyl)phenyl, cyano (trifluoromethoxy) , (hydroxymethyl)phenyl, (hydroxycarbonyl)phenyl, (methoxycarbonyl)phenyl, (ethoxycarbonyl)phenyl, (propoxycarbonyl)phenyl, (isopropoxycarbonyl) Phenyl, fluoropyridyl, difluoropyridyl, chloropyridyl, dichloropyridyl, chlorofluoropyridyl, methylpyridyl, dimethylpyridyl, ethylpyridyl, fluoromethylpyridyl, chloro Methylpyridyl, (trifluoromethyl)pyridyl, fluoro(trifluoromethyl)pyridyl, chloro(trifluoromethyl)pyridinyl, methyl(trifluoromethyl)pyridinyl, methoxypyridyl , fluoromethoxypyridyl, chloromethoxypyridyl, methoxymethylpyridyl, (trifluoromethoxy)pyridinyl, fluoro(trifluoromethoxy)pyridinyl, chloro(trifluoromethoxy) Pyridyl, methyl (trifluoromethoxy) pyridyl, fluoropyrimidinyl, difluoropyrimidinyl, chloropyrimidinyl, dichloropyrimidinyl, chlorofluoropyrimidinyl, methylpyrimidinyl, dimethylpyrimidinyl , ethylpyrimidinyl, fluoromethylpyrimidinyl, chloromethylpyrimidinyl, (trifluoromethyl)pyrimidinyl, fluoro(trifluoromethyl)pyrimidinyl, chloro(trifluoromethyl)pyrimidinyl, methyl ( Trifluoromethyl)pyrimidinyl, methoxypyrimidinyl, Fluoromethoxypyrimidinyl, chloromethoxypyrimidinyl, methoxymethylpyrimidinyl, (trifluoromethoxy)pyrimidinyl, fluoro(trifluoromethoxy)pyrimidinyl, chloro(trifluoromethoxy) Pyrimidyl or methyl (trifluoromethoxy)pyrimidinyl.

"A methyl group in which one to three arbitrary hydrogen atoms may be substituted by a fluorine atom" means a methyl group, a fluoromethyl group, a difluoromethyl group or a trifluoromethyl group.

"A methoxy group of one to three arbitrary hydrogen atoms which may be substituted by a fluorine atom" is a methoxy group, a fluoromethoxy group, a difluoromethoxy group or a trifluoromethoxy group.

"One or two arbitrary hydrogen atoms may be substituted with a phenyl group selected from the group consisting of a fluorine atom, a chlorine atom, a cyano group, an isopropyl group, or any one of three to three hydrogen atoms. a fluorine atom-substituted methyl group and one to three arbitrary hydrogen atoms may be substituted with a fluorine atom by a fluorine atom, meaning that one or two of the phenyl groups may independently be selected from fluorine. An atom, a chlorine atom, a cyano group, an isopropyl group, a methyl group in which any one of the above-mentioned one or three hydrogen atoms may be substituted by a fluorine atom, and a hydrogen atom substituted by any one of the above-mentioned one to three hydrogen atoms may be substituted by a fluorine atom. Examples of the group-substituted group of the oxygen group include a phenyl group, a fluorophenyl group, a difluorophenyl group, a chlorophenyl group, a dichlorophenyl group, a chlorofluorophenyl group, a tolyl group, and a dimethylphenyl group. Isopropylphenyl, fluoromethylphenyl, chloromethylphenyl, (fluoromethyl)phenyl, (difluoromethyl)phenyl, (trifluoromethyl)phenyl, (trichloromethyl) Phenyl, fluoro(trifluoromethyl)phenyl, chloro(trifluoromethyl)phenyl, methyl(trifluoromethyl)phenyl, methoxyphenyl, (fluoromethoxy)phenyl, ( Difluoromethoxy)phenyl, (trifluoromethoxy)phenyl, (trichloro) Methoxy)phenyl, fluoromethoxyphenyl, chloromethoxyphenyl, methoxymethylphenyl, methoxy(trifluoromethyl)phenyl, fluoro(trifluoromethoxy)benzene , chloro(trifluoromethoxy)phenyl, methyl(trifluoromethoxy)phenyl, methoxy(trifluoromethoxy)phenyl, cyanophenyl, cyanofluorophenyl, chloro Cyanophenyl, cyanomethylphenyl, cyano(trifluoromethyl)phenyl or cyano(trifluoromethoxy)phenyl.

"One or two arbitrary hydrogen atoms may be substituted with a phenyl group 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 "Trifluoromethoxy" means that any one or two of the phenyl groups of the phenyl group are independently selected from the group consisting of a fluorine atom, a chlorine atom, a methyl group, an isopropyl group, a trifluoromethyl group, and a difluoromethyl group. Examples of the substituent of the oxy group and the trifluoromethoxy group include a phenyl group, a fluorophenyl group, a difluorophenyl group, a chlorophenyl group, a dichlorophenyl group, a chlorofluorophenyl group, a tolyl group, and a dimethyl group. Phenyl, isopropylphenyl, fluoromethylphenyl, chloromethylphenyl, (trifluoromethyl)phenyl, fluoro(trifluoromethyl)phenyl, chloro(trifluoromethyl)phenyl, Methyl (trifluoromethyl)phenyl, (difluoromethoxy)phenyl, (trifluoromethoxy)phenyl, fluoro(trifluoromethoxy)phenyl, chloro(trifluoromethoxy) Phenyl or methyl (trifluoromethoxy)phenyl.

"a heteroaryl group in which one or two arbitrary hydrogen atoms may be substituted with an alkyl group having 1 to 3 carbon atoms" means that one or two of the hydrogen atom systems of the above heteroaryl group are independently capable of being subjected to the above Examples of the alkyl group-substituted group having 1 to 3 carbon atoms include a thienyl group, a pyrrolyl group, a furyl group, a thiazolyl group, and an imidazolyl group. Azyl, pyrazolyl, isothiazolyl, iso Azolyl, triazolyl, Diazolyl, tetrazolyl, pyridyl, anthracene Base, pyrimidinyl, pyridyl Base, three , methylthienyl, dimethylthienyl, ethylthienyl, methylpyrrolyl, dimethylpyrrolyl, ethylpyrrolyl, methylfuranyl, dimethylfuranyl, ethylfuranyl, Methylthiazolyl, dimethylthiazolyl, ethylthiazolyl, methylimidazolyl, dimethylimidazolyl, ethylimidazolyl, methyl Azolyl, dimethyl Azolyl, ethyl Azyl, methylpyrazolyl, dimethylpyrazolyl, ethylpyrazolyl, methylisothiazolyl, dimethylisothiazolyl, ethylisothiazolyl, methyliso Azolyl, dimethyliso Azyl, ethyl Azyl, methyltriazolyl, dimethyltriazolyl, ethyltriazolyl, methyl Diazolyl, ethyl Diazolyl, methyltetrazolyl, ethyltetrazolyl, methylpyridyl, dimethylpyridyl, ethylpyridyl, methylhydrazine Dimethyl hydrazine Base, ethyl hydrazine Methylpyrimidinyl, dimethylpyrimidinyl, ethylpyrimidinyl, methylpyridyl Dimethylpyridyl Ethyl pyridyl Base, methyl three Base, dimethyl three Base or ethyl three base.

The "heteroaryl group in which one or two arbitrary hydrogen atoms may be substituted by a methyl group" means a group in which one or two of any of the above heteroaryl groups may be substituted with a methyl group, and examples thereof include a thiophene group. Base, pyrrolyl, furyl, thiazolyl, imidazolyl, Azyl, pyrazolyl, isothiazolyl, iso Azolyl, triazolyl, Diazolyl, tetrazolyl, pyridyl, anthracene Base, pyrimidinyl, pyridyl Base, three , methylthienyl, dimethylthienyl, methylpyrrolyl, dimethylpyrrolyl, methylfuranyl, dimethylfuranyl, methylthiazolyl, dimethylthiazolyl, methylimidazolyl Dimethylimidazolyl, methyl Azolyl, dimethyl Azyl, methylpyrazolyl, dimethylpyrazolyl, methylisothiazolyl, dimethylisothiazolyl, methyliso Azolyl, dimethyliso Azyl, methyltriazolyl, dimethyltriazolyl, methyl Diazolyl, methyltetrazolyl, methylpyridyl, dimethylpyridyl, methylhydrazine Dimethyl hydrazine Methylpyrimidinyl, dimethylpyrimidinyl, methylpyridyl Dimethylpyridyl Base, methyl three Base or dimethyl three base.

"Imidazolyl, pyrazolyl, triazolyl, 1,3,4-" in which one or two arbitrary hydrogen atoms may be substituted by a methyl group "Adiazolyl, tetrazolyl or pyridyl" means imidazolyl, pyrazolyl, triazolyl, 1,3,4- A group in which one or two arbitrary hydrogen atoms of the oxazolyl, tetrazolyl or pyridyl group may be substituted with a methyl group, and examples thereof include an imidazolyl group, a pyrazolyl group, a triazolyl group, a tetrazolyl group, and 1,3. , 4- Diazolyl, pyridyl, methylimidazolyl, dimethylimidazolyl, methylpyrazolyl, dimethylpyrazolyl, methyltriazolyl, dimethyltriazolyl, methyl-1,3 , 4- A oxazolyl group, a methyltetrazolyl group, a methylpyridyl group or a dimethylpyridyl group.

"1 or 2 of any hydrogen atom may be substituted by a methyl group, a triazolyl group, 1,3,4- "oxadiazolyl or tetrazolyl" means triazolyl, 1,3,4- A group in which one or two arbitrary hydrogen atoms of the oxazolyl or tetrazolyl group may be substituted with a methyl group, and examples thereof include a triazolyl group, 1,3,4- Diazolyl, tetrazolyl, methyltriazolyl, dimethyltriazolyl, methyl-1,3,4- Diazolyl or methyltetrazolyl.

The cyclic amine derivative represented by the formula (I), a stereoisomer thereof or a hydrate of the above, or a pharmacologically acceptable salt thereof, means a compound represented by the formula (I) a cyclic amine derivative, a stereoisomer of a cyclic amine derivative represented by the formula (I), a hydrate of a cyclic amine derivative represented by the formula (I), or a compound represented by the formula (I) a hydrate of a stereoisomer of a cyclic amine derivative, a pharmacologically acceptable salt of a cyclic amine derivative represented by the formula (I), and a cyclic amine derivative represented by the formula (I) A pharmacologically acceptable salt of a stereoisomer, a pharmacologically acceptable salt of a hydrate of a cyclic amine derivative represented by the formula (I) or a cyclic amine derivative represented by the formula (I) a pharmacologically acceptable salt of a hydrate of a stereoisomer of matter.

In the above formula (I), R ^{1 is} preferably one or two of any hydrogen atom which may be substituted with a phenyl group, a pyridyl group or a pyrimidinyl group selected from the group consisting of the group below. : 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 (the alkyl group 1) Any one of the three hydrogen atoms may be substituted by a fluorine atom or a chlorine atom) and an alkoxy group having a carbon number of 1 to 3 (the alkoxy group may have one to three arbitrary hydrogen atoms which may be substituted by a fluorine atom or a chlorine atom) More preferably, any one or two hydrogen atoms may be substituted with a phenyl group selected from the group consisting of a fluorine atom, a chlorine atom, a cyano group, an isopropyl group, and one to three. a methyl group in which a hydrogen atom may be substituted with a fluorine atom and a methoxy group in which one to three arbitrary hydrogen atoms may be substituted with a fluorine atom; further preferably one or two hydrogen atoms may be selected from the group consisting of the following Group-substituted phenyl groups: fluorine atom, chlorine atom, methyl group, isopropyl group, trifluoromethyl group, difluoromethoxy group, and trifluoromethoxy group.

R ^{2 is} preferably a fluorine atom or a chlorine atom, 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, still more preferably an integer of 0 to 2.

R ^{4 is} preferably cyano, hydroxy, -N(R ⁶ )R ⁷ , -NH-C(=Y)-NHR ⁶ , -NH-S(=O) ₂ -NHR ⁶ , -C(=O) -OR ⁶ , -C(=O)-NHR ⁶ , oxo-3-yl, alkyl having 1 to 3 carbon atoms (the alkyl group is one to three of any hydrogen atom which may pass through a fluorine atom or a chlorine atom) Substituting), or a heteroaryl group in which one or two hydrogen atoms may be substituted by a methyl group, more preferably a methyl group, a cyano group, -N(R ⁶ )R ⁷ or -NH-C(=Y)- NHR ⁶ , -NH-S(=O) ₂ -NHR ⁶ , oxon-3-yl, or one or two of any hydrogen atom may be substituted with a methyl group, an imidazolyl group, a pyrazolyl group, a triazolyl group, 1,3,4- Further, oxadiazolyl, tetrazolyl or pyridyl, more preferably methyl, cyano, -N(R ⁶ )R ⁷ , -NH-C(=Y)-NHR ⁶ , -NH-S(=O) ₂ -NHR ⁶ , or one or two of any hydrogen atom which may be substituted by a methyl group, a triazolyl group, 1,3,4- A oxazolyl or tetrazolyl group.

R ^{5 is} preferably a methyl group.

R ^{6 is} preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (any one hydrogen atom of the alkyl group may be substituted by a fluorine atom or a chlorine atom), and more preferably a hydrogen atom or a methyl group.

R ^{7 is} preferably a hydrogen atom, a methyl group, an ethyl sulfonyl group or a methylsulfonyl group.

Y is preferably an oxygen atom or =N-CN.

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

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

In the above cyclic amine derivative represented by the formula (I), preferred R ¹ , preferred R ² , preferred R ³ , preferred R ⁴ above, and the above are preferred. Preferably, R ⁵ , the above preferred R ⁶ , the above preferred R ⁷ , the above preferred n, the above preferred Y, the above preferred formula (I), and the above preferred A may be selected arbitrarily. Aspects and combine them. For example, the following combinations are exemplified, but are not limited thereto.

In the cyclic amine derivative represented by the above formula (I), it is preferred that any one of the hydrogen atoms of R ¹ to 1 may be substituted with an aryl group or a hetero group selected from the group consisting of the following groups. Aryl group: halogen atom, cyano group, hydroxymethyl group, -C(=O)-OR ³ , alkylsulfonyl group having 1 to 3 carbon atoms, alkyl group having 1 to 3 carbon atoms (one alkyl group) ~3 of any hydrogen atom may be substituted by a halogen atom) and an alkoxy group having 1 to 3 carbon atoms (the alkoxy group may be substituted by a halogen atom with any one of 3 to 3); R ² is a halogen atom R ³ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and the double line of the solid line and the dotted line is a single bond or a double bond, and the wavy line is a combination point with the following general formula (Ia), and X is -C (=O)-(CH ₂ ) _n -R ⁴ or -S(=O) ₂ -R ⁵ , n is an integer from 0 to 5, and R ⁴ is a cyano group, a hydroxyl 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 , ring constituent atomic number 4 a cyclic ether group of ~6, an alkyl group having 1 to 3 carbon atoms (any one or three hydrogen atoms of the alkyl group may be substituted by a halogen atom), or one or two arbitrary hydrogen atoms may pass through the carbon the alkyl group having 1 to 3 substituted heteroaryl, R ⁵ is alkyl of 1 to 3, R ⁶ is hydrogen Or a carbon number of 1 to 3 alkyl group (which alkyl group any hydrogen atom Department 1 to 3 of halogen atom may be substituted), R ⁷ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, the carbon number of 2 to a mercapto group of 4 or an alkylsulfonyl group having 1 to 3 carbon atoms, Y is an oxygen atom, a sulfur atom or =N-CN, and the formula (I) is the following formula (Ia), and A is as follows a group represented by the formula (II-1), (II-2-a), (II-3-a), (II-4), (II-5-a) or (II-5-b).

In another aspect, in the cyclic amine derivative represented by the above formula (I), it is more preferred that any one of hydrogen atoms having 1 or 2 of R ¹ may be substituted with a group selected from the group consisting of the following: Phenyl group: fluorine atom, chlorine atom, methyl group, isopropyl group, trifluoromethyl group, difluoromethoxy group and trifluoromethoxy group; R ² is a chlorine atom, n is an integer of 0 to 2, R ⁴ Is methyl, cyano, -N(R ⁶ )R ⁷ , -NH-C(=Y)-NHR ⁶ , -NH-S(=O) ₂ -NHR ⁶ , or 1 or 2 of any hydrogen a triazolyl, 1,3,4- A oxazolyl or tetrazolyl 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 ethyl sulfonyl group or a methylsulfonyl group, and Y is an oxygen atom or =N- CN, the general formula (I) is the above general formula (Ia), and A is the above general formula (II-1), (II-2-a), (II-3-a), (II-4), The group represented by (II-5-a) or (II-5-b).

Specific examples of preferred compounds of the cyclic amine derivative represented by the above 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 the stereoisomers thereof and the hydrates thereof, and their pharmacologically acceptable salts, and mixtures thereof.

The cyclic amine derivative represented by the above formula (I) may be a stereoisomer, and includes not only a single isomer but also a mixture of a racemic body and a mixture of non-image isomers.

"Stereoisomer" means a compound having the same chemical structure but different configurations in a three-dimensional space, and examples thereof include a configuration isomer, a rotational isomer, a tautomer, an optical isomer, and a non- Mirror isomers, etc.

The cyclic amine derivative represented by the above formula (I) can be identified by one or more isotopes, and examples of the labeled isotopes include: ² H, ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁵ O, ¹⁸ O and / or ¹²⁵ I.

The "pharmacologically acceptable salt" of the cyclic amine derivative represented by the above formula (I) includes, for example, a salt with an inorganic base, a salt with an organic base, and a salt with an inorganic acid. Or with organic acids. The salt of the inorganic base may, for example, be an alkali metal salt such as a sodium salt or a potassium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, an ammonium salt, an aluminum salt or a zinc salt; In terms of, for example, triethylamine, ethanolamine, a salt of an organic amine such as a porphyrin, piperidine or dicyclohexylamine or a salt of a basic amino acid such as arginine or lysine. The salt of the inorganic acid may, for example, be a hydrochloride, a sulfate, a nitrate, a hydrobromide, a hydroiodide or a phosphate; and the salt of the organic acid may, for example, be: Oxalate, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzene Formate, ascorbate, glutarate, mandelate, citrate, methanesulfonate, ethanesulfonate, besylate, p-toluenesulfonate, camphorsulfonate, aspartate Salt, glutamate or cinnamate. In addition, the "pharmacologically acceptable salt" of the stereoisomer of the cyclic amine derivative represented by the above formula (I), and the cyclic amine derivative represented by the above formula (I) The "pharmacologically acceptable salt" of the hydrate and the "pharmacologically acceptable salt" of the hydrate of the stereoisomer of the cyclic amine derivative represented by the above formula (I) are also the same.

The cyclic amine derivative represented by the above formula (I), or a stereoisomer thereof, or a pharmacologically acceptable salt thereof may be an anhydride or may form a solvent compound such as a hydrate. Among them, in the case of a solvent, a pharmacologically acceptable solvent is preferred. The pharmacologically acceptable solvent may be either a hydrate or a non-hydrate, but is preferably a hydrate. Examples of the solvent constituting the solvent include an alcohol-based solvent such as methanol, ethanol or n-propanol, N,N-dimethylformamide (hereinafter, DMF), and dimethylammonium (hereinafter). , DMSO) or water.

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

The cyclic amine derivative (I) and the intermediates and starting materials used in the production thereof can be isolated and purified by a known means. As the well-known means for the isolation purification, for example, solvent extraction, recrystallization or chromatography can be mentioned.

In the case where the cyclic amine derivative (I) contains a stereoisomer, the optical isomer or the non-image isomer of each of the single optically active forms can be obtained by a known method. As a well-known method, crystallization, enzyme isolation, or palm chromatography is mentioned, for example.

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

The solvent used for the crystallization of the cyclic amine derivative (I), a stereoisomer thereof, or a hydrate of the above, or a pharmacologically acceptable salt thereof, may, for example, be tetrahydrofuran (hereinafter, , THF), 1,4-two An ether solvent such as an alkane, diethyl ether, tert-butyl methyl ether or anisole; methanol, ethanol, 2-methoxyethanol, 2-ethoxyethanol, n-propanol, 2-propanol, 2 - an alcohol-based solvent such as methyl-1-propanol, n-butanol, 2-butanol, 3-methyl-1-butanol, n-pentanol or ethylene glycol; toluene, xylene, cumene or Aromatic hydrocarbon solvent such as tetralin; aprotic polarity such as DMF, N,N-dimethylacetamide, formamide, N-methylpyrrolidone, DMSO or cyclobutyl hydrazine Solvent; nitrile-based solvent such as acetonitrile or propionitrile; ester-based solvent such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate or ethyl formate; acetone, A a ketone-based solvent such as methyl ethyl ketone, methyl butyl ketone or methyl isobutyl ketone; dichloromethane, chloroform, 1,2-dichloroethylene, 1,1,2-trichloroethylene or chlorobenzene A halogen-based solvent; a hydrocarbon-based solvent such as hexane, pentane, heptane, cyclohexane or methylcyclohexane; a nitro-based solvent such as nitromethane; a pyridine-based solvent such as pyridine; acetic acid or formic acid, etc. Carboxylic acid solvent; water or a mixture of them Vehicles, their vehicle or with a mixed solvent of the above solvent of the pharmacologically tolerable salts with bases or acids to form a cyclic amine derivative (I).

In each reaction of the production method described below, when the starting compound has an amine group or a carboxyl group, a protecting group can be introduced into the group, and the target compound can be obtained by deprotecting the protecting group if necessary after the reaction.

Examples of the protecting group of the amine group include an alkylcarbonyl group having 2 to 6 carbon atoms (for example, an ethyl fluorenyl group), a benzinyl group, and an alkoxycarbonyl group having 2 to 8 carbon atoms (for example, a tertiary butyl group). An oxycarbonyl group or a benzyloxycarbonyl group, an aralkyl group having 7 to 10 carbon atoms (for example, a benzyl group) or a fluorenyl group.

The protective group of the carboxyl group may, for example, be an alkyl group having 1 to 6 carbon atoms (for example, a methyl group, an ethyl group or a tertiary butyl group) or a carbon number 7 to 10 aralkyl group (for example, a benzyl group).

The deprotection of the protecting group varies depending on the type of the protecting group, but can be carried out by a known method (for example, Greene, T. W., "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method according thereto.

The cyclic amine derivative (I) is, for example, as shown in Scheme 1, and can be obtained by the following methods: aniline derivative (III) and 2-piperidinecarboxylic acid (pipecolic) in the presence of a condensing agent and a base The condensation reaction of the derivative (IV) (step 1); followed by the N-tertiary butoxycarbonyl 2-piperidinecarboxylic acid decylamine derivative (V) obtained in the first step in the presence of an acid Deprotection reaction of a tertiary butoxycarbonyl group (second step); followed by a 2-piperidinecarboxylic acid decylamine derivative (VI) obtained in the second step in the presence of a base and an organic acid chloride derivative (VII) Condensation reaction (step 3). Further, the cyclic amine derivative (I) can also be obtained by a condensation reaction of a 2-piperidinecarboxylic acid decylamine derivative (VI) with an organic acid anhydride derivative (VIII). Further, a cyclic amine derivative (I) can also be obtained by a condensation reaction of a 2-piperidinecarboxylic acid decylamine derivative (VI) with an organic acid derivative (IX) in the presence of a condensing agent and a base. Further, a cyclic amine derivative (I) can also be obtained by a condensation reaction of a 2-piperidinecarboxylic acid decylamine derivative (VI) with trimethylsilyl isocyanate in the presence of a base. Further, the optically active substance of the cyclic amine derivative (I) can be obtained by using, for example, an optically active substance of the 2-piperidinecarboxylic acid derivative (IV).

Further, in the case where the above cyclic amine derivative (I) contains, for example, an amine group, the amine group may be converted into a guanamine group or a sulfonamide by a condensation reaction or a reductive amination reaction or the like. Or the like or an N-alkyl group. Further, in the case of containing an ester group, the ester group can be converted into a carboxyl group by a hydrolysis reaction. Further, in the case where a double bond is contained, the double bond can be converted into a single bond by a reduction reaction.

[In the formula, A and X are the same as defined above].

 (Step 1)  

The amount of the 2-piperidinecarboxylic acid derivative (IV) used in the condensation reaction is preferably 0.1 to 10 equivalents, more preferably 0.5 to 3 equivalents based on the aniline derivative (III).

The condensing agent used for the condensation reaction may, for example, be N,N'-dicyclohexylcarbodiimide or N-ethyl-N'-3-dimethylaminopropylcarbodiimide salt. Acid salt (hereinafter, EDC‧HCl), N,N'-carbonyldiimidazole, {{[(1-cyano-2-ethoxy-2-oxooxyethyl)amino]oxy}-4 - Polinylmethylene}dimethylammonium hexafluorophosphate (hereinafter, COMU), O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethylurea Hexafluorophosphate (hereinafter, HATU) or O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (hereinafter, HBTU), but Good for HATU or HBTU.

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

The base to be used in the condensation reaction may, for example, be an organic base such as triethylamine or diisopropylethylamine; an inorganic base such as sodium hydrogencarbonate or potassium carbonate; sodium hydride, potassium hydride or calcium hydride. a hydrogenated metal compound; an alkyl lithium such as methyl lithium or butyl lithium; a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide; A mixture of the above, but is preferably an organic base such as triethylamine or diisopropylethylamine.

The amount of the base used in the condensation reaction is preferably from 0.5 to 10 equivalents, more preferably from 1 to 5 equivalents, per equivalent of the aniline derivative (III).

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

The reaction solvent to be used in the condensation reaction is appropriately selected depending on the type of the reagent to be used, and the like, and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF and 1,4-two. An ether-based solvent such as an alkane, ethylene glycol dimethyl ether or dimethoxyethane; a halogen-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane; or aprotic such as DMF or DMSO The polar solvent or a nitrile-based solvent such as acetonitrile or propionitrile is preferably a halogen-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane or an aprotic polar solvent such as DMF or DMSO.

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

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

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

The aniline derivative (III) and the 2-piperidinecarboxylic acid derivative (IV) used for the condensation reaction can be purchased or can be produced by a known method or a method according thereto.

 (Step 2)  

The acid used for the deprotection reaction may, for example, be an acid such as hydrochloric acid, trifluoroacetic acid or hydrofluoric acid, but is preferably hydrochloric acid or trifluoroacetic acid.

The amount of the acid used for the deprotection reaction is preferably from 0.5 to 100 equivalents, more preferably from 1 to 30 equivalents, per equivalent of the N-tertiary butoxycarbonyl 2-piperidinecarboxylic acid decylamine derivative (V).

The reaction solvent for the deprotection reaction is appropriately selected depending on the type of the reagent to be used, etc., and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include diethyl ether, THF, dimethoxyethane or 1, 4-two An ether-based solvent such as an alkoxide; an ester-based solvent such as ethyl acetate or propyl acetate; a chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane; an alcohol-based solvent such as methanol or ethanol; The solvent is mixed, and the like is preferably an ester solvent such as ethyl acetate or propyl acetate or a chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane.

The reaction temperature for the deprotection reaction is preferably -78 ° C to 200 ° C, more preferably -20 ° C to 100 ° C.

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

The concentration at the start of the reaction of the N-tertiary butoxycarbonyl 2-piperidinecarboxylic acid decylamine derivative (V) used for the deprotection reaction is preferably from 1 mmol/L to 1 mol/L.

 (Step 3)  

The amount of the organic acid chloride derivative (VII), the organic acid anhydride derivative (VIII), the organic acid derivative (IX) or the trimethylsulfonium isocyanate used for the condensation reaction, which is derived relative to the 2-piperidinecarboxylic acid decylamine The substance (VI) is preferably from 0.5 to 10 equivalents, more preferably from 1 to 3 equivalents.

As the condensing agent used for the condensation reaction, for example, EDC‧HCl, COMU, HATU or HBTU may be mentioned, but HATU or HBTU is preferred.

The base to be used in the condensation reaction may, for example, be an organic base such as triethylamine or diisopropylethylamine; an inorganic base such as sodium hydrogencarbonate or potassium carbonate; sodium hydride, potassium hydride or calcium hydride. a hydrogenated metal compound; an alkyl lithium such as methyl lithium or butyl lithium; a lithium amide such as lithium hexamethyldiamine or lithium diisopropylamide; or a mixture thereof, preferably An organic base such as triethylamine or diisopropylethylamine.

The amount of the base used in the condensation reaction is preferably from 0.5 to 10 equivalents, more preferably from 1 to 5 equivalents, per equivalent of the 2-piperidinecarboxylic acid oxime derivative (VI).

The 2-piperidinecarboxylic acid decylamine derivative (VI) used for the condensation reaction may be a free form or a salt of a hydrochloride or the like.

The reaction solvent to be used in the condensation reaction is appropriately selected depending on the type of the reagent to be used, and the like, and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF and 1,4-two. An ether-based solvent such as an alkane, ethylene glycol dimethyl ether or dimethoxyethane; a chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane; or aprotic such as DMF or DMSO The polar solvent or a nitrile-based solvent such as acetonitrile or propionitrile is preferably a halogen-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane or an aprotic polar solvent such as DMF or DMSO.

The reaction temperature of the condensation reaction is preferably -78 ° C to 200 ° C, 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, and is preferably 0.5 to 30 hours.

The concentration at the start of the reaction of the 2-piperidinecarboxylic acid decylamine derivative (VI) used for the condensation reaction is preferably from 1 mmol/L to 1 mol/L.

The organic acid chloride derivative (VII), the organic acid anhydride derivative (VIII), the organic acid derivative (IX) and the trimethylsulfonium isocyanate used for the condensation reaction may be purchased or may be obtained by a known method or according to the same. Method of manufacture.

In the aniline derivative (III) shown in the scheme 1, A is an aniline derivative (III-a) of the group represented by the above formula (II-1), (II-2) or (II-3). For example, as shown in Scheme 2, a nucleophilic substitution reaction of an alcohol derivative (X) with a fluorophenyl derivative (XI) in the presence of a base (step 1); a deprotection reaction of a tertiary butoxycarbonyl group of the phenyl ether derivative (XII) obtained in the first step in the presence of an acid (second step); then, in the presence of a metal catalyst, a ligand and a base, Coupling reaction of the aliphatic amine derivative (XIII) obtained in the second step with a halogenated aryl derivative (XIV) (step 3); followed by nitrophenyl derivative obtained in the third step in the presence of a metal and an acid Reduction reaction of the substance (XV) (step 4). Further, the optically active substance of the aniline derivative (III-a) can be obtained, for example, by using an optically active substance of the alcohol derivative (X).

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

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

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

 (Step 1)  

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

Examples of the base used for the nucleophilic substitution reaction include an organic base such as triethylamine or diisopropylethylamine; an inorganic base such as sodium carbonate or potassium carbonate; sodium hydride, potassium hydride or hydrogenation; a hydrogenated metal compound such as calcium; a lithium aluminide such as lithium hexamethyldiamine or lithium diisopropylamide; a metal alkoxide such as sodium butoxide or potassium tert-butoxide or the like The mixture is preferably a hydrogenated metal compound such as sodium hydride, potassium hydride or calcium hydride.

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

The reaction solvent for the nucleophilic substitution reaction is appropriately selected depending on the type of the reagent to be used, and the like, and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF and 1,4-two. An ether-based solvent such as an alkane, ethylene glycol dimethyl ether or dimethoxyethane; a nitrile-based solvent such as acetonitrile or propionitrile; an aromatic hydrocarbon solvent such as benzene or toluene; and an aprotic such as DMF or DMSO. A polar solvent; water or a mixed solvent thereof, but preferably an aprotic polar solvent such as DMF or DMSO.

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

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

The concentration at the start of the reaction of the alcohol derivative (X) used for the nucleophilic substitution reaction is preferably from 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 a method according thereto.

 (Step 2)  

The acid used for the deprotection reaction may, for example, be an acid such as hydrochloric acid, trifluoroacetic acid or hydrofluoric acid, preferably hydrochloric acid or trifluoroacetic acid.

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

The reaction solvent for the deprotection reaction is appropriately selected depending on the type of the reagent to be used, and the like, and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include diethyl ether, THF, dimethoxyethane or , 4- 2 An ether-based solvent such as an alkoxide; an ester-based solvent such as ethyl acetate or propyl acetate; a chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane; an alcohol-based solvent such as methanol or ethanol; The solvent is mixed, and the like is preferably an ester solvent such as ethyl acetate or propyl acetate or a chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane.

The reaction temperature for the deprotection reaction is preferably -78 ° C to 200 ° C, more preferably -20 ° C to 100 ° C.

The reaction time for the deprotection reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably from 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 from 1 mmol/L to 1 mol/L.

 (Step 3)  

The amount of the halogenated aryl derivative (XIV) used in the coupling reaction is preferably from 0.5 to 10 equivalents, more preferably from 1 to 3 equivalents, per equivalent of the aliphatic amine derivative (XIII).

As the metal catalyst for the coupling reaction, for example, 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) dichloromethane adduct, palladium chloride (II) , palladium acetate (II), ginseng (dibenzylideneacetone) dipalladium (0), ruthenium triphenylphosphine palladium (0) or dichlorobistriphenylphosphine palladium (0), but preferably palladium acetate (II).

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 based on the aliphatic amine derivative (XIII).

As the ligand for the coupling reaction, for example, tri-tertiary butylphosphine or 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, but preferably three - Tert-butylphosphine.

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

The base used for the coupling reaction may, for example, be an organic base such as triethylamine or diisopropylethylamine; an inorganic base such as sodium carbonate or potassium carbonate; or lithium hexamethyldiamine; a lithium aluminide such as lithium diisopropylamide; a metal alkoxide such as sodium butoxide or potassium tert-butoxide; or a mixture thereof; preferably a sodium butoxide or tertiary butanol a metal alkoxide such as potassium.

The amount of the base used in the coupling reaction is preferably from 0.5 to 10 equivalents, more preferably from 1 to 5 equivalents, per equivalent of the aliphatic amine derivative (XIII).

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

The reaction solvent for the coupling reaction is appropriately selected depending on the type of the reagent to be used, and the like, and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF and 1,4-two. An ether-based solvent such as an alkane, ethylene glycol dimethyl ether or dimethoxyethane; a nitrile-based solvent such as acetonitrile or propionitrile; an aromatic hydrocarbon solvent such as benzene or toluene; and an aprotic such as DMF or DMSO. A polar solvent; water or a mixed solvent thereof, preferably an aromatic hydrocarbon solvent such as benzene or toluene.

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

The reaction time of the coupling reaction is appropriately selected depending on the conditions such as the reaction temperature, and is preferably from 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 from 1 mmol/L to 1 mol/L.

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

 (Step 4)  

The metal used for the reduction reaction may, for example, be iron powder or tin (II) chloride, but is preferably iron powder.

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

The acid used for the reduction reaction may, for example, be an aqueous solution of acetic acid, hydrochloric acid or ammonium chloride, but is preferably an aqueous solution of ammonium chloride.

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

The reaction solvent to be used for the reduction reaction is appropriately selected depending on the type of the reagent to be used, and the like, and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include an alcohol-based solvent such as methanol or ethanol; diethyl ether; THF, dimethoxyethane or 1,4-two An ether-based solvent such as an alkane; water or a mixed solvent thereof; preferably, it is a mixed solvent of an alcohol-based solvent such as methanol or ethanol and water.

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

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

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

In the aniline derivative (III) shown in the scheme 1, A is an aniline derivative (III-b) of the group represented by the above formula (II-4) or (II-5), for example, as in the scheme As shown in Fig. 3, a coupling reaction of a 2-stage amine derivative (XVIII) with a halogenated aryl derivative (XIV) in the presence of a metal catalyst, a ligand and a base can be obtained (step 1). Next, the deprotection reaction of the cyclic acetal group of the tertiary amine derivative (XIX) obtained in the first step in the presence of an acid (second step); followed by the ethynylmagnesium bromide pair a nucleophilic addition reaction of the ketone derivative (XX) obtained in the second step (step 3); followed by the fluorophenyl group derived from the third-order alcohol derivative (XXI) obtained in the third step in the presence of a base Nucleophilic substitution reaction of the compound (XI) (step 4); followed by reduction of the nitrophenyl derivative (XXII) obtained in the fourth step in the presence of a metal and an acid (step 5); The cyclization reaction of the aniline derivative (XXIII) obtained in the fifth step (step 6).

[wherein, m represents an integer of 1 to 2, A represents a group represented by the above formula (II-4) or (II-5), and R ¹ , R ² and Q are the same as defined above].

 (Step 1)  

The amount of the halogenated aryl derivative (XIV) used in the coupling reaction is preferably from 0.5 to 10 equivalents, more preferably from 1 to 3 equivalents, per equivalent of the amine derivative (XVIII).

As the metal catalyst for the coupling reaction, for example, 1,1'-bis(diphenylphosphino)ferrocene dichloropalladium (II) dichloromethane adduct, palladium chloride (II) ), palladium (II) acetate, bis(dibenzylideneacetone) dipalladium (0), ruthenium triphenylphosphine palladium (0) or dichlorobistriphenylphosphine palladium (0), but preferably ginseng ( 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, per equivalent of the amine derivative (XVIII).

As the ligand for the coupling reaction, for example, tris-tertiary butylphosphine or 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, but preferably 2 is exemplified. , 2'-bis(diphenylphosphino)-1,1'-binaphthyl.

The amount of the ligand used in the coupling reaction is preferably from 0.01 to 5 equivalents, more preferably from 0.05 to 0.5 equivalents, per equivalent of the amine derivative (XVIII).

The base used for the coupling reaction may, for example, be an organic base such as triethylamine or diisopropylethylamine; an inorganic base such as sodium carbonate or potassium carbonate; or lithium hexamethyldiamine; a lithium aluminide such as lithium diisopropylamide; a metal alkoxide such as sodium tributoxide or potassium tert-butoxide or a mixture thereof, but preferably a sodium tert-butoxide or a tertiary butanol a metal alkoxide such as potassium.

The amount of the base used in the coupling reaction is preferably from 0.5 to 10 equivalents, more preferably from 1 to 5 equivalents, per equivalent of the amine derivative (XVIII).

The secondary amine derivative (XVIII) used in the coupling reaction may be a free form or a salt of a hydrochloride or the like.

The reaction solvent for the coupling reaction is appropriately selected depending on the type of the reagent to be used, and the like, and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF and 1,4-two. An ether-based solvent such as an alkane, ethylene glycol dimethyl ether or dimethoxyethane; a nitrile-based solvent such as acetonitrile or propionitrile; an aromatic hydrocarbon solvent such as benzene or toluene; and an aprotic such as DMF or DMSO. A polar solvent; water or a mixed solvent thereof, preferably an aromatic hydrocarbon solvent such as benzene or toluene.

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

The reaction time of the coupling reaction is appropriately selected depending on the conditions such as the reaction temperature, and is preferably from 1 to 60 hours.

The concentration at the start of the reaction of the second-order amine derivative (XVIII) for the coupling reaction is preferably from 1 mmol/L to 1 mol/L.

The secondary amine derivative (XVIII) and the halogenated aryl derivative (XIV) used in the coupling reaction are commercially available or can be produced by a known method or a method according thereto.

 (Step 2)  

The acid used for the deprotection reaction may, for example, be an acid such as hydrochloric acid, acetic acid, trifluoroacetic acid or hydrofluoric acid, but is preferably acetic acid.

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

The reaction solvent for the deprotection reaction is appropriately selected depending on the type of the reagent to be used, and the like, and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include diethyl ether, THF, dimethoxyethane or , 4-two An ether-based solvent such as an alkane; an ester-based solvent such as ethyl acetate or propyl acetate; a chlorine-based solvent such as dichloromethane, chloroform or 1,2-dichloroethane; or a mixed solvent of water or the like; Preferably it is diethyl ether, THF, dimethoxyethane or 1,4-two A mixed solvent of an ether-based solvent and water.

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

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

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

 (Step 3)  

The amount of the ethynylmagnesium bromide used for the nucleophilic addition reaction is preferably from 0.5 to 10 equivalents, more preferably from 1 to 3 equivalents, per equivalent of the ketone derivative (XX).

The reaction solvent for the nucleophilic addition reaction is appropriately selected depending on the type of the reagent to be used, and the like, and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include diethyl ether, THF or dimethoxyethane. An ether-based solvent; a hydrocarbon-based solvent such as hexane or pentane; an aromatic hydrocarbon-based solvent such as benzene or toluene; or a mixed solvent thereof, preferably diethyl ether, THF or dimethoxy An ether-based solvent such as an alkane.

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 from 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 from 1 mmol/L to 1 mol/L.

 (Step 4)  

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

Examples of the base used for the nucleophilic substitution reaction include an organic base such as triethylamine or diisopropylethylamine; an inorganic base such as sodium carbonate or potassium carbonate; sodium hydride, potassium hydride or hydrogenation; a hydrogenated metal compound such as calcium; a lithium aluminide such as lithium hexamethyldiamine or lithium diisopropylamide; a metal alkoxide such as sodium butoxide or potassium tert-butoxide or the like The mixture is preferably a hydrogenated metal compound such as sodium hydride, potassium hydride or calcium hydride.

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

The reaction solvent for the nucleophilic substitution reaction is appropriately selected depending on the type of the reagent to be used, and the like, and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF and 1,4-two. An ether-based solvent such as an alkane, ethylene glycol dimethyl ether or dimethoxyethane; a nitrile-based solvent such as acetonitrile or propionitrile; an aromatic hydrocarbon solvent such as benzene or toluene; and an aprotic such as DMF or DMSO. A polar solvent; water or a mixed solvent thereof, but preferably an aprotic polar solvent such as DMF or DMSO.

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

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

The concentration at the start of the reaction of the tertiary alcohol derivative (XXI) used for the nucleophilic substitution reaction is preferably from 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 according thereto.

 (Step 5)  

The metal used for the reduction reaction may, for example, be iron powder or tin (II) chloride, preferably iron powder.

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

The acid used for the reduction reaction may, for example, be an aqueous solution of acetic acid, hydrochloric acid or ammonium chloride, but is preferably an aqueous solution of ammonium chloride.

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

The reaction solvent to be used for the reduction reaction is appropriately selected depending on the type of the reagent to be used, and the like, and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include an alcohol-based solvent such as methanol or ethanol; diethyl ether; THF, dimethoxyethane or 1,4-two An ether-based solvent such as an alkane; water or a mixed solvent thereof; preferably, it is a mixed solvent of an alcohol-based solvent such as methanol or ethanol and water.

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

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

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

 (Step 6)  

The reaction solvent to be used in the cyclization reaction is appropriately selected depending on the type of the reagent to be used, and the like. The reaction is not particularly limited, and examples thereof include an aromatic hydrocarbon-based solvent such as benzene, toluene or xylene.

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

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

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

Further, the optically active substance of the cyclic amine derivative (I) wherein A is a group represented by the above formula (II-5), for example, a compound is known by a known method (for example, palm chromatography) The racemate or other mixture is separated, whereby the respective optical or non-image isomers of the single optically active body can be obtained. Further, for example, by using the induction of homochiral acid, the non-image isomer derivative can be separated by a known method (for example, crystallization or chromatography). The respective optical or non-image isomers of the individual optically active bodies are obtained.

A pharmaceutical or ROR gamma antagonist of the present invention, and a therapeutic or prophylactic agent for an autoimmune disease or an allergic disease, which comprises a cyclic amine derivative (I), a stereoisomer thereof or a hydrate thereof, Or their pharmacologically acceptable salts as active ingredients. The above autoimmune disease is preferably multiple sclerosis or dryness, and the allergic disease is preferably allergic dermatitis, more preferably contact dermatitis or atopic dermatitis.

The "ROR gamma antagonist" means a compound which inhibits the function of RORγ and has an action of abolishing or attenuating its activity.

"Autoimmune disease" is a general term for diseases that cause symptoms due to an excessive immune response to attack normal cells or tissues, and examples thereof include multiple sclerosis, dryness, rheumatoid arthritis, systemic lupus erythematosus, and inflammation. Enteropathy, ankylosing spondylitis, uveitis, rheumatic polymyalgia, scleroderma, vasculitis, pemphigus, pemphigoid or dermatomyositis. Further, the autoimmune disease of the present invention comprises acne, vitiligo or alopecia areata.

"Allergic disease" refers to a disease derived from an excessive immune response to a specific antigen, and examples thereof include allergic dermatitis, contact dermatitis, atopic dermatitis, allergic rhinitis (hay fever), and allergies. Conjunctivitis, allergic gastroenteritis, bronchial asthma, childhood asthma or food allergies.

"Multiple sclerosis" is a disease characterized by demyelination in which the myelin sheath of the nerve fibers such as the brain, the spinal cord, and the optic nerve is destroyed, and the recurrence and remission are repeated, and the disease continues. The symptoms vary depending on the lesion, and various types of neurological symptoms such as visual impairment, paralysis of the limbs, sensory disturbances, and walking disorders are displayed. Examples of the multiple sclerosis include relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, and secondary progressive multiple sclerosis.

"Cognac" refers to an inflammatory disease associated with the following skin: infiltration and activation of immune cells, and epidermal hypertrophy accompanying them. Typically, in a wide variety of places throughout the body, in addition to the red rash, thick white scales are attached, causing symptoms of flaking. Examples of the cognac include, for example, cognac vulgaris, pustular dry cognac, arthritic cognac, drip cognac, and dry erythrodony.

"Allergic dermatitis" refers to a general term for skin diseases that are caused by allergic reactions, characterized by chronic itching and rash on the face, neck, elbow, and/or knee. Examples of allergic dermatitis include contact dermatitis, atopic dermatitis, and the like.

"Contact dermatitis" refers to an eczema inflammatory disease caused by the contact of a foreign antigen with the skin, and examples thereof include allergic contact dermatitis, photocontact dermatitis, systemic contact with dermatitis or contact. Sexual urticaria. Further, examples of the antigen include metal allergens (cobalt, nickel, etc.), plant allergens (lacquer tree, primrose), and food allergens (mango, ginkgo, etc.).

"Atopic dermatitis" refers to a skin disease in which most patients have an atopic constitution. Repeated deterioration and relief of bilateral symmetrical systemic eczema are characterized by, for example, diffuse neurodermatitis, atopic eczema, atopic neurodermatitis, Benier's prurigo, acute Baby eczema, flexion eczema, limb eczema in children, atopic eczema in children, dry eczema in children, eczema in children, atopic dermatitis in adults, endogenous eczema, infant dermatitis, chronic baby wet rash.

The cyclic amine derivative (I), a stereoisomer thereof or a hydrate thereof, or a pharmacologically acceptable salt thereof, inhibits the function of RORγ by inhibiting the combination of RORγ and a co-activator Characterized. Since RORγ is known to be involved in various diseases, it is expected that the improvement of the pathological state or the relief of symptoms can be expected by the inhibition of its function, so the cyclic amine derivative (I), its stereoisomer or the like A hydrate, or a pharmacologically acceptable salt thereof, can be used as a medicine for a disease which can be expected to be ameliorated or a symptom to be relieved by inhibiting the function of RORγ, and particularly, can be used as an autoimmune disease or allergy. A therapeutic or prophylactic agent for a sexual disease. The above therapeutic or prophylactic agent for autoimmune diseases is preferably used as multiple sclerosis, dryness, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, ankylosing spondylitis, uveitis, A therapeutic or prophylactic agent for rheumatoid polymyalgia, scleroderma, vasculitis, pemphigus, pemphigus, dermatomyositis, acne, leukoplakia or alopecia areata, preferably as multiple sclerosis or dryness a therapeutic or prophylactic agent. The above-mentioned therapeutic or prophylactic agent for allergic diseases is preferably used as allergic dermatitis, atopic dermatitis, allergic rhinitis (hay fever), allergic conjunctivitis, allergic gastroenteritis, bronchial asthma, children A therapeutic or prophylactic agent for asthma or food allergy, preferably used as a therapeutic or prophylactic agent for contact dermatitis or atopic dermatitis.

The cyclic amine derivative (I), a stereoisomer thereof or a hydrate thereof, or a pharmacologically acceptable salt thereof, has an ROR gamma antagonist activity which inhibits binding of RORγ to a co-activator, and a living body can be used. External test to evaluate. For the in vitro test, for example, a method of evaluating the combination of RORγ and an agonist (for example, cholesterol) (International Publication No. 2012/158784, International Publication No. 2013/018695), and evaluation of the distribution of RORγ A method of combining a body binding domain with a co-activator (International Publication No. 2012/064744, International Publication No. 2013/018695). Further, the transcriptional activity inhibitory action of RORγ can be evaluated using various reporter gene assays (International Publication No. 2012/158784, International Publication No. 2012/064744, International Publication No. 2013/018695).

The cyclic amine derivative (I), a stereoisomer thereof, or a hydrate of the above, or a pharmacologically acceptable salt thereof, can inhibit the function of RORγ, and various organs derived from the spleen or peripheral blood can be used. The lymphocyte cells were evaluated by the production of IL-17 or the differentiation of Th17 cells. As a method of producing IL-17 as an index, for example, a method of measuring IL-17 production by IL-23 stimulation using mouse spleen cells can be cited (The Journal of Biological Chemistry, 2003, p. 278). Volume, No. 3, p.1910-1914). As a method of using Th17 cell differentiation as an index, for example, a CD4-positive primary T cell derived from mouse spleen cells or human PBMC can be used, and various interleukins (for example, IL-1β, IL-6, IL-23 and/or TGF-β) are stimulated with various antibodies (eg, anti-CD3 antibodies, anti-CD28 antibodies, anti-IL-4 antibodies, anti-IFN-γ antibodies, and/or anti-IL-2 antibodies) In order to differentiate into Th17, a method of measuring the amount of IL-17 production or the ratio of IL-17 positive cells (International Publication No. 2012/158784, International Publication No. 2013/018695).

The cyclic amine derivative (I), a stereoisomer thereof, or a hydrate of these, or a pharmacologically acceptable salt thereof, is effective for the treatment or prevention of an autoimmune disease, and can be evaluated using a pathological pattern. . As far as the pathological pattern is concerned, for example, an experimental autoimmune encephalomyelitis model (Journal of Neuroscience Research, 2006, Vol. 84, p. 1225-1234), imiquimod-induced dryness mode (Journal of Journal of Neuron Immunology, 2009, Vol. 182, p. 5836-5845), Collagen Arthritis Model (Annual Review of Immunology, 1984, Vol. 2, p. 199-218), the natural onset pattern of systemic lupus erythematosus ( Nature, 2000, Vol. 404, p. 995-999), TNBS-induced colitis model (European Journal of Pharmacology, 2001, Vol. 431, p. 103-110), ankylosing spondylitis model (Arthritis Research & Therapy, 2012, Vol. 14, p. 253-265), experimental autoimmune uveitis model (Journal of Immunology, 2006, Vol. 36, p. 3071-3081), scleroderma pattern ( Journal of Investigative Dermatology, 1999, Vol. 112, p. 456-462), The Journal of Clinical Investigation (2002, Vol. 110, p. 955-963), The Journal of Pestle Clinical Investigation, 2000, Vol. 105, p. 625-631), Pemphigus Model (Experimental Dermatology, 2012, Vol. 21, p. 901-905), Dermatitis model (American Journal of Pathology, 1985, Vol. 120, p. 323-325), natural pathogenesis of acne (European Journal of Dermatology, 2005, Vol. 15, p. 459-464), white spot pattern (Pigment Cell & Melanoma Research, 2014, Vol. 27, p. 1075-1085), or the Journal of Investigative Dermatology , 2015, Vol. 135, p. 2530-2532). The experimental autoimmune encephalomyelitis model is generally used as a model for multiple sclerosis. Moreover, the imiquimod-induced dryness mode is generally used as a mode of dryness.

Further, the cyclic amine derivative (I), a stereoisomer thereof, or a hydrate of the above, or a pharmacologically acceptable salt thereof, is effective for the treatment or prevention of an allergic disease, and a pathological pattern can be used. Evaluation. As for the pathological pattern, for example, dinitrofluorobenzene (hereinafter, DNFB)-induced allergic dermatitis mode (Pharmacological Reports, 2013, Vol. 65, p. 1237-1246), Oxazolinone-induced atopic dermatitis pattern (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 (British Journal of Ophthalmology, 2012, Vol. 96, p. 1332-1336), allergic gastroenteritis model (Gastroenterology, 1997, Vol. 113, p. 1560-1569), ovalbumin-induced asthmatic pattern (American Journal of Respiratory and Critical Care Medicine, 1997, Vol. 156, p. 766-775), or ovalbumin-induced food allergy model (Clinical & Experimental Allergy, 2005, Volume 35, p.461-466). The DNFB-induced allergic dermatitis pattern is generally used as a model of allergic dermatitis, especially as a contact dermatitis model. also, The oxazolinone-induced atopic dermatitis pattern is generally used as a pattern of atopic dermatitis.

The effectiveness of the cyclic amine derivative (I), its stereoisomers or hydrates thereof, or their pharmacologically acceptable salts, for the treatment or prevention of autoimmune diseases or allergic diseases, The above-described in vitro test can be used, for example, by using a decrease in the binding amount of the ligand binding domain of RORγ and the coactivator, or a decrease in the amount of IL-17 produced by the function of RORγ as an index. Further, for the effectiveness of the treatment or prevention of multiple sclerosis, the above-described experimental autoimmune encephalomyelitis model can be used, for example, the reduction of the neurological symptom score for the characteristic index of multiple sclerosis is used as an index. To evaluate. Further, for the effectiveness of the treatment or prevention of dryness, the above-described imiquimod-induced dryness mode can be used, and for example, the decrease in skin thickness of the ear shell or the like which increases with the symptoms of the dryness mode can be evaluated as an index. Further, for allergic dermatitis, particularly for the treatment or prevention of contact dermatitis, the above-mentioned DNFB-induced allergic dermatitis pattern can be used, for example, an ear shell which increases with the progress of dermatitis symptoms. The decrease in skin thickness was evaluated as an index. Also, for the effectiveness of the treatment or prevention of atopic dermatitis, the above may be used The oxazolinone-induced atopic dermatitis pattern is evaluated, for example, as a decrease in skin thickness of an ear shell or the like which is accompanied by an increase in the symptoms of dermatitis.

a cyclic amine derivative (I), a stereoisomer thereof or a hydrate thereof, or a pharmacologically acceptable salt thereof, for a mammal (for example, a mouse, a rat, a hamster, a rabbit, a dog) , cats, monkeys, cows, sheep or humans, especially in the case of humans, can be used as a useful medicine (especially, a therapeutic or prophylactic agent for autoimmune diseases or allergic diseases). When the cyclic amine derivative (I), a stereoisomer thereof, or a hydrate of the above, or a pharmacologically acceptable salt thereof, is used clinically as a medicine, a cyclic amine derivative can be directly used. (I), a stereoisomer thereof or a hydrate of these, or a pharmacologically acceptable salt thereof, or a pharmaceutically acceptable carrier, may be administered orally or parenterally. The above medicine may be appropriately mixed with a binder, an excipient, a lubricant, a disintegrating agent, a sweetener, a stabilizer, a flavoring agent, a flavoring agent, a coloring agent, a fluidizing agent, a preservative, a buffering agent, a dissolution aid, if necessary. Additives such as emulsifiers, surfactants, suspending agents, diluents or isotonic agents. As the pharmacologically acceptable carrier, such additives may be mentioned. Further, the above-mentioned medicine can be produced by a usual method by suitably using such a carrier for a drug. Examples of the pharmaceutical administration form include oral preparations such as a tablet, a capsule, a granule, a powder, or a syrup; and an inhalation, an injection, a suppository, or a liquid. An ointment, cream or patch for topical administration. Moreover, it can also be made into a well-known continuous preparation.

Examples of the binder include syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride or tragacanth.

Examples of the excipient include granulated sugar, lactose, corn starch, calcium phosphate, sorbitol or glycine.

The lubricant may, for example, be magnesium stearate, calcium stearate, polyethylene glycol, talc or vermiculite.

Examples of the disintegrating agent include starch or calcium carbonate.

As the sweetener, for example, glucose, fructose, invert sugar, sorbitol, xylitol, glycerin or a monosaccharide syrup can be mentioned.

The above-mentioned medicine preferably contains 0.00001 to 90% by weight of the cyclic amine derivative (I), a stereoisomer thereof or a hydrate thereof, or a pharmacologically acceptable salt thereof, and more preferably contains 0.01 to 70% by weight. The dosage is appropriately selected depending on the symptoms, age and body weight of the patient, and the administration method. The amount of the active ingredient for the adult is preferably 0.1 μg to 1 g per day, and the oral preparation is preferably per administration. 1 μg to 10 g on the 1st, and the case of the patch is preferably 1 μg to 10 g per day, and each of them may be administered once or divided into several doses.

The above-mentioned medicine may be used in an appropriate amount or in combination with other agents in order to supplement or enhance the therapeutic or prophylactic effect, or to reduce the administration amount.

The invention is further illustrated by the following reference examples and examples, but the invention is not limited thereto.

 [Examples]  

For the compounds used in the synthesis of the compounds of the Reference Examples and the Examples and not described in the synthetic method, commercially available compounds were used. The "room temperature" in the following Reference Examples and Examples generally means from about 10 ° C to about 35 ° C. % represents the mol/mol% in the yield, and the solvent used in the column chromatography and the high-speed liquid chromatography represents the volume %, and the others are % by weight unless otherwise specified. The solvent name shown in the NMR data indicates the solvent used for the measurement. Further, the 400 MHz NMR spectrum was measured using a JNM-AL400 type nuclear magnetic resonance apparatus (Japan Electronics Co., Ltd.) or a JNM-ECS400 type nuclear magnetic resonance apparatus (Japan Electronics Co., Ltd.). The chemical shift is represented by δ (unit: ppm) based on tetramethyl decane, and the signal system is s (single peak), d (double peak), t (triplet), q (quadruple), quint (five peaks), sept (seven peaks), m (multiple peaks), br (wide peaks), dd (double doublets), dt (double triplets), ddd (double doublets), dq (double four) Heavy peak), td (triple doublet), tt (triple triplet). The case where the proton of a hydroxyl group or an amine group is very moderate is not described. The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (Agilent Technology). For the silicone rubber, silicone 60 (Merck) was used, the amine silicone was amide DM1020 (Fuji Silysia Chemical Co.), and the chromatography was YFLC W-prep2XY (Shanshan).

(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) were dissolved in N,N-dimethyl Guanidine (2.85 mL) was added cesium carbonate (1.86 g, 5.70 mmol) at rt. 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 a saturated aqueous solution of sodium hydrogencarbonate, distilled water and brine, and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = EtOAc / EtOAc / , 1.94mmol, 68%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.92-1.94 (m, 4H), 3.66-3.68 (m, 4H), 4.74-4.78 (m, 1H), 5.15 (s, 2H), 6.99 (d, J = 9.5 Hz, 1H), 7.31-7.38 (m, 5H), 8.14 (dd, J = 9.5, 2.7 Hz, 1H), 8.31 (d, J = 2.7 Hz, 1H).

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), and 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, and distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = EtOAc / EtOAc / , 1.46mmol, 76%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.81-1.84 (m, 4H), 3.45 (ddd, J = 13.4, 6.8, 4.1 Hz, 2H), 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, 1H), 6.73 (d, J = 2.7 Hz, 1H) ), 6.80 (d, J = 8.6 Hz, 1H), 7.31-7.37 (m, 5H).

ESI-MS: m/z = 361 (M+H) ⁺ .

(Reference Example 3) Synthesis of 4-(4-(1-ethenylpiperidine-2-carboxamide)-2-chlorophenoxy)piperidine-1-carboxylic acid benzyl ester:

The compound of Reference Example 2 (0.150 g, 0.416 mmol) and 1-ethylhydrazinopiperidine-2-carboxylic acid (0.0854 g, 0.499 mmol) were dissolved in DMF (2.08 mL) and HATU was added at room temperature (0.205 g, 0.540) Methyl) and diisopropylethylamine (0.109 mL, 0.624 mmol). 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 a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 60/40 to 5/95) to give the title compound as a pale yellow solid (hereinafter, the compound of Reference Example 3) (0.175 g, 0.340) M, 82%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.49-1.55 (m, 2H), 1.71-1.78 (m, 2H), 1.85-1.97 (m, 5H), 2.20 (s, 3H), 2.25-2.28 ( m, 1H), 3.11-3.19 (m, 1H), 3.50-3.56 (m, 2H), 3.68-3.78 (m, 3H), 4.45-4.50 (m, 1H), 5.14 (s, 2H), 5.24 ( d, J = 5.4 Hz, 1H), 6.88 (d, J = 9.1 Hz, 1H), 7.29-7.37 (m, 6H), 7.63 (d, J = 2.7 Hz, 1H), 8.32 (s, 1H).

ESI-MS: m/z = 536 (M+Na) ⁺ .

(Reference Example 4) Synthesis of 1-ethenyl-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 mixture, and the aqueous layer was washed with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. %).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.60 (m, 2H), 1.70-2.01 (m, 7H), 2.20 (s, 3H), 2.25-2.29 (m, 1H), 2.70-2.76 ( m, 2H), 3.14-3.20 (m, 3H), 3.74-3.78 (m, 1H), 4.32-4.38 (m, 1H), 5.25 (d, J = 5.4 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 7.29 (dd, J = 8.6, 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 8.34 (s, 1H).

ESI-MS: m/z = 380 (M+H) ⁺ .

(Example 1) Synthesis of 1-ethenyl-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) was dissolved in toluene (1.05 mL), and iodobenzene (0.0176 mL, 0.158 mmol), palladium(II) acetate (0.00473 g, 0.0211 mmol), tri- Tert-butylphosphinotetrafluoroborate (0.00611 g, 0.0211 mmol) and tertiary sodium butoxide (0.0304 g, 0.316 mmol). After stirring at 120 ° C for 1 hour, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=60/40~10/90) to give the title compound as a white solid (the compound of Example 1 below) (0.00852g, 0.0189mmol) , 18%).

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, 2H), 3.74-3.78 (m, 1H), 4.42-4.47 (m, 1H), 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, 1H), 7.63 (d, J = 2.7 Hz, 1H), 8.32 (s, 1H).

ESI-MS: m/z = 456 (M+H) ⁺ .

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

3-Hydroxypiperidine-1-carboxylic acid tert-butyl ester (2.43 g, 12.1 mmol) and sodium hydride (55 wt% mineral oil dispersion, 0.552 g, 12.7 mmol) were suspended in DMF (11.5 mL) at 0 ° C After stirring 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 at the same temperature for 2 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate=90/10-75/25) to give the title compound as a pale yellow solid (hereinafter, the compound of Reference Example 5) (3.65 g, 10.2 M, 89%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.48 (s, 9H), 1.84-1.98 (m, 4H), 3.51-3.65 (m, 4H), 4.71-4.76 (m, 1H), 7.00 (d, J = 9.5 Hz, 1H), 8.14 (dd, J = 9.5, 2.7 Hz, 1H), 8.31 (d, J = 2.7 Hz, 1H).

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 ethyl hydrogen chloride-ethyl acetate solution (4.0 M, 38.4 mL, 153 mmol) was added at room temperature. After stirring at the same temperature for 1 hour, the reaction solution was filtered, and the filtered solid was washed with ethyl acetate and evaporated to give the title compound (yield of the compound of Reference Example 6) (2.94 g, 10.0 mmol, 98%).

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 1.89-1.97 (m, 2H), 2.13-2.20 (m, 2H), 3.08-3.14 (m, 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, 1H), 8.35 (d, J = 3.2 Hz, 1H), 8.97 (brs , 2H).

ESI-MS: m/z = 257 (M+H) ⁺ .

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

Reference compound 6 (0.100 g, 0.342 mmol), palladium (II) acetate (0.0154 g, 0.0682 mmol), tris-tert-butylphosphinotetrafluoroborate (0.0199 g, 0.0682 mmol) and tertiary butyl Sodium alkoxide (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 at 110 ° C for 2 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate-ethyl acetate=95/5-85/15) to give the title compound as a pale yellow solid (hereinafter, the compound of Reference Example 7) (0.0524 g, 0.149 M, 44%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.07-2.24 (m, 4H), 3.08-3.14 (m, 2H), 3.30-3.36 (m, 2H), 4.72-4.77 (m, 1H), 6.93 7.10 (m, 5H), 8.15 (dd, J = 9.1, 2.9 Hz, 1H), 8.32 (d, J = 2.9 Hz, 1H).

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), and iron powder (0.0398 g, 0.713 mmol) and ammonium chloride (0.0381 g, 0.713 mmol) were added at room temperature. ). After stirring at 80 ° C for 3 hours, the reaction solution was filtered, and distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=90/10 to 50/50) to give the title compound (hereinafter, the compound of Reference Example 8) (0.0470 g, 0.147 mmol, quantitative).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.04-2.09 (m, 4H), 2.93-2.99 (m, 2H), 3.35-3.41 (m, 2H), 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, 1H), 6.85 (d, J = 8.8 Hz, 1H), 6.92-7.08 (m, 4H) ).

ESI-MS: m/z = 321 (M+H) ⁺ .

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

The compound of Reference Example 8 (0.0250 g, 0.0779 mmol) and 1-ethylhydrazinopiperidine-2-carboxylic acid (0.0160 g, 0.0935 mmol) were dissolved in DMF (1.00 mL), and HATU (0.0356 g, 0.0935) was added at room temperature. Methyl) and diisopropylethylamine (0.0204 mL, 0.117 mmol). 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 a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) , 56%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.48-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.89-1.98 (m, 1H), 2.00-2.15 (m, 4H), 2.21 ( s, 3H), 2.26-2.29 (m, 1H), 2.98-3.04 (m, 2H), 3.12-3.20 (m, 1H), 3.32-3.38 (m, 2H), 3.75-3.78 (m, 1H), 4.44-4.49 (m, 1H), 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, 1H), 7.64 (d, J = 2.4 Hz, 1H), 8.32 (s, 1H).

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, the compound of Reference Example 9) was obtained as a pale yellow solid. (0.0863 g, 0.246 mmol, 72%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.00-2.17 (m, 4H), 3.24-3.30 (m, 2H), 3.45-3.51 (m, 2H), 4.72-4.77 (m, 1H), 6.52- 6.57 (m, 1H), 6.61-6.65 (m, 1H), 6.70-6.73 (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, 1H).

ESI-MS: m/z = 351 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 10) (0.0783 g, 0.244) was obtained as a yellow oil. Mmmol, quantitative).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.90-2.07 (m, 4H), 3.08-3.14 (m, 2H), 3.52-3.58 (m, 4H), 4.27-4.32 (m, 1H), 6.48- 6.54 (m, 2H), 6.59-6.63 (m, 1H), 6.68-6.71 (m, 1H), 6.74 (d, J = 2.9 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 7.15 -7.21 (m, 1H).

ESI-MS: m/z = 321 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 3) (0.0211 g, 0.0445 mmol) was obtained as a white solid. 57%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.48-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.90-2.08 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m,1H),3.12-3.19(m,3H), 3.48-3.54(m,2H), 3.75-3.78(m,1H),4.44-4.49(m,1H),5.24-5.26(m,1H), 6.48-6.53 (m, 1H), 6.59-6.64 (m, 1H), 6.68-6.71 (m, 1H), 6.92 (d, J = 9.0 Hz, 1H), 7.15 - 7.21 (m, 1H), 7.31 ( Dd, J = 9.0, 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 8.32 (s, 1H).

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) was obtained as a pale yellow solid by the procedure of the same procedure as in the above. (0.113 g, 0.322 mmol, 94%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.03-2.20 (m, 4H), 3.12-3.18 (m, 2H), 3.34-3.40 (m, 2H), 4.70-4.75 (m, 1H), 6.91- 7.04 (m, 5H), 8.15 (dd, J = 9.1, 2.8 Hz, 1H), 8.32 (d, J = 2.8 Hz, 1H).

ESI-MS: m/z = 351 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 12) (0.0987 g, 0.308 mmol,) was obtained as a yellow solid. 98%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.93-2.10 (m, 4H), 2.96-3.02 (m, 2H), 3.40-3.46 (m, 2H), 3.52 (brs, 2H), 4.23-4.29 ( m,1H), 6.53 (dd, J=8.5, 2.9 Hz, 1H), 6.74 (d, J=2.9 Hz, 1H), 6.84 (d, J=8.5 Hz, 1H), 6.89-6.98 (m, 4H) ).

ESI-MS: m/z = 321 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 4) (0.0259 g, 0.0546 mmol) was obtained as a white solid. 70%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.47-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.90-2.11 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m,1H), 3.01-3.07 (m, 2H), 3.12-3.19 (m, 1H), 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, 1H), 7.63 (d, J=2.7 Hz, 1H), 8.32 (s, 1H) .

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) was obtained as a pale yellow solid by the procedure of the same procedure as in the above. (0.0475 g, 0.129 mmol, 38%).

^{1 H-NMR (400MHz, 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=9.1Hz,1H),7.09(dd,J=8.2,1.4Hz,1H),7.22-7.26(m,1H) , 7.38 (dd, J = 7.9, 1.6 Hz, 1H), 8.16 (dd, J = 9.1, 2.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 367 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 14) (0.0380 g, 0.113) as a yellow oil was obtained by the same procedure as the compound of the above. M, 92%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.99-2.11 (m, 4H), 2.89-2.94 (m, 2H), 3.30-3.36 (m, 2H), 3.52 (brs, 2H), 4.27-4.33 ( m,1H), 6.53 (dd, J=8.8, 2.9 Hz, 1H), 6.75 (d, J=2.9 Hz, 1H), 6.86 (d, J=8.8 Hz, 1H), 6.94-6.98 (m, 1H) ), 7.06-7.09 (m, 1H), 7.19-7.23 (m, 1H), 7.35-7.37 (m, 1H).

ESI-MS: m/z = 338 (M+H) ⁺ .

(Example 5) 1-Ethyl-N-(3-chloro-4-((1-(2-chlorophenyl)piperidin-4-yl)oxy)phenyl)piperidine-2-yl Synthesis of guanamine:

The title compound (hereinafter, the compound of Example 5) (0.0233 g, 0.0475 mmol) as a pale yellow solid was obtained by the same procedure as in the procedure of the same. , 80%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.90-1.98 (m, 1H), 2.01-2.16 (m, 4H), 2.21. s, 3H), 2.26-2.29 (m, 1H), 2.93-2.99 (m, 2H), 3.12-3.20 (m, 1H), 3.27-3.33 (m, 2H), 3.75-3.78 (m, 1H), 4.45-4.50 (m, 1H), 5.25-5.26 (m, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.94-6.98 (m, 1H), 7.08 (dd, J = 8.2, 1.4 Hz, 1H), 7.20-7.24 (m, 1H), 7.30 (dd, J = 8.8, 2.5 Hz, 1H), 7.36 (dd, J = 7.7, 1.4 Hz, 1H), 7.64 (d, J = 2.5 Hz, 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) was obtained as a pale yellow solid by the procedure of the same procedure as the the the (0.110 g, 0.300 mmol, 88%).

¹ H-NMR (400MHz, 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, 2H), 4. 4.77 (m, 1H), 6.81-6.84 (m, 2H), 6.92-6.93 (m, 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, 1H).

ESI-MS: m/z = 367 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 16) (0.0220 g, 0.0652 mmol) as a pale yellow solid was obtained by the procedure of the same. ,twenty one%).

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, 2H), 3.54 ( Brs, 2H), 4.27-4.32 (m, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.78-6.84 (m, 2H), 6.84 (d, J = 8.6 Hz, 1H), 6.90 - 6.92 (m, 1H), 7.14 - 7.18 (m, 1H).

ESI-MS: m/z = 338 (M+H) ⁺ .

(Example 6) 1-Ethyl-N-(3-chloro-4-((1-(3-chlorophenyl)piperidin-4-yl)oxy)phenyl)piperidine-2-yl Synthesis of guanamine:

The title compound (hereinafter, the compound of Example 6) (0.0245 g, 0.0500 mmol) was obtained as a pale yellow solid (yield of the compound of Example 6). , 84%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.49-1.61 (m, 2H), 1.72-1.78 (m, 2H), 1.91-2.07 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m,1H),3.12-3.19(m,3H), 3.47-3.53(m,2H), 3.75-3.78(m,1H),4.44-4.49(m,1H),5.24-5.26(m,1H), 6.78-6.83 (m, 2H), 6.90-6.91 (m, 1H), 6.92 (d, J = 8.8 Hz, 1H), 7.16 (dd, J = 8.2, 8.2 Hz, 1H), 7.31 (dd, J = 8.8, 2.5 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 8.32 (s, 1H).

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, the compound of Reference Example 17) was obtained as a pale yellow solid by the procedure of the same procedure as in the above. (0.118 g, 0.321 mmol, 94%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.01-2.09 (m, 2H), 2.11-2.18 (m, 2H), 3.19-3.25 (m, 2H), 3.40-3.46 (m, 2H), 4.71- 4.76 (m, 1H), 6.89 (d, J = 9.1 Hz, 2H), 7.02 (d, J = 9.1 Hz, 1H), 7.22 (d, J = 9.1 Hz, 2H), 8.15 (dd, J = 9.1) , 2.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 367 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 18) (0.108 g, 0.320) was obtained as a yellow oily compound. Mmmol, quantitative).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.91-1.99 (m, 2H), 2.01-2.08 (m, 2H), 3.02-3.09 (m, 2H), 3.46-3.52 (m, 2H), 3.52 ( Brs, 2H), 4.25-4.31 (m, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H) ), 6.87 (d, J = 9.1 Hz, 2H), 7.19 (d, J = 9.1 Hz, 2H).

ESI-MS: m/z = 338 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 7) (0.0234 g, 0.0477 mmol) as a pale yellow solid was obtained by the same procedure as in the procedure of the same. , 80%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.49-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.89-2.09 (m, 5H), 2.21 (s, 3H), 2.25-2.29 ( m,1H),3.08-3.19(m,3H),3.43-3.48(m,2H),3.74-3.78(m,1H),4.43-4.48(m,1H),5.24-5.25(m,1H), 6.87 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 9.1 Hz, 1H), 7.20 (d, J = 8.6 Hz, 2H), 7.30 (dd, J = 9.1, 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 8.32 (s, 1H).

ESI-MS: m/z = 490 (M+H) ⁺ .

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

The title compound was obtained as a pale yellow solid (m. Compound) (0.105 g, 0.289 mmol, 56%).

^{1 H-NMR (400MHz, 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, 2H), 3.89 ( s, 3H), 4.70-4.75 (m, 1H), 6.88-6.90 (m, 1H), 6.92-6.96 (m, 1H), 6.99-7.05 (m, 3H), 8.15 (dd, J = 9.5, 2.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 363 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 20) (0.0834 g, 0.251 mmol) as a pale yellow solid was obtained by the procedure of the same. , 91%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.99-2.15 (m, 4H), 2.86-2.92 (m, 2H), 3.34-3.39 (m, 2H), 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, 1H), 6.85-6.87 (m, 2H), 6.90-6.94 (m, 1H), 6.98-7.02 (m, 2H).

ESI-MS: m/z = 333 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 8) (0.0518 g, 0.107 mmol) was obtained as a white solid. 89%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.59 (m, 2H), 1.71-1.78 (m, 2H), 1.90-1.98 (m, 1H), 2.00-2.16 (m, 4H), 2.21. s, 3H), 2.26-2.29 (m, 1H), 2.92-2.97 (m, 2H), 3.12-3.20 (m, 1H), 3.30-3.36 (m, 2H), 3.74-3.78 (m, 1H), 3.88 (s, 3H), 4.42-4.47 (m, 1H), 5.25-5.26 (m, 1H), 6.86-7.02 (m, 4H), 6.94 (d, J = 8.9 Hz, 1H), 7.30 (dd, J=8.9, 2.6 Hz, 1H), 7.63 (d, J=2.6 Hz, 1H), 8.30 (brs, 1H).

ESI-MS: m/z = 486 (M+H) ⁺ .

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

The title compound was obtained as a pale yellow solid (yield: Reference Example 21). Compound) (0.144 g, 0.397 mmol, 77%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.00-2.18 (m, 4H), 3.21-3.27 (m, 2H), 3.45-3.51 (m, 2H), 3.80 (s, 3H), 4.70-4.76 ( m,1H), 6.42-6.45 (m, 1H), 6.51 (dd, J=2.3, 2.3 Hz, 1H), 6.57-6.60 (m, 1H), 7.03 (d, J = 9.1 Hz, 1H), 7.19 (dd, J = 8.2, 8.2 Hz, 1H), 8.15 (dd, J = 9.1, 2.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 363 (M+H) ⁺ .

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

The title compound (hereinafter, referred to as the compound of Reference Example 22) (0.126 g, 0.376) was obtained as a yellow oil. M, 91%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.90-2.09 (m, 4H), 3.04-3.10 (m, 2H), 3.52-3.58 (m, 2H), 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, 3H), 6.74 (d, J = 2.5 Hz, 1H), 6.84 (d, J = 8.0 Hz) , 1H), 7.15-7.19 (m, 1H).

ESI-MS: m/z = 333 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 9) (0.0448 g, 0.0922 mmol) was obtained as a white solid. 77%).

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, 3H), 2.26-2.29 ( m,1H),3.10-3.19(m,3H), 3.48-3.54(m,2H), 3.74-3.78(m,1H),3.79(s,3H),4.42-4.47(m,1H),5.24- 5.26 (m, 1H), 6.41 (dd, J = 8.0, 2.2 Hz, 1H), 6.49 (dd, J = 2.2, 2.2 Hz, 1H), 6.57 (dd, J = 8.3, 2.2 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 7.17 (dd, J = 8.3, 8.0 Hz, 1H), 7.30 (dd, J = 8.8, 2.6 Hz, 1H), 7.63 (d, J = 2.6 Hz, 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 was obtained as a pale yellow solid (m. Compound) (0.163 g, 0.449 mmol, 88%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.03-2.21 (m, 4H), 3.07-3.13 (m, 2H), 3.32-3.38 (m, 2H), 3.78 (s, 3H), 4.68-4.73 ( m,1H), 6.85 (d, J = 9.1 Hz, 2H), 6.95 (d, J = 9.1 Hz, 2H), 7.03 (d, J = 9.1 Hz, 1H), 8.15 (dd, J = 9.1, 2.7 Hz, 1H), 8.31 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 363 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 24) (0.152 g, 0.457) was obtained as a yellow oily product. Mmmol, quantitative).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.94-2.11 (m, 4H), 2.91-2.97 (m, 2H), 3.38-3.43 (m, 2H), 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, 1H), 6.82 - 6.85 (m, 3H), 6.94 (d) , J = 9.3 Hz, 2H).

ESI-MS: m/z = 333 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 10) (0.0385 g, 0.0792 mmol) was obtained as a white solid. 66%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.49-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.89-2.12 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m,1H), 2.96-3.02 (m, 2H), 3.12-3.19 (m, 1H), 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, 1H), 6.84 (d, J = 9.0 Hz, 2H), 6.93 (d, J = 8.8 Hz, 1H), 6.94 (d, J = 9.0 Hz, 2H) ), 7.30 (dd, J = 8.8, 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 8.31 (s, 1H).

ESI-MS: m/z = 486 (M+H) ⁺ .

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

The title compound was obtained as a pale yellow solid (yield, the compound of the reference compound 25) was obtained by the procedure of the same procedure as the same. (0.162 g, 0.467 mmol, 92%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.04-2.11 (m, 2H), 2.15-2.22 (m, 2H), 2.33 (s, 3H), 2.85-2.91 (m, 2H), 3.16-3.22 ( m, 2H), 4.67-4.73 (m, 1H), 6.98-7.07 (m, 3H), 7.16-7.23 (m, 2H), 8.15 (dd, J = 9.1, 2.7 Hz, 1H), 8.32 (d, J=2.7Hz, 1H).

ESI-MS: m/z = 347 (M+H)+.

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

The title compound (hereinafter, the compound of Reference Example 26) was obtained as a yellow solid (0.137 g, 0.432 mmol, m. 91%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.94-2.03 (m, 2H), 2.05-2.12 (m, 2H), 2.32 (s, 3H), 2.73-2.79 (m, 2H), 3.15-3.21 ( m, 2H), 3.51 (s, 2H), 4.21-4.27 (m, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H), 6.75 (d, J = 2.7 Hz, 1H), 6.86 (d) , J = 8.6 Hz, 1H), 6.95-6.99 (m, 1H), 7.03-7.05 (m, 1H), 7.14 - 7.19 (m, 2H).

ESI-MS: m/z = 317 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 11) (0.0360 g, 0.0766 mmol) as a pale yellow solid was obtained by the same procedure as in the procedure of the same. , 97%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.89-2.04 (m, 3H), 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, 2H), 3.12-3.20 (m, 3H), 3.75-3.78 (m, 1H), 4.40- 4.43 (m, 1H), 5.25-5.26 (m, 1H), 6.93-6.99 (m, 2H), 7.04-7.06 (m, 1H), 7.14-7.19 (m, 2H), 7.30 (dd, J = 9.1 , 2.7 Hz, 1H), 7.64 (d, J = 2.7 Hz, 1H), 8.31 (s, 1H).

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, reference compound 27) was obtained as a pale yellow solid by the procedure of the same procedure as in the above. ) (0.129 g, 0.372 mmol, 73%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.01-2.09 (m, 2H), 2.12-2.19 (m, 2H), 2.32 (s, 3H), 3.19-3.25 (m, 2H), 3.44 - 3.50 ( m, 2H), 4.70-4.75 (m, 1H), 6.70-6.72 (m, 1H), 6.78-6.80 (m, 2H), 7.03 (d, J = 9.1 Hz, 1H), 7.15-7.19 (m, 1H), 8.15 (dd, J = 9.1, 2.7 Hz, 1H), 8.31 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 347 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 28) (0.0857 g, 0.270) was obtained as a yellow oily product. M, 76%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.91-1.99 (m, 2H), 2.03-2.10 (m, 2H), 2.32 (s, 3H), 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, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.74 (d , J = 2.9 Hz, 1H), 6.76-6.78 (m, 2H), 6.84 (d, J = 8.8 Hz, 1H), 7.15 (dd, J = 7.7, 7.7 Hz, 1H).

ESI-MS: m/z = 317 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 12) (0.0330 g, 0.0702 mmol) as a pale yellow solid was obtained by the procedure of the procedure of , 89%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.89-2.01 (m, 3H), 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, 1H), 6.68 (d, J = 7.2 Hz, 1H), 6.76-6.78 (m, 2H), 6.93 (d, J = 9.1 Hz, 1H), 7.13 -7.17 (m, 1H), 7.30 (dd, J = 9.1, 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 8.31 (s, 1H).

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, reference compound 29) was obtained as a pale yellow solid by the procedure of the same procedure (0.167 g, 0.482 mmol, 94%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.02-2.09 (m, 2H), 2.14 - 2.18 (m, 2H), 2.28 (s, 3H), 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, 1H), 7.09 (d, J = 8.6 Hz, 2H), 8.15 (dd, J = 9.1, 2.7 Hz, 1H), 8.31 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 347 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 30) (0.140 g, 0.442 mmol) was obtained as a yellow solid. 93%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.92-2.00 (m, 2H), 2.03-2.10 (m, 2H), 2.27 (s, 3H), 2.97-3.03 (m, 2H), 3.46-3.51 ( m, 2H), 3.51 (s, 2H), 4.22-4.28 (m, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.84 (d) , J = 8.6 Hz, 1H), 6.88 (d, J = 8.2 Hz, 2H), 7.07 (d, J = 8.2 Hz, 2H).

ESI-MS: m/z = 317 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 13) (0.0325 g, 0.0691 mmol) as a pale yellow solid was obtained by the same procedure as in the procedure of the same. , 88%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.60 (m, 2H), 1.71-1.77 (m, 2H), 1.89-2.02 (m, 3H), 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, 2H), 3.12-3.19 (m, 1H), 3.42-3.48 (m, 2H), 3.74 3.78 (m, 1H), 4.40-4.45 (m, 1H), 5.24-5.26 (m, 1H), 6.88 (d, J = 8.6 Hz, 2H), 6.92 (d, J = 9.1 Hz, 1H), 7.07 (d, J = 8.6 Hz, 2H), 7.30 (dd, J = 9.1, 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 8.31 (s, 1H).

ESI-MS: m/z = 470 (M+H) ⁺ .

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

The title compound was obtained as a yellow oil (yield, m.p.). Reference compound of Example 31) (0.0195 g, 0.0487 mmol, 10%).

^{1 H-NMR (400MHz, 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, 2H), 4.72- 4.77 (m, 1H), 7.03 (d, J = 9.5 Hz, 1H), 7.23 - 7.26 (m, 1H), 7.41 (dd, J = 7.7, 0.9 Hz, 1H), 7.52 - 7.56 (m, 1H) , 7.64 (dd, J = 7.7, 1.4 Hz, 1H), 8.16 (dd, J = 9.5, 2.7 Hz, 1H), 8.33 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 401 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 32) (0.0193 g, 0.0521) was obtained as a brown oil. Mmmol, quantitative).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.96-2.09 (m, 4H), 2.77-2.83 (m, 2H), 3.17-3.23 (m, 2H), 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, 1H), 6.85 (d, J=8.6 Hz, 1H), 7.19-7.23 (m, 1H) ), 7.39 (d, J = 7.7 Hz, 1H), 7.49 - 7.53 (m, 1H), 7.62 (d, J = 7.7 Hz, 1H).

ESI-MS: m/z = 371 (M+H) ⁺ .

(Example 14) 1-Ethyl-N-(3-chloro-4-((1-(2-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)phenyl)piperidyl Synthesis of pyridine-2-carbamide:

The title compound (hereinafter, the compound of Example 14) (0.0118 g, 0.0225 mmol) was obtained as a white solid. 52%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.47-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.90-2.10 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m,1H), 2.79-2.84 (m, 2H), 3.12-3.23 (m, 3H), 3.74-3.78 (m, 1H), 4.45-4.50 (m, 1H), 5.25-5.26 (m, 1H), 6.93 (d, J = 8.6 Hz, 1H), 7.21 (dd, J = 7.5, 7.5 Hz, 1H), 7.30 (dd, J = 8.6, 2.7 Hz, 1H), 7.40 (d, J = 8.2 Hz, 1H) ), 7.50-7.53 (m, 1H), 7.61-7.63 (m, 1H), 7.65 (d, J = 2.7 Hz, 1H), 8.30 (s, 1H).

ESI-MS: m/z = 524 (M+H) ⁺ .

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

The title compound was obtained as a yellow oil (yield, m.p.), using 1-bromo-4-(trifluoromethyl)benzene. Reference compound of Example 33) (0.118 g, 0.294 mmol, 58%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.01-2.08 (m, 2H), 2.10-2.17 (m, 2H), 3.36-3.42 (m, 2H), 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, 1H), 7.50 (d, J = 9.1 Hz, 2H), 8.16 (dd, J = 9.1) , 2.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 401 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 34) (0.113 g, 0.305) was obtained as a brown oil (yield of the compound of Example 34). Mmmol, quantitative).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90-1.98 (m, 2H), 2.00-2.07 (m, 2H), 3.19-3.25 (m, 2H), 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, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H) ), 6.94 (d, J = 9.1 Hz, 2H), 7.47 (d, J = 9.1 Hz, 2H).

ESI-MS: m/z = 371 (M+H) ⁺ .

(Example 15) 1-Ethyl-N-(3-chloro-4-((1-(4-(trifluoromethyl)phenyl)piperidin-4-yl)oxy)phenyl)piperidin Synthesis of pyridine-2-carbamide:

The title compound (hereinafter, the compound of Example 15) (0.0195 g, 0.0372 mmol) was obtained as a white solid. 69%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.62 (m, 2H), 1.71-1.78 (m, 2H), 1.91-2.08 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m, 1H), 3.12-3.19 (m, 1H), 3.25-3.31 (m, 2H), 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=8.8Hz, 1H), 6.95 (d, J=8.6Hz, 2H), 7.31 (dd, J=8.8, 2.7Hz, 1H), 7.48(d , J = 8.6 Hz, 2H), 7.64 (d, J = 2.7 Hz, 1H), 8.33 (s, 1H).

ESI-MS: m/z = 524 (M+H) ⁺ .

(Example 16) 1-Ethyl-N-(3-chloro-4-((1-(2-cyanophenyl)piperidin-4-yl)oxy)phenyl)piperidin-2- Synthesis of methotrexate:

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 was added at room temperature. (0.257 g, 0.790 mmol). 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 brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc (EtOAc) Mmmol, 17%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.90-2.02 (m, 1H), 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, 1H), 4.52-4.57 (m, 1H), 5.25-5.26 (m, 1H), 6.93 (d, J = 9.1 Hz, 1H), 6.98-7.02 (m, 1H), 7.06 (d, J = 8.2 Hz, 1H), 7.30 (dd, J = 9.1, 2.7 Hz, 1H), 7.46-7.50 (m, 1H), 7.56 (dd, J = 7.5, 1.6 Hz, 1H), 7.65 (d, J = 2.7 Hz, 1H), 8.32 (s, 1H).

ESI-MS: m/z = 503 (M+Na) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 35) (0.0199) was obtained as a pale yellow solid by the procedure of the same procedure as in the above. g, 0.0556 mmol, 14%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.03-2.18 (m, 4H), 3.29-3.35 (m, 2H), 3.46-3.52 (m, 2H), 4.76-4.80 (m, 1H), 7.03 ( d, J = 9.1 Hz, 1H), 7.10-7.13 (m, 1H), 7.14 - 7.17 (m, 2H), 7.32 - 7.36 (m, 1H), 8.16 (dd, J = 9.1, 2.7 Hz, 1H) , 8.33 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 358 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 36) (0.0204 g, 0.0622) was obtained as a yellow oily compound. Mmmol, quantitative).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.92-2.07 (m, 4H), 3.13-3.19 (m, 2H), 3.53-3.59 (m, 2H), 3.56 (brs, 2H), 4.30-4.35 ( m,1H), 6.54 (dd, J=8.7, 2.8 Hz, 1H), 6.74 (d, J=2.8 Hz, 1H), 6.84 (d, J=8.7 Hz, 1H), 7.06-7.08 (m, 1H) ), 7.12-7.14 (m, 2H), 7.29-7.33 (m, 1H).

ESI-MS: m/z = 328 (M+H) ⁺ .

(Example 17) 1-Ethyl-N-(3-chloro-4-((1-(3-cyanophenyl)piperidin-4-yl)oxy)phenyl)piperidin-2- Synthesis of methotrexate:

The title compound (hereinafter, the compound of Example 17) (0.0207 g, 0.0430 mmol) was obtained as a white solid. 86%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.89-2.08 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m,1H),3.13-3.25(m,3H), 3.49-3.55(m,2H), 3.75-3.78(m,1H),4.47-4.52(m,1H),5.24-5.26(m,1H), 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, 1H) , 8.35 (s, 1H).

ESI-MS: m/z = 503 (M+H) ⁺ .

(Example 18) 1-Ethyl-N-(3-chloro-4-((1-(4-cyanophenyl)piperidin-4-yl)oxy)phenyl)piperidin-2- Synthesis of methotrexate:

The title compound (hereinafter, the compound of Example 18) (0.0299 g) was obtained as a pale yellow solid. 0.0622 mmol, 24%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.89-2.05 (m, 5H), 2.21 (s, 3H), 2.25-2.29 ( m,1H), 3.13-3.20 (m,1H),3.33-3.39 (m,2H), 3.60-3.66 (m,2H), 3.75-3.78 (m,1H), 4.51-4.56 (m,1H), 5.24-5.26 (m, 1H), 6.88 (d, J = 9.1 Hz, 2H), 6.91 (d, J = 9.1 Hz, 1H), 7.31 (dd, J = 9.1, 2.7 Hz, 1H), 7.49 (d) , J = 9.1 Hz, 2H), 7.64 (d, J = 2.7 Hz, 1H), 8.36 (s, 1H).

ESI-MS: m/z = 481 (M+H) ⁺ .

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

The title compound was obtained as a yellow oil (yield: m. m. , the compound of Reference 37) (0.140 g, 0.336 mmol, 98%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.02-2.19 (m, 4H), 3.21-3.27 (m, 2H), 3.41-3.48 (m, 2H), 4.72-4.77 (m, 1H), 6.94 ( d, J = 9.1 Hz, 2H), 7.03 (d, J = 9.1 Hz, 1H), 7.13 (d, J = 9.1 Hz, 2H), 8.16 (dd, J = 9.1, 2.7 Hz, 1H), 8.32 ( d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 417 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 38) (0.125 g, 0.323 mmol) was obtained as a pale yellow solid. , 96%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.92-2.09 (m, 4H), 3.05-3.11 (m, 2H), 3.48-3.54 (m, 2H), 3.51 (brs, 2H), 4.26-4.31 ( m, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.91 (d, J = 9.1) Hz, 2H), 7.10 (d, J = 9.1 Hz, 2H).

ESI-MS: m/z = 387 (M+H) ⁺ .

(Example 19) 1-Ethyl-N-(3-chloro-4-((1-(4-(trifluoromethoxy)phenyl)piperidin-4-yl)oxy)phenyl) Synthesis of piperidine-2-carbamide:

The title compound (hereinafter, the compound of Example 19) (0.0302 g, 0.0559 mmol) was obtained as a white solid. 87%).

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, 3H), 2.26-2.29 ( m,1H),3.10-3.20(m,3H),3.44-3.50(m,2H), 3.75-3.78(m,1H),4.44-4.49(m,1H),5.24-5.26(m,1H), 6.90-6.93 (m, 3H), 7.10 (d, J = 8.6 Hz, 2H), 7.31 (dd, J = 8.6, 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 8.32 (s) , 1H).

ESI-MS: m/z = 540 (M+H) ⁺ .

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

The title compound was obtained as a brown oil (yield: m.) , the compound of Reference Example 39) (0.128 g, 0.321 mmol, 69%).

¹ H-NMR (400MHz, 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, 2H), 4.71 4.76 (m, 1H), 6.43 (t, J = 74.3 Hz, 1H), 6.94 (d, J = 9.1 Hz, 2H), 7.03 (d, J = 9.1 Hz, 1H), 7.06 (d, J = 9.1) Hz, 2H), 8.16 (dd, J = 9.1, 2.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 399 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 40) (0.114 g, 0.309 mmol) was obtained as a brown solid. Quantitative).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.92-2.00 (m, 2H), 2.02-2.09 (m, 2H), 3.01-3.07 (m, 2H), 3.45-3.51 (m, 2H), 3.52 ( Brs, 2H), 4.25-4.31 (m, 1H), 6.41 (t, J = 74.3 Hz, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H) ), 6.84 (d, J = 8.6 Hz, 1H), 6.92 (d, J = 9.1 Hz, 2H), 7.03 (d, J = 9.1 Hz, 2H).

ESI-MS: m/z = 369 (M+H) ⁺ .

(Example 20) 1-Ethyl-N-(3-chloro-4-((1-(4-(difluoromethoxy)phenyl)piperidin-4-yl)oxy)phenyl) Synthesis of piperidine-2-carbamide:

The title compound (hereinafter, the compound of Example 20) (0.0204 g, 0.0391 mmol) as a pale yellow solid was obtained by the same procedure as in the procedure of the same. , 72%).

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, 3H), 2.25-2.29 ( m,1H),3.07-3.20(m,3H),3.42-3.48(m,2H),3.75-3.78(m,1H),4.43-4.48(m,1H),5.24-5.26(m,1H), 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, 1H), 8.33 (s, 1H).

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 a saturated aqueous solution of sodium hydrogencarbonate, distilled water and brine, and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=70/30 to 40/60) to give the title compound (yield of the compound of reference 41) (0.0700 g, 0.170 mmol , 50%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.01-2.16 (m, 4H), 3.03 (s, 3H), 3.48-3.54 (m, 2H), 3.60-3.67 (m, 2H), 4.80-4.85 ( m, 1H), 6.98 (d, J = 9.1 Hz, 2H), 7.03 (d, J = 9.5 Hz, 1H), 7.79 (d, J = 9.1 Hz, 2H), 8.16 (dd, J = 9.5, 2.7 Hz, 1H), 8.33 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 411 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 42) (0.0602 g, 0.158 mmol) was obtained as a yellow solid. 99%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.90-2.05 (m, 4H), 3.02 (s, 3H), 3.32-3.38 (m, 2H), 3.54 (s, 2H), 3.67-3.74 (m, 2H), 4.35-4.40 (m, 1H), 6.54 (dd, J = 8.6, 2.7 Hz, 1H), 6.75 (d, J = 2.7 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 9.1 Hz, 2H), 7.76 (d, J = 9.1 Hz, 2H).

ESI-MS: m/z = 381 (M+H) ⁺

(Example 21) 1-Ethyl-N-(3-chloro-4-((1-(4-(methylsulfonyl)phenyl)piperidin-4-yl)oxy)phenyl) Synthesis of piperidine-2-carbamide:

The title compound (hereinafter, the compound of Example 21) (0.0405 g, 0.0758 mmol) as a pale yellow solid was obtained by the same procedure as in the procedure of the same. , 96%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.90-2.04 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m, 1H), 3.02 (s, 3H), 3.12-3.19 (m, 1H), 3.37-3.43 (m, 2H), 3.63-3.70 (m, 2H), 3.75-3.79 (m, 1H), 4.52- 4.57 (m, 1H), 5.24 - 5.26 (m, 1H), 6.92 (d, J = 9.1 Hz, 1H), 6.95 (d, J = 9.1 Hz, 2H), 7.32 (dd, J = 9.1, 2.7 Hz) , 1H), 7.65 (d, J = 2.7 Hz, 1H), 7.76 (d, J = 9.1 Hz, 2H), 8.35 (s, 1H).

ESI-MS: m/z = 556 (M+Na) ⁺ .

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

The title compound was obtained as a yellow solid (yield, below). Compound 43) (0.0619 g, 0.153 mmol, 30%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.37 (t, J = 7.2Hz, 3H), 2.00-2.07 (m, 2H), 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, 1H), 6.91 (d, J = 9.1 Hz, 2H), 7.03 (d, J = 9.1) Hz, 1H), 7.94 (d, J = 9.1 Hz, 2H), 8.16 (dd, J = 9.1, 2.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 405 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 44) (0.0600 g, 0.160 mmol) was obtained as a yellow solid. Quantitative).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.37 (t, J = 7.0 Hz, 3H), 1.89-1.97 (m, 2H), 1.99-2.06 (m, 2H), 3.25-3.31 (m, 2H) , 3.53 (brs, 2H), 3.66-3.72 (m, 2H), 4.33 (q, J = 7.0 Hz, 2H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 9.1 Hz, 2H), 7.92 (d, J = 9.1 Hz, 2H).

ESI-MS: m/z = 375 (M+H) ⁺ .

(Example 22) Synthesis of ethyl 4-(4-(4-(1-ethenylpiperidine-2-carboxamide)-2-chlorophenoxy)piperidin-1-yl)benzoate:

The title compound (hereinafter, the compound of Example 22) (0.0483 g, 0.0915 mmol) was obtained as a white solid. 62%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.37 (t, J = 7.2 Hz, 3H), 1.47-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.90-2.07 (m, 5H) , 2.21 (s, 3H), 2.26-2.29 (m, 1H), 3.12-3.19 (m, 1H), 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, 2H), 4.48-4.53 (m, 1H), 5.24-5.26 (m, 1H), 6.89 (d, J = 9.1 Hz, 2H), 6.92 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 8.6, 2.7 Hz, 1H), 7.64 (d, J = 2.7 Hz, 1H), 7.92 (d, J = 9.1 Hz, 2H), 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) was dissolved in dichloromethane (1.24 mL), and diisobutylaluminum hydride-toluene solution (1.0 M, 0.247 mL, 0.247 mmol) was added at -78 °C. ). After stirring at 0 ° C for 2 hours, an aqueous solution of sodium potassium tartrate 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 brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 70 / 30 to 40 / 60) to give the title compound (yield of compound of reference 45) (0.0305 g, 0.0841 M, 68%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.51 (t, J = 5.9 Hz, 1H), 2.02-2.09 (m, 2H), 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, 1H), 6.97 (d, J = 8.6 Hz, 2H), 7.03 (d, J = 9.1) Hz, 1H), 7.29 (d, J = 8.6 Hz, 2H), 8.15 (dd, J = 9.1, 2.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 363 (M+H) ⁺ .

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

The title compound (hereinafter, referred to as the compound of Reference Example 46) (0.0533 g, 0.160 mmol) was obtained as a yellow solid. 83%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.48 (brs, 1H), 1.92-2.00 (m, 2H), 2.03-2.09 (m, 2H), 3.05-3.11 (m, 2H), 3.52-3.58 ( m, 2H), 3.53 (brs, 2H), 4.25-4.31 (m, 1H), 4.60 (s, 2H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H), 6.74 (d, J = 2.7 Hz) , 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.95 (d, J = 8.6 Hz, 2H), 7.27 (d, J = 8.6 Hz, 2H).

ESI-MS: m/z = 333 (M+H) ⁺ .

(Example 23) 1-Ethyl-N-(3-chloro-4-((1-(4-(hydroxymethyl)phenyl)piperidin-4-yl)oxy)phenyl)piperidine Synthesis of 2-carbamamine:

The title compound (hereinafter, the compound of Example 23) (0.0155 g, 0.0319 mmol) as a pale yellow solid was obtained by the same procedure as in the procedure of the same. , 43%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.60 (m, 3H), 1.70-1.78 (m, 2H), 1.90-2.10 (m, 5H), 2.21 (s, 3H), 2.25-2.29 ( m, 1H), 3.11-3.20 (m, 3H), 3.48-3.54 (m, 2H), 3.74-3.78 (m, 1H), 4.43-4.48 (m, 1H), 4.60 (d, J = 5.0 Hz, 2H), 5.24-5.26 (m, 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, 1H), 8.31 (s, 1H).

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 was obtained as a pale-yellow solid (yield, below), using 1-bromo-2,4-dimethylbenzene instead of 1-fluoro-2-iodobenzene. Compound 47) (0.0692 g, 0.192 mmol, 56%).

^{1 H-NMR (400MHz, 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, 4H), 8.15 (dd, J = 9.1, 2.7 Hz, 1H), 8.32 (d, J = 2.7Hz, 1H).

ESI-MS: m/z = 361 (M+H)+.

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

The title compound (hereinafter referred to as the compound of Reference Example 48) (0.0647 g, m.p. 0.196 mmol, quantitative).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.93-2.01 (m, 2H), 2.05-2.11 (m, 2H), 2.27 (s, 3H), 2.28 (s, 3H), 2.70-2.75 (m, 2H), 3.11-3.17 (m, 2H), 3.51 (s, 2H), 4.20-4.25 (m, 1H), 6.53 (dd, J = 8.6, 2.9 Hz, 1H), 6.74 (d, J = 2.9 Hz) , 1H), 6.86 (d, J = 8.6 Hz, 1H), 6.93-7.00 (m, 3H).

ESI-MS: m/z = 331 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 24) (0.0285 g, 0.0589 mmol) was obtained as a white solid. 68%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.49-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.91-2.03 (m, 3H), 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, 1H), 5.25-5.26 (m, 1H), 6.94 (d, J = 9.1 Hz, 1H), 6.96-7.00 (m, 3H), 7.30 (dd, J = 9.1, 2.7 Hz, 1H), 7.64 (d, J = 2.7 Hz, 1H), 8.31 (s, 1H).

ESI-MS: m/z = 484 (M+H) ⁺ .

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

The title compound was obtained as a pale yellow solid (m. Compound of Example 49) (0.0515 g, 0.141 mmol, 41%).

¹ H-NMR (400MHz, 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), 4.70-4.75 (m, 1H), 6.85-6.93 (m, 3H), 7.03 (d, J = 9.1 Hz, 1H), 8.15 (dd, J = 9.1, 2.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H).

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:

The title compound (hereinafter, the compound of Reference Example 50) (0.0453 g, 0.135) was obtained as a brown oil. M, 99%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.97-2.12 (m, 4H), 2.28 (s, 3H), 2.88-2.94 (m, 2H), 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, 1H), 6.83-6.91 (m, 4H).

ESI-MS: m/z = 335 (M+H) ⁺ .

(Example 25) 1-Ethyl-N-(3-chloro-4-((1-(2-fluoro-4-methylphenyl)piperidin-4-yl)oxy)phenyl)piperidin Synthesis of pyridine-2-carbamide:

The title compound (hereinafter, the compound of Example 25) (0.0235 g, 0.0482 mmol) was obtained as a white solid. 72%).

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, 3H), 2.26-2.28 ( m,1H), 2.28(s,3H), 2.93-2.98(m,2H),3.12-3.20(m,1H), 3.27-3.33(m,2H),3.74-3.78(m,1H),4.42- 4.47 (m, 1H), 5.25-5.26 (m, 1H), 6.84-6.90 (m, 3H), 6.93 (d, J = 9.1 Hz, 1H), 7.30 (dd, J = 9.1, 2.3 Hz, 1H) , 7.63 (d, J = 2.3 Hz, 1H), 8.31 (s, 1H).

ESI-MS: m/z = 488 (M+H) ⁺ .

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

The compound of Reference Example 4 (0.100 g, 0.263 mmol) was dissolved in 1,4-two Alkane (1.32 mL), 2-bromopyridine (0.0385 mL, 0.395 mmol), [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene] (3- [1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)dichloride) (0.0179 g, 0.0263 mmol) and Tertiary potassium butoxide (0.0886 g, 0.790 mmol). After stirring at 80 ° C for 16 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc (EtOAc) 15%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.59 (m, 2H), 1.71-1.78 (m, 2H), 1.86-2.05 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m, 1H), 3.13-3.20 (m, 1H), 3.48-3.54 (m, 2H), 3.75-3.78 (m, 1H), 3.85-3.91 (m, 2H), 4.48-4.54 (m, 1H), 5.25-5.26 (m, 1H), 6.59-6.61 (m, 1H), 6.69 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 8.6, 2.3 Hz, 1H), 7.45-7.49 (m, 1H), 7.64 (d, J = 2.3 Hz, 1H), 8.18-8.20 (m, 1H), 8.33 (s, 1H).

ESI-MS: m/z = 457 (M+H) ⁺ .

(Example 27) 1-Ethyl-N-(3-chloro-4-((1-(5-chloropyridin-2-yl)piperidin-4-yl)oxy)phenyl)piperidine- Synthesis of 2-formamide:

The title compound (hereinafter, the compound of Example 27) was obtained as a white solid (yield: 0.0033 g, using the same procedure as in Example 16). 0.0067 mmol, 6%).

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, 3H), 2.26-2.29 ( m, 1H), 3.12-3.20 (m, 1H), 3.48-3.54 (m, 2H), 3.75-3.85 (m, 3H), 4.49-4.54 (m, 1H), 5.25-5.26 (m, 1H), 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, 1H) ), 7.64 (d, J = 2.7 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 8.33 (s, 1H).

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 was obtained as a yellow solid (m.p. Hereinafter, the compound of Reference Example 51) (0.119 g, 0.308 mmol, 90%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.97-2.05 (m, 2H), 2.09-2.16 (m, 2H), 3.50-3.56 (m, 2H), 3.70-3.76 (m, 2H), 4.76- 4.81 (m, 1H), 7.03 (d, J = 9.1 Hz, 1H), 7.28 (dd, J = 12.2, 2.3 Hz, 1H), 7.98 (d, J = 2.3 Hz, 1H), 8.16 (dd, J = 9.1, 2.7 Hz, 1H), 8.32 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 386 (M+H)+.

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

The title compound (hereinafter, the compound of Reference Example 52) (0.105 g, 0.295) was obtained as a yellow oil. Mmmol, quantitative).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.88-1.96 (m, 2H), 2.00-2.07 (m, 2H), 3.30-3.36 (m, 2H), 3.52 (s, 2H), 3.78-3.84 ( m, 2H), 4.29-4.35 (m, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H) ), 7.25 (dd, J = 12.5, 2.0 Hz, 1H), 7.96 (d, J = 2.0 Hz, 1H).

ESI-MS: m/z = 356 (M+H)+.

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

The title compound (hereinafter, the compound of Example 28) (0.0251 g, 0.0493 mmol) was obtained as a white solid. 72%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.90-1.97 (m, 3H), 2.00-2.08 (m, 2H), 2.21. s, 3H), 2.26-2.29 (m, 1H), 3.12-3.19 (m, 1H), 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, 1H), 7.25 (dd, J = 12.2, 1.8 Hz, 1H), 7.31 (dd, J = 9.1, 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 7.96 (d, J = 1.8 Hz, 1H), 8.32 (s, 1H).

ESI-MS: m/z = 509 (M+H) ⁺ .

(Example 29) 1-Ethyl-N-(3-chloro-4-((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)phenyl)piperidine-2-yl Synthesis of guanamine:

The compound of Reference Example 4 (0.0300 g, 0.0790 mmol) and 2-chloropyrimidine (0.0235 g, 0.158 mmol) were 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 brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) 90%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.83-2.01 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m, 1H), 3.12-3.20 (m, 1H), 3.75-3.82 (m, 3H), 4.08-4.14 (m, 2H), 4.51-4.56 (m, 1H), 5.25-5.26 (m, 1H), 6.47 (t, J = 4.8 Hz, 1H), 6.94 (d, J = 9.0 Hz, 1H), 7.31 (dd, J = 9.0, 2.7 Hz, 1H), 7.64 (d, J = 2.7 Hz, 1H), 8.31 (d, J = 4.8 Hz, 2H), 8.32 (brs, 1H).

ESI-MS: m/z = 458 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 30) (0.0319 g, 0.0648 mmol) as a white solid was obtained by the same procedure as in the procedure , 82%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.49-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.83-1.98 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m,1H),3.12-3.19(m,1H),3.74-3.84(m,3H),4.00-4.07(m,2H),4.52-4.57(m,1H),5.24-5.26(m,1H), 6.93 (d, J = 9.0 Hz, 1H), 7.31 (dd, J = 9.0, 2.4 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 8.22 (s, 2H), 8.33 (s, 1H) ).

ESI-MS: m/z = 492 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 31) (0.0205 g, as a white solid) was obtained by the same procedure as in Example 29, using 2-chloro-5-methylpyrimidine. 0.0434 mmol, 55%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.49-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.81-2.00 (m, 5H), 2.12 (s, 3H), 2.21 (s, 3H), 2.26-2.29 (m, 1H), 3.12-3.19 (m, 1H), 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, 1H), 7.31 (dd, J = 9.0, 2.4 Hz, 1H), 7.63 (d, J = 2.4 Hz, 1H), 8.16 (s, 2H) ), 8.32 (s, 1H).

ESI-MS: m/z = 472 (M+H) ⁺ .

(Example 32) 1-Ethyl-N-(3-chloro-4-((1-(5-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)benzene Synthesis of piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 32) was obtained as a white solid by the same procedure as in Example 29, using 2-chloro-5-(trifluoromethyl)pyrimidine. (0.0282 g, 0.0536 mmol, 68%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.49-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.89-1.98 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m, 1H), 3.12-3.20 (m, 1H), 3.75-3.78 (m, 1H), 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, 1H), 7.65 (d, J = 2.3 Hz, 1H), 8.35 (s, 1H), 8.48 (s, 2H) ).

ESI-MS: m/z = 472 (M+H) ⁺ .

(Example 33) 1-Ethyl-N-(3-chloro-4-((1-(4-methoxypyrimidin-2-yl)piperidin-4-yl)oxy)phenyl)peran Synthesis of pyridine-2-carbamide:

The title compound (hereinafter, the compound of Example 33) (0.0192 g) was obtained as a white solid. , 0.0393 mmol, 75%).

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, 3H), 2.26-2.29 ( m, 1H), 3.12-3.20 (m, 1H), 3.74-3.81 (m, 3H), 3.89 (s, 3H), 4.07-4.13 (m, 2H), 4.50-4.56 (m, 1H), 5.25- 5.26 (m, 1H), 5.97 (d, J = 5.9 Hz, 1H), 6.93 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 8.6, 2.3 Hz, 1H), 7.64 (d, J) =2.3 Hz, 1H), 8.05 (d, J = 5.9 Hz, 1H), 8.33 (s, 1H).

ESI-MS: m/z = 488 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 34) was obtained as a white solid (0.0214 g, m. m. 0.0453 mmol, 86%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.47-1.59 (m, 2H), 1.71-1.78 (m, 2H), 1.82-2.00 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m,1H), 2.33(s,3H),3.13-3.20(m,1H),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, 1H), 6.94 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 8.6, 2.7 Hz, 1H), 7.64 (d, J) =2.7 Hz, 1H), 8.16 (d, J = 5.0 Hz, 1H), 8.32 (s, 1H).

ESI-MS: m/z = 472 (M+H) ⁺ .

(Example 35) 1-Ethyl-N-(3-chloro-4-((1-(4-(trifluoromethyl)pyrimidin-2-yl)piperidin-4-yl)oxy)benzene Synthesis of piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 35) was obtained as a white solid by the same procedure as in Example 29, except that 2-chloro-4-(trifluoromethyl)pyrimidine was used instead of 2-chloropyrimidine. (0.0117 g, 0.0222 mmol, 42%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.61 (m, 2H), 1.72-1.78 (m, 2H), 1.88-2.00 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m,1H), 3.13-3.20(m,1H), 3.75-3.78(m,1H), 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, 1H), 6.93 (d, J = 8.6 Hz, 1H), 7.32 (dd, J = 8.6, 2.7 Hz, 1H), 7.65 (d , J = 2.7 Hz, 1H), 8.34 (s, 1H), 8.48 (d, J = 5.0 Hz, 1H).

ESI-MS: m/z = 548 (M+Na) ⁺ .

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

Reference compound 6 (0.200 g, 0.682 mmol), palladium (II) acetate (0.0306 g, 0.136 mmol), tris-tert-butylphosphinotetrafluoroborate (0.0396 g, 0.136 mmol) and tertiary butyl Sodium alkoxide (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 at 110 ° C for 2 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=95/5 to 80/20) to give the title compound as a yellow solid (hereinafter, the compound of Reference Example 53) (0.210 g, 0.631 mmol) , 93%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.02-2.10 (m, 2H), 2.13-2.20 (m, 2H), 3.21-3.27 (m, 2H), 3.45-3.51 (m, 2H), 4.71- 4.76 (m, 1H), 6.86-6.90 (m, 1H), 6.97-6.99 (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, 1H).

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), and 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, and distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=80/20 to 50/50) to give the title compound as a pale yellow solid (hereinafter, the compound of reference 54) (0.337 g, 1.11) M, 98%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.92-2.00 (m, 2H), 2.03-2.10 (m, 2H), 3.04-3.10 (m, 2H), 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, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.82-6.86 (m, 1H), 6.84 (d, J = 8.6 Hz, 1H), 6.95-6.97 (m, 2H), 7.25-7.27 (m, 2H).

ESI-MS: m/z = 303 (M+H) ⁺ .

(Reference Example 55) 2-((3-Chloro-4-((1-phenylpiperidin-4-yl)oxy)phenyl)aminecarboxamido)piperidine-1-carboxylic acid tert-butyl butylate synthesis:

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) were dissolved in DMF (1.32 mL). (0.121 g, 0.317 mmol) and diisopropylethylamine (0.0692 mL, 0.396 mmol). 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 a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate=90/10 to 60/40) to give the title compound (yield of the compound of reference 55) (0.132 g, 0.257) M, 97%).

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, 2H), 2.06-2. m, 2H), 2.32-2.35 (m, 1H), 2.78-2.85 (m, 1H), 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, 1H), 6.83-6.87 (m, 1H), 6.95 (d, J = 8.6 Hz, 1H), 6.95-6.98 (m, 2H), 7.25-7.29 ( m, 2H), 7.31 (dd, J = 8.6, 2.7 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 514 (M+H) ⁺ .

(Reference 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, EtOAc) (m. After stirring at room temperature for 3 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. ).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.43-1.63 (m, 4H), 1.79-1.84 (m, 1H), 1.95-2.03 (m, 3H), 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, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.95-6.98 (m, 2H), 7.25-7.29 (m, 2H), 7.44 (dd, J = 8.8, 2.3 Hz, 1H), 7.66 (d, J = 2.3 Hz, 1H), 8.85 (s, 1H).

ESI-MS: m/z = 414 (M+H) ⁺ .

(Example 36) N-(3-chloro-4-((1-phenylpiperidin-4-yl)oxy)phenyl)-1-(2-hydroxyethyl)piperidin-2-yl Synthesis of guanamine:

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), and HATU (0.0202 g, 0.0531 mmol) and diisopropyl Ethylamine (0.0127 mL, 0.0725 mmol). 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 sulfate and brine and dried over anhydrous sodium sulfate. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc(EtOAc) 65%).

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, 1H), 4.31 (d, J=15.9 Hz, 1H), 4.44-4.49 (m, 1H), 5.22-5.23 (m, 1H), 6.83-6.87 (m, 1H), 6.94 (d, J=9.1 Hz, 1H), 6.96-6.98 (m, 2H), 7.25-7.29 (m, 2H), 7.29 (dd, J = 9.1, 2.7 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 7.93 (s, 1H).

ESI-MS: m/z = 472 (M+H) ⁺ .

(Example 37) N-(3-chloro-4-((1-phenylpiperidin-4-yl)oxy)phenyl)-1-(3-hydroxypropionyl)piperidin-2-yl Synthesis of guanamine:

The title compound (hereinafter, the compound of Example 37) (0.0169 g, 0.0348 mmol, 72) was obtained as a white solid, m. %).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.48-1.63 (m, 2H), 1.71-1.78 (m, 2H), 1.83-1.91 (m, 1H), 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, 1H), 2.71 (dt, J = 16.3, 5.4 Hz, 1H), 3.07 (t, J = 6.3 Hz, 1H), 3.10-3.20 (m, 3H), 3.48-3.54 (m, 2H), 3.79-3.83 (m, 1H), 3.94-3.98 (m, 2H), 4.43-4.48 (m, 1H) , 5.30-5.32 (m, 1H), 6.83-6.87 (m, 1H), 6.93 (d, J = 9.1 Hz, 1H), 6.95-6.98 (m, 2H), 7.24-7.29 (m, 2H), 7.31 (dd, J = 9.1, 2.3 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 8.16 (s, 1H).

ESI-MS: m/z = 486 (M+H) ⁺ .

(Reference Example 57) (2-(2-((3-chloro-4-((1-phenylpiperidin-4-yl)oxy)phenyl)))))) Synthesis of -2-oxoethyl)amine carboxylic acid tert-butyl butyl ester:

The title compound was obtained as a white solid (yield: </ br </ br> </ br> </ br> Compound) (0.0340 g, 0.0595 mmol, 99%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46 (s, 9H), 1.47-1.62 (m, 2H), 1.72-1.86 (m, 3H), 1.94-2.02 (m, 2H), 2.05-2. m, 2H), 2.34-2.38 (m, 1H), 3.10-3.22 (m, 3H), 3.48-3.54 (m, 2H), 3.70-3.73 (m, 1H), 3.94 (dd, J = 16.8, 5.0 Hz, 1H), 4.11 (dd, J = 16.8, 5.0 Hz, 1H), 4.43-4.48 (m, 1H), 5.28-5.29 (m, 1H), 5.42 (brs, 1H), 6.83-6.87 (m, 1H), 6.93 (d, J = 8.6 Hz, 1H), 6.95-6.98 (m, 2H), 7.25-7.29 (m, 2H), 7.42 (dd, J = 8.6, 2.3 Hz, 1H), 7.63 (d , J = 2.3 Hz, 1H), 8.08 (s, 1H).

ESI-MS: m/z = 571 (M+H) ⁺ .

(Example 38) 1-(2-Aminoethyl)-N-(3-chloro-4-((1-phenylpiperidin-4-yl)oxy)phenyl)piperidin-2- Synthesis of methotrexate:

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, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) 84%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.64 (m, 2H), 1.74-1.76 (m, 2H), 1.88-2.02 (m, 3H), 2.04-2.11 (m, 2H), 2.28- 2.31 (m, 1H), 3.10-3.17 (m, 3H), 3.48-3.54 (m, 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,1H),6.83-6.87(m,1H), 6.93(d,J=9.1Hz,1H), 6.95-6.97(m,2H),7.25-7.29(m, 2H), 7.31 (dd, J = 9.1, 2.3 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H), 8.12 (s, 1H).

ESI-MS: m/z = 471 (M+H) ⁺ .

(Reference Example 58) (3-(2-((3-chloro-4-((1-phenylpiperidin-4-yl)oxy)phenyl)))))))) Synthesis of 3-oxopropyl propylamine carboxylic acid tert-butyl butyl ester:

The title compound was obtained as a white solid (yield, mp. 58), m. m. Compound) (0.0345 g, 0.0590 mmol, 98%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.40 (s, 9H), 1.45-1.57 (m, 2H), 1.72-1.75 (m, 2H), 1.82-1.88 (m, 1H), 1.94-2.02 ( m, 2H), 2.04-2.11 (m, 2H), 2.32-2.35 (m, 1H), 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, 1H), 6.96-6.98 (m, 2H), 7.25-7.29 (m, 2H), 7.41 (dd, J = 8.6, 2.3 Hz, 1H), 7.65 (d, J = 2.3 Hz, 1H), 8.35 (s, 1H).

ESI-MS: m/z = 585 (M+H) ⁺ .

(Example 39) 1-(3-Aminopropenyl)-N-(3-chloro-4-((1-phenylpiperidin-4-yl)oxy)phenyl)piperidin-2- Synthesis of methotrexate:

The title compound (hereinafter, the compound of Example 39) (0.0209 g, 0.0431 mmol) was obtained as a white solid. 72%).

¹ H-NMR (400MHz, 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, 1H), 2.75 (dt, J = 15.1, 6.2 Hz, 1H), 3.10-3.16 (m, 4H), 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, 1H), 6.93 ( d, J = 8.6 Hz, 1H), 6.95-6.97 (m, 2H), 7.24 - 7.29 (m, 2H), 7.33 (dd, J = 8.6, 2.3 Hz, 1H), 7.55 (d, J = 2.3 Hz) , 1H), 8.79 (s, 1H).

ESI-MS: m/z = 485 (M+H) ⁺ .

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

The title compound was obtained as a yellow solid (m.p. Hereinafter, the compound of Reference Example 59) (0.248 g, 0.729 mmol, 73%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (s, 9H), 1.80-1.87 (m, 2H), 1.94-2.00 (m, 2H), 3.38-3.44 (m, 2H), 3.67-3.74 ( m, 2H), 4.64-4.69 (m, 1H), 7.03-7.07 (m, 1H), 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:

The title compound (hereinafter, the compound of Reference Example 60) (0.136 g, 0.492 mmol) as a pale yellow solid was obtained by the procedure of the same. , 71%).

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, 2H), 3.20-3.26 (m, 2H), 4.92-4.96 (m, 1H), 7.52-7.56 (m, 1H), 8.11-8.14 (m, 1H), 8.19-8.22 (m, 1H), 8.96 (s, 2H).

ESI-MS: m/z = 241 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 61) (0.0726 g, 0.230 mmol) as a pale yellow solid was obtained by the procedure of the the the , 85%).

^{1 H-NMR (400MHz, 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, 2H), 4.64- 4.70 (m, 1H), 6.86-6.90 (m, 1H), 6.96-6.98 (m, 2H), 7.06-7.10 (m, 1H), 7.26-7.30 (m, 2H), 7.99-8.07 (m, 2H) ).

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) was obtained as a pale yellow solid. , 83%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.88-1.96 (m, 2H), 2.03-2.10 (m, 2H), 2.99-3.05 (m, 2H), 3.52-3.58 (m, 2H), 3.55 ( s, 2H), 4.16-4.22 (m, 1H), 6.35-6.38 (m, 1H), 6.46 (dd, J = 12.7, 2.7 Hz, 1H), 6.82-6.88 (m, 2H), 6.95-6.97 ( m, 2H), 7.24 - 7.28 (m, 2H).

ESI-MS: m/z = 287 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 40) (0.0340 g, 0.0774 mmol) was obtained as a white solid. 89%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.90-1.98 (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, 1H), 3.50-3.56 (m, 2H), 3.75-3.78 (m, 1H), 4.33-4.39(m,1H),5.24-5.26(m,1H),6.83-6.87(m,1H),6.93-6.98(m,3H),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) (R)-2-((3-Chloro-4-((1-phenylpiperidin-4-yl)oxy)phenyl)aminecarboxamido)piperidine-1-carboxylic acid Synthesis of butyl ester:

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) were dissolved in DMF (1.10 mL) HATU (0.0753 g, 0.198 mmol) and diisopropylethylamine (0.0433 mL, 0.248 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 a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = EtOAc / EtOAc / Mmmol, quantitative).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.70 (m, 5H), 1.52 (s, 9H), 1.95-2.03 (m, 2H), 2.06-2.12 (m, 2H), 2.32-2.35 ( m, 1H), 2.79-2.86 (m, 1H), 3.10-3.16 (m, 2H), 3.48-3.54 (m, 2H), 4.06 (brs, 1H), 4.43-4.48 (m, 1H), 4.83 4.86 (m, 1H), 6.83-6.87 (m, 1H), 6.94-6.98 (m, 3H), 7.25-7.33 (m, 3H), 7.62 (d, J = 2.7 Hz, 1H).

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) was dissolved in ethyl acetate (yield: EtOAc). After stirring at room temperature for 1 hour, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. ).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.43-1.63 (m, 4H), 1.80-1.84 (m, 1H), 1.95-2.12 (m, 5H), 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, 1H), 3.49-3.55 (m, 2H), 4.43-4.48 (m, 1H), 6.83 6.87 (m, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.96-6.98 (m, 2H), 7.25-7.29 (m, 2H), 7.44 (dd, J = 8.8, 2.5 Hz, 1H) , 7.65 (d, J = 2.5 Hz, 1H), 8.84 (s, 1H).

ESI-MS: m/z = 414 (M+H) ⁺ .

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

The compound of Reference Example 64 (0.0300 g, 0.0725 mmol) was dissolved in dichloromethane (1.45 mL), and triethylamine (0.0152 mL, 0.109 mmol) and ethyl chlorobenzene (0.00618 mL, 0.870 mmol) were added at 0 °C. After stirring at the same temperature for 1 hour, methanol was added to the reaction solution, and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) , 98%).

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, 2H), 3.74-3.78 (m, 1H), 4.42-4.47 (m, 1H), 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, 1H), 7.63 (d, J = 2.7 Hz, 1H), 8.32 (s, 1H).

ESI-MS: m/z = 456 (M+H) ⁺ .

(Reference 65) Synthesis of 2-(N-methylmethylsulfonamide) acetic acid tert-butyl acrylate:

2-(Methylamino)acetic acid tert-butyl ester hydrochloride (0.100 g, 0.550 mmol) was dissolved in dichloromethane (2.00 mL), and triethylamine (0.192 mL, 1.385 mmol) was added at 0 ° C and Methanesulfonium chloride (0.0515 mL, 0.661 mmol). After stirring at room temperature for 3 hours, a saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the aqueous layer was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate and filtered and evaporated. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate=90/10 to 70/30) to give the title compound (hereinafter, the compound of reference 65) (0.117 g, 0.524 mmol, 95%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48 (s, 9H), 2.98 (s, 3H), 3.00 (s, 3H), 3.98 (s, 2H).

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

The compound of Reference Example 65 (0.117 g, 0.524 mmol) was dissolved in EtOAc (EtOAc) (EtOAc) After stirring at room temperature for 16 hours, the reaction mixture was evaporated. mjjjjjjjjjj

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.99 (s, 3H), 3.01 (s, 3H), 4.14 (s, 2H).

ESI-MS: m/z = 168 (M+H) ⁺ .

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

The compound of Reference Example 64 (0.0318 g, 0.0768 mmol) and the compound of Reference 66 (0.0154 g, 0.0922 mmol) were dissolved in DMF (1.00 mL), and HATU (0.0351 g, 0.0922 mmol) and diisopropyl Ethylethylamine (0.0201 mL, 0.115 mmol). After stirring at the same temperature for 2 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) , 77%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.40-2.10 (m, 9H), 2.32 - 2.36 (m, 1H), 3.03 (s, 3H), 3.03 (s, 3H), 3.10-3.16 (m, 2H), 3.19-3.27 (m, 1H), 3.47-3.54 (m, 2H), 3.68-3.72 (m, 1H), 4.14 (d, J = 16.8 Hz, 1H), 4.24 (d, J = 16.8 Hz) ,1H),4.44-4.47(m,1H),5.22(d,J=4.9Hz,1H),6.83-6.87(m,1H),6.92-7.00(m,3H),7.23-7.31(m,3H ), 7.66 (d, J = 2.7 Hz, 1H), 8.00 (brs, 1H).

ESI-MS: m/z = 564 (M+H) ⁺ .

(Reference Example 67) (R)-2-((3-Chloro-4-((1-(o-tolyl)piperidin-4-yl)oxy)phenyl)aminemethanyl)piperidine-1 - Synthesis of tertiary butyl formate:

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) were dissolved in DMF (1. HATU (0.144 g, 0.379 mmol) and diisopropylethylamine (0.0827 mL, 0.473 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 a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=90/10 to 75/25) to give the title compound as a white solid (hereinafter, the compound of reference 67) (0.172 g, 0.326 mmol ,Quantitative).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.44-1.69 (m, 5H), 1.52 (s, 9H), 1.97-2.05 (m, 2H), 2.07-2.14 (m, 2H), 2.32-2.35 ( m, 1H), 2.32 (s, 3H), 2.77-2.86 (m, 3H), 3.15-3.21 (m, 2H), 4.06-4.08 (m, 1H), 4.40-4.45 (m, 1H), 4.85- 4.85 (m, 1H), 6.96-7.00 (m, 1H), 6.96 (d, J = 9.1 Hz, 1H), 7.04-7.06 (m, 1H), 7.14 - 7.19 (m, 2H), 7.31 (dd, J = 9.1, 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 528 (M+H) ⁺ .

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

The compound of Reference 67 (0.217 g, 0.411 mmol) was dissolved in ethyl acetate (2.06 mL). After stirring at room temperature for 2 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. ).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.64 (m, 4H), 1.80-1.85 (m, 1H), 1.97-2.06 (m, 3H), 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, 2H), 3.39 (dd, J = 9.7, 3.4 Hz, 1H), 4.41-4.44 ( m, 1H), 6.96-7.00 (m, 1H), 6.96 (d, J = 9.1 Hz, 1H), 7.04-7.06 (m, 1H), 7.14 - 7.19 (m, 2H), 7.44 (dd, J = 9.1, 2.7 Hz, 1H), 7.68 (d, J = 2.7 Hz, 1H), 8.90 (s, 1H).

ESI-MS: m/z = 428 (M+H) ⁺ .

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

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) After stirring at the same temperature for 1 hour, methanol was added to the reaction solution, and concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) , 83%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.91-2.05 (m, 3H), 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, 2H), 3.12-3.19 (m, 3H), 3.74-3.78 (m, 1H), 4.40- 4.43 (m, 1H), 5.25-5.26 (m, 1H), 6.93-6.99 (m, 2H), 7.04-7.06 (m, 1H), 7.15-7.18 (m, 2H), 7.30 (dd, J = 8.8 , 2.3Hz, 1H), 7.64 (d, J = 2.3Hz, 1H), 8.31 (s, 1H).

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- Synthesis of trifluoroethenyl) piperidine-2-carboxamide:

The compound of Reference Example 68 (0.0276 g, 0.0646 mmol) was dissolved in dichloromethane (1.40 mL), and triethylamine (0.0244 mL, 0.162 mmol) and anhydrous trifluoroacetic acid (0.0119 mL, . 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 brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) , 54%).

^{1 H-NMR (400MHz, 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, 1H), 2.32 ( s, 3H), 2.77-2.83 (m, 2H), 3.15-3.20 (m, 2H), 3.30-3.38 (m, 1H), 3.97-4.00 (m, 1H), 4.42-4.46 (m, 1H), 5.14-5.15 (m, 1H), 6.96-7.00 (m, 1H), 6.96 (d, J = 9.1 Hz, 1H), 7.04-7.06 (m, 1H), 7.15-7.19 (m, 2H), 7.27 ( Dd, J = 9.1, 2.3 Hz, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.66 (s, 1H).

ESI-MS: m/z = 524 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 45) (0.0292 g, 0.0620 mmol, 96) was obtained as a white solid, m. %).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.49-1.65 (m, 2H), 1.70-1.75 (m, 2H), 1.81-1.89 (m, 1H), 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, 2H), 4.97-4.98 (m, 1H), 6.95 (d, J = 9.1 Hz, 1H), 6.96-6.99 (m, 1H), 7.04-7.06 ( m, 1H), 7.14 - 7.19 (m, 2H), 7.33 (dd, J = 9.1, 2.7 Hz, 1H), 7.66 (d, J = 2.7 Hz, 1H), 8.59 (s, 1H).

ESI-MS: m/z = 471 (M+H) ⁺ .

(Example 46) (R)-1-(2-(1H-1,2,3-triazol-1-yl)ethenyl)-N-(3-chloro-4-((1-(o) Synthesis of tolyl)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) were dissolved in DMF (1.00 mL) HATU (0.0426 g, 0.112 mmol) and diisopropylethylamine (0.0245 mL, 0.140 mmol) were added. 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 a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) , 85%). As a result of analysis using a palmar column, the obtained compound of Example 46 was maintained for 20.0 minutes, and the optical purity at this time was 99.9% ee. The analytical conditions for using the palm column are as follows.

Measuring machine: Shimadzu Corporation High-speed liquid chromatography LC-2010CHT

Pipe column: DAICEL CHEMICAL INDUSTRIES Co., Ltd. CHIRALCEL OZ-3R 0.46cmφ×15cm particle size 3μm

Column temperature: 40 ° C

Mobile phase: (A solution) 20 mM potassium dihydrogen phosphate aqueous solution, (B solution) acetonitrile

The composition of the mobile phase: liquid A: liquid B = 45:55, and liquid is supplied for 30 minutes.

Flow rate: 1.0 mL/min

Detection: UV (210nm)

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.68 (m, 2H), 1.76-1.81 (m, 3H), 1.97-2.05 (m, 2H), 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=15.9Hz,1H), 5.39(d,J=15.9Hz,1H),6.95-7.00(m,2H) , 7.04-7.06 (m, 1H), 7.15-7.19 (m, 2H), 7.38 (dd, J = 8.6, 2.7 Hz, 1H), 7.75 (d, J = 0.9 Hz, 1H), 7.78 (d, J) =2.7 Hz, 1H), 7.81 (d, J = 0.9 Hz, 1H), 8.24 (s, 1H).

ESI-MS: m/z = 537 (M+H) ⁺ .

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

The same procedure as in Example 46 was carried out except that 2-(1H-imidazol-1-yl)acetic acid was used instead of 2-(1H-1,2,3-triazol-1-yl)acetic acid. The title compound (hereinafter, compound of Example 47) (0.0246 g, 0.0459 mmol, 98%)

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.44-1.55 (m, 1H), 1.62-1.84 (m, 3H), 1.90-2.04 (m, 3H), 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=16.8Hz,1H),4.89(d,J=16.8Hz,1H),5.16-5.17(m,1H),6.92(d,J=9.1Hz , 1H), 6.96 (s, 1H), 6.98-7.00 (m, 1H), 7.04-7.06 (m, 1H), 7.12-7.19 (m, 4H), 7.51 (s, 1H), 7.62 (d, J =2.3 Hz, 1H), 8.15 (s, 1H).

ESI-MS: m/z = 536 (M+H) ⁺ .

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

The same procedure as in Example 46 was carried out except that 2-(1H-pyrazol-1-yl)acetic acid was used instead of 2-(1H-1,2,3-triazol-1-yl)acetic acid. The title compound (hereinafter, the compound of Example 48) (0.0246 g, 0.0459 mmol, 98%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.48-1.76 (m, 5H), 1.98-2.06 (m, 2H), 2.08-2.15 (m, 2H), 2.32 (s, 3H), 2.51-2.54 ( m,1H), 2.78-2.83 (m, 2H), 3.02-3.09 (m, 1H), 3.16-3.22 (m, 2H), 3.63-3.67 (m, 1H), 4.41-4.47 (m, 1H), 4.98 (d, J = 14.5 Hz, 1H), 5.21 (d, J = 14.5 Hz, 1H), 5.40-5.41 (m, 1H), 6.38-6.39 (m, 1H), 6.96-7.00 (m, 1H) , 6.98 (d, J = 8.8 Hz, 1H), 7.05-7.07 (m, 1H), 7.15-7.19 (m, 2H), 7.46 (dd, J = 8.8, 2.5 Hz, 1H), 7.52 (d, J =2.1 Hz, 1H), 7.56 (d, J = 2.1 Hz, 1H), 7.67 (d, J = 2.5 Hz, 1H), 8.86 (s, 1H).

ESI-MS: m/z = 536 (M+H) ⁺ .

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

Using 2-(4H-1,2,4-triazol-4-yl)acetic acid instead of 2-(1H-1,2,3-triazol-1-yl)acetic acid, by way of example The title compound (hereinafter, the compound of Example 49) (0.0389 g, 0.0724 mmol, 77%) was obtained as a white solid.

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.54-1.88 (m, 5H), 1.94-2.02 (m, 2H), 2.06-2.11 (m, 2H), 2.26-2.31 (m, 1H), 2.31 ( s, 3H), 2.75-2.81 (m, 2H), 3.13-3.19 (m, 2H), 3.55-3.69 (m, 2H), 4.39-4.43 (m, 1H), 4.90 (d, J = 17.2 Hz, 1H), 5.00 (d, J = 17.2 Hz, 1H), 5.17-5.18 (m, 1H), 6.92 (d, J = 8.6 Hz, 1H), 6.95-6.99 (m, 1H), 7.03-7.05 (m) , 1H), 7.14-7.21 (m, 3H), 7.65 (d, J = 2.3 Hz, 1H), 8.17 (s, 2H), 8.58 (s, 1H).

ESI-MS: m/z = 537 (M+H) ⁺ .

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

The use of sodium 2-(1H-1,2,4-triazol-1-yl)acetate in place of 2-(1H-1,2,3-triazol-1-yl)acetic acid, in addition to 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 (400MHz, CDCl} 3) δ: 1.52-1.68 (m, 2H), 1.75-1.86 (m, 3H), 1.97-2.04 (m, 2H), 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=15.4Hz,1H), 5.20(d, J=15.4Hz,1H), 5.25-5.26(m,1H),6.94-6.99(m,2H) , 7.04-7.06 (m, 1H), 7.15-7.19 (m, 2H), 7.29 (dd, J = 9.1, 2.3 Hz, 1H), 7.63 (d, J = 2.3 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)ethenyl)-N-(3-chloro-4-((1-(o) Synthesis of tolyl)piperidin-4-yl)oxy)phenyl)piperidine-2-carboxamide:

The use of 2-(2H-1,2,3-triazol-2-yl)acetic acid in place of 2-(1H-1,2,3-triazol-1-yl)acetic acid, in addition to the examples The title compound (hereinafter, the compound of Example 51) (0.0351 g, 0.0654 mmol, 70%) was obtained 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, 2H), 2.32 ( s, 3H), 2.47-2.50 (m, 1H), 2.78-2.83 (m, 2H), 2.96-3.03 (m, 1H), 3.16-3.21 (m, 2H), 3.53-3.56 (m, 1H), 4.42-4.47(m,1H), 5.31(d,J=15.0Hz,1H), 5.38-5.39(m,1H),5.55(d,J=15.0Hz,1H),6.98(d,J=9.1Hz , 1H), 6.98-7.00 (m, 1H), 7.05-7.06 (m, 1H), 7.15-7.19 (m, 2H), 7.44 (dd, J = 9.1, 2.7 Hz, 1H), 7.65 (d, J =2.7 Hz, 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)ethenyl)-N-(3-chloro-4-((1-(o-tolyl))piperidine- Synthesis of 4-yl)oxy)phenyl)piperidine-2-carboxamide:

The same procedure as in Example 46 was carried out except that 2-(1H-tetrazol-1-yl)acetic acid was used instead of 2-(1H-1,2,3-triazol-1-yl)acetic acid. The title compound (hereinafter, the compound of Example 52) (0.0274 g, 0.0509 mmol, 73%).

^{1 H-NMR (400MHz, 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, 2H), 2.25- 2.29 (m, 1H), 2.32 (s, 3H), 2.77-2.83 (m, 2H), 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,1H), 5.39(d,J=16.6Hz,1H),5.45(d,J=16.6Hz,1H),6.94-7.00(m,2H) , 7.04-7.06(m,1H),7.14-7.19(m,2H),7.22(dd,J=8.7,2.4Hz,1H),7.66(d,J=2.4Hz,1H),7.83(s,1H ), 8.84 (s, 1H).

ESI-MS: m/z = 538 (M+H) ⁺ .

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

Ethyl 2-(1H-tetrazol-5-yl)acetate (0.500 g, 3.20 mmol) was dissolved in dichlorohexane (6.40 mL). After stirring at 100 ° C for 11 hours, a 1 M aqueous sodium hydroxide solution was added to the reaction mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with a 1M aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 40/60) to give the title compound ( 0.534 mmol, 17%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.29 (t, J = 7.2Hz, 3H), 2.55 (s, 3H), 3.92 (s, 2H), 4.23 (q, J = 7.2Hz, 2H).

ESI-MS: m/z = 171 (M+H) ⁺ .

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

The compound of Reference Example 69 (0.0900 g, 0.529 mmol) was dissolved in THF (1.00 mL) and ethanol (1.00 mL), and 1M aqueous sodium hydroxide (1.06 mL, 1.06 mmol) was added at room temperature. After stirring at the same temperature for 2 hours, the reaction mixture was evaporated.

¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 2.41 (s, 3H), 3.38 (s, 2H).

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-A) Base-1,3,4- Synthesis of oxazol-2-yl)ethenyl)piperidine-2-carboxamide:

The title compound was obtained as a white solid (yield: m. m. , the compound of Example 53) (0.0333 g, 0.0603 mmol, 65%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.50-1.63 (m, 3H), 1.72-1.75 (m, 2H), 1.97-2.05 (m, 2H), 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, 2H), 3.16-3.21 (m, 2H), 3.24-3.31 (m, 1H), 3.58- 3.61(m,1H), 3.92(d,J=16.8Hz,1H), 4.19(d,J=16.8Hz,1H), 4.40-4.46(m,1H),5.50-5.51(m,1H),6.96 -6.99 (m, 1H), 7.00 (d, J = 8.6 Hz, 1H), 7.04-7.06 (m, 1H), 7.15-7.19 (m, 2H), 7.61 (dd, J = 8.6, 2.7 Hz, 1H) ), 8.03 (d, J = 2.7 Hz, 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-(pyridine-2) Synthesis of -yl)ethinyl)piperidine-2-carboxamide:

The same procedure as in Example 46 was carried out except that 2-(1H-, pyridin-2-yl)acetic acid hydrochloride was used instead of 2-(1H-1,2,3-triazol-1-yl)acetic acid. The title compound (hereinafter, the compound of Example 54) (0.0390 g, 0.0713 mmol, 76%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.66 (m, 4H), 1.74-1.75 (m, 1H), 2.00-2.07 (m, 2H), 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, 1H), 3.17-3.22 (m, 2H), 3.65-3.68 (m, 1H), 4.03 (d, J = 16.3 Hz, 1H), 4.29 (d, J = 16.3 Hz, 1H), 4.44 - 4.48 (m, 1H), 5.53-5.54 (m, 1H), 6.96-7.00 (m, 1H) , 7.00 (d, J = 8.6 Hz, 1H), 7.05-7.07 (m, 1H), 7.15-7.19 (m, 3H), 7.26-7.29 (m, 1H), 7.42 (dd, J = 8.6, 2.7 Hz , 1H), 7.60 (d, J = 2.7 Hz, 1H), 7.68-7.72 (m, 1H), 8.32-8.33 (m, 1H), 9.54 (s, 1H).

ESI-MS: m/z = 547 (M+H) ⁺ .

(Example 55) (R)-N-(3-Chloro-4-((1-(o-tolyl)piperidin-4-yl)oxy)phenyl)-1-(2-(pyridine-3) Synthesis of -yl)ethinyl)piperidine-2-carboxamide:

The same procedure as in Example 46 was carried out except that 2-(1H-,pyridin-3-yl)acetic acid hydrochloride was used instead of 2-(1H-1,2,3-triazol-1-yl)acetic acid. The title compound (hereinafter, compound of Example 55) (0.0316 g, 0.0578 mmol, 62%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.34-1.45 (m, 1H), 1.55-1.75 (m, 3H), 1.89-2.05 (m, 3H), 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, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.96-7.00 (m, 1H), 7.04-7.06 (m, 1H), 7.15 -7.19 (m, 2H), 7.23 (dd, J = 8.8, 2.5 Hz, 1H), 7.29 (dd, J = 8.2, 5.0 Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.62 7.64 (m, 1H), 8.14 (s, 1H), 8.53 (d, J = 1.8 Hz, 1H), 8.54 - 8.56 (m, 1H).

ESI-MS: m/z = 547 (M+H) ⁺ .

(Example 56) (R)-N-(3-Chloro-4-((1-(o-tolyl)piperidin-4-yl)oxy)phenyl)-1-(2-(pyridine-4) Synthesis of -yl)ethinyl)piperidine-2-carboxamide:

The same procedure as in Example 46 was carried out except that 2-(1H-1,2,3-triazol-1-yl)acetic acid was used instead of 2-(1H-1,2,3-triazol-1-yl)acetic acid. The title compound (hereinafter, compound of Example 56) (0.0360 g, 0.0658 mmol, 70%)

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.32-1.42 (m, 1H), 1.56-1.63 (m, 1H), 1.70-1.72 (m, 2H), 1.87-2.05 (m, 3H), 2.07- 2.14 (m, 2H), 2.26-2.29 (m, 1H), 2.32 (s, 3H), 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, 1H), 5.26-5.27 (m, 1H), 6.94 (d, J = 9.1 Hz, 1H), 6.96-7.00 (m, 1H), 7.04-7.06 ( m,1H), 7.15-7.22 (m, 5H), 7.61 (d, J = 2.7 Hz, 1H), 8.12 (s, 1H), 8.58 (d, J = 6.3 Hz, 2H).

ESI-MS: m/z = 547 (M+H) ⁺ .

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

The compound of Reference Example 64 (0.0800 g, 0.187 mmol) and 2-((tertiary butoxycarbonyl)amino)acetic acid (0.0393 g, 0.224 mmol) were dissolved in DMF (1.00 mL), and HATU was added at room temperature ( 0.0851 g, 0.224 mmol) and diisopropylethylamine (0.0490 mL, 0.280 mmol). 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 a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane-ethyl-ethyl acetate-ethyl acetate) , 93%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.46 (s, 9H), 1.51-1.62 (m, 2H), 1.72-1.87 (m, 3H), 1.97-2.13 (m, 4H), 2.32 (s, 3H), 2.32-2.37 (m, 1H), 2.76-2.82 (m, 2H), 3.15-3.22 (m, 3H), 3.70-3.73 (m, 1H), 3.92-3.97 (m, 1H), 4.09- 4.14 (m, 1H), 4.41-4.44 (m, 1H), 5.28-5.29 (m, 1H), 5.39-5.44 (m, 1H), 6.94-6.99 (m, 2H), 7.04-7.06 (m, 1H) ), 7.14 - 7.19 (m, 2H), 7.41 (dd, J = 8.8, 2.3 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 8.07 (s, 1H).

ESI-MS: m/z = 585 (M+H) ⁺ .

(Example 57) (R)-1-(2-Aminoethyl)-N-(3-chloro-4-((1-(o-tolyl)piperidin-4-yl)oxy)benzene Synthesis of piperidine-2-carboxamide:

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. After stirring at room temperature for 2 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) 91%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.64 (m, 2H), 1.72-1.76 (m, 2H), 1.89-2.13 (m, 5H), 2.28-2.32 (m, 1H), 2.32 ( s, 3H), 2.76-2.82 (m, 2H), 3.15-3.20 (m, 3H), 3.58-3.67 (m, 3H), 4.40-4.45 (m, 1H), 5.24-5.25 (m, 1H), 6.94-6.99 (m, 2H), 7.04-7.06 (m, 1H), 7.14-7.19 (m, 2H), 7.31 (dd, J = 8.6, 2.7 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 8.13 (s, 1H).

ESI-MS: m/z = 486 (M+H) ⁺ .

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

The same procedure as in Reference Example 71 was carried out except that 3-((tertiary butoxycarbonyl)amino)propionic acid was used instead of 2-((tertiarybutoxycarbonyl)amino)acetic acid. The title compound (hereinafter, the compound of Reference Example 72) (0.0548 g, 0.0915 mmol, 97%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.41 (s, 9H), 1.47-1.59 (m, 2H), 1.72-1.75 (m, 2H), 1.82-1.89 (m, 1H), 1.96-2.03 ( m, 2H), 2.07-2.13 (m, 2H), 2.32 (s, 3H), 2.32-2.35 (m, 1H), 2.54-2.71 (m, 2H), 2.76-2.82 (m, 2H), 3.12 3.20 (m, 3H), 3.41-3.53 (m, 2H), 3.77-3.80 (m, 1H), 4.39-4.45 (m, 1H), 5.10-5.15 (m, 1H), 5.29-5.30 (m, 1H) ), 6.94-6.99 (m, 2H), 7.04-7.06 (m, 1H), 7.14-7.19 (m, 2H), 7.39-7.41 (m, 1H), 7.66 (d, J = 2.7 Hz, 1H), 8.34(s,1H).

ESI-MS: m/z = 599 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 58) (0.0300 g, 0.0601 mmol) was obtained as a white solid. 69%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.48-1.56 (m, 2H), 1.73-1.76 (m, 3H), 1.96-2.04 (m, 2H), 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, 1H), 2.71-2.82 (m, 3H), 3.10-3.20 (m, 5H), 3.85-3.88 ( m, 1H), 4.39-4.43 (m, 1H), 5.40-5.41 (m, 1H), 6.93-6.99 (m, 2H), 7.04-7.06 (m, 1H), 7.14-7.18 (m, 2H), 7.33 (dd, J = 8.6, 2.3 Hz, 1H), 7.56 (d, J = 2.3 Hz, 1H), 8.77 (s, 1H).

ESI-MS: m/z = 499 (M+H) ⁺ .

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

The same procedure as in Reference Example 71 except that 3-((tertiary butoxycarbonyl)(methyl)amino)propionic acid was used instead of 2-((tertiarybutoxycarbonyl)amino)acetic acid. 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, 3H), 1.56 (s, 9H), 1.68-1.74 (m, 2H), 1.96-2.03 (m, 2H), 2.06-2. m, 2H), 2.32 (s, 3H), 2.39-2.42 (m, 1H), 2.54-2.82 (m, 5H), 2.92 (s, 3H), 3.15-3.28 (m, 3H), 3.80-3.83 ( m,1H),3.93-3.96 (m,1H), 4.39-4.45 (m,1H), 5.35-5.36 (m,1H), 6.93-6.99 (m,2H), 7.04-7.06 (m,1H), 7.14-7.19 (m, 2H), 7.56-7.58 (m, 1H), 7.75-7.75 (m, 1H), 8.85 (s, 1H).

ESI-MS: m/z = 613 (M+H) ⁺ .

(Example 59) (R)-N-(3-Chloro-4-((1-(o-tolyl)piperidin-4-yl)oxy)phenyl)-1-(3-(methylamine) Synthesis of propyl)propanyl) piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 59) (0.0318 g, 0.0620 mmol) was obtained as a white solid. 70%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.48-1.57 (m, 2H), 1.72-1.75 (m, 3H), 1.96-2.12 (m, 4H), 2.32 (s, 3H), 2.39-2.41 ( m,1H), 2.45 (s, 3H), 2.55-2.62 (m, 1H), 2.76-2.83 (m, 3H), 2.93-2.97 (m, 2H), 3.11-3.20 (m, 3H), 3.84 3.87 (m, 1H), 4.40-4.44 (m, 1H), 5.39-5.40 (m, 1H), 6.94-6.99 (m, 2H), 7.04-7.06 (m, 1H), 7.14-7.19 (m, 2H) ), 7.33 (dd, J = 8.8, 2.3 Hz, 1H), 7.53 (d, J = 2.3 Hz, 1H), 8.67 (s, 1H).

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-cyanide) Synthesis of hydrazino)ethylidenepiperidine-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 at the same temperature for 3 hours, the reaction solution was concentrated. The obtained crude product was used in the subsequent reaction without purification.

The above crude product was dissolved in acetonitrile (1.00 mL), and aqueous ammonia (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 residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) 90%).

^{1 H-NMR (400MHz, 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, 1H), 4.11 (dd, J = 17.4, 4.3 Hz, 1H), 4.55 - 4.58 (m, 1H), 5.08-5.09 (m, 1H), 6.92 ( Brs, 2H), 6.92-6.96 (m, 1H), 7.02-7.03 (m, 1H), 7.12-7.16 (m, 2H), 7.23 (d, J = 9.1 Hz, 1H), 7.42 (dd, J = 9.1, 2.7 Hz, 1H), 7.75 (d, J = 2.7 Hz, 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-cyanide) Synthesis of 3-methylmethyl)ethylidene)piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 61) (0.0266 g, 0.0470 mmol, 57%) as a white solid was obtained by the same procedure as in Example 60. ).

^{1 H-NMR (400MHz, DMSO} -D 6) δ: 1.32-1.50 (m, 2H), 1.63-1.69 (m, 3H), 1.79-1.86 (m, 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,1H), 6.76 (brs, 1H), 6.92-6.96 (m, 1H), 7.01-7.03 (m, 1H), 7.12-7.16 (m, 3H), 7.22-7.25 (m, 1H), 7.40- 7.47 (m, 1H), 7.77 (d, J = 2.3 Hz, 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-ureidoethyl hydrazide) Synthesis of piperidine-2-carboxamide:

The compound of Example 57 (0.0400 g, 0.0825 mmol) was dissolved in dichloromethane (1.00 mL), and triethylamine (0.0287 mL, 0.206 mmol) and trimethyldecyl isocyanate (0.0134 mL, 0.0990) were added at 0 °C. Mm). After stirring at room temperature for 24 hours, methanol was added to the reaction solution, and the mixture was evaporated. The residue obtained was purified by EtOAc EtOAc (EtOAc/EtOAc (EtOAc) ).

^{1 H-NMR (400MHz, 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,2H),3.33-3.39(m,1H),3.68-3.71(m,1H ), 3.89 (dd, J = 17.0, 4.8 Hz, 1H), 3.98 (dd, J = 17.0, 4.8 Hz, 1H), 4.55-4.58 (m, 1H), 5.08-5.09 (m, 1H), 5.72 ( s, 2H), 6.09 (brs, 1H), 6.92-6.96 (m, 1H), 7.02-7.03 (m, 1H), 7.12-7.16 (m, 2H), 7.22 (d, J = 9.1 Hz, 1H) , 7.44 (dd, J = 9.1, 2.3 Hz, 1H), 7.78 (d, J = 2.3 Hz, 1H), 9.82 (s, 1H).

ESI-MS: m/z = 528 (M+H) ⁺ .

(Reference Example 74) (R)-1-(2-(3-benzylmercaptothioureido)ethinyl)-N-(3-chloro-4-((1-(o-tolyl))piperidine- Synthesis of 4-yl)oxy)phenyl)piperidine-2-carboxamide:

The compound of Example 57 (0.0500 g, 0.103 mmol) was dissolved in dichloromethane (1.00 mL), and benzyl thiocyanate (0.0152 mL, 0.113 mmol) was added at room temperature. After stirring at the same temperature for 0.5 hour, methanol was added to the reaction solution, and concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) M, 75%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.67 (m, 2H), 1.75-1.86 (m, 2H), 1.89-2.04 (m, 3H), 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, 1H), 4.66 (dd, J = 17.7, 4.3 Hz, 1H), 5.31-5.33 (m, 1H), 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, 1H), 7.51-7.55 (m, 2H), 7.62-7.68 ( m, 2H), 7.88-7.90 (m, 2H), 8.06 (s, 1H), 9.10 (s, 1H), 11.49 (s, 1H).

ESI-MS: m/z = 648 (M+H) ⁺ .

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

The compound of Reference Example 74 (0.0500 g, 0.0771 mmol) was dissolved in THF (0.500 mL) and methanol (0.500 mL) After stirring at the same temperature for 0.5 hour, 1 M hydrochloric acid was added to the reaction mixture, and ethyl acetate was evaporated. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The residue obtained was purified by EtOAc EtOAc (EtOAc (EtOAc) ).

^{1 H-NMR (400MHz, 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, 1H), 5.10-5.11 (m, 1H), 6.92-6.96 (m, 1H), 7.02-7.03 (m, 1H), 7.12-7.16 (m, 2H), 7.23 (d, J = 9.1 Hz, 1H), 7.34 (brs, 2H), 7.43 (dd, J = 9.1, 2.3 Hz, 1H), 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-(3-chloro-4-((1-(o-tolyl))piperidin-4-yl)oxy)phenyl)aminecarboxamide Synthesis of tert-butyl butyl sulfonyl-1-yl)-2-oxoethyl)amine sulfonylamine carboxylic acid:

Chlorosulfonyl isocyanate (0.00790 mL, 0.0908 mmol) was dissolved in dichloromethane (1.00 mL), and tris-butanol (0.00947 mL, 0.0990 mmol) was added at 0 °C. After stirring at the same temperature for 0.5 hour, 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 at room temperature for 4 hours, methanol was added to the reaction solution, and the mixture was evaporated. The obtained residue was purified by silica gel column chromatography (hexane-ethyl-ethyl acetate-ethylamine-ethylamine-ethylamine-ethylamine) M, 51%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43 (s, 9H), 1.50-1.66 (m, 2H), 1.73-1.88 (m, 3H), 1.96-2.06 (m, 2H), 2.06-2. m, 2H), 2.32 (s, 3H), 2.32-2.34 (m, 1H), 2.77-2.82 (m, 2H), 3.15-3.20 (m, 2H), 3.25-3.32 (m, 1H), 3.61 3.65 (m, 1H), 4.12 (d, J = 16.3 Hz, 1H), 4.19 (d, J = 16.3 Hz, 1H), 4.40 - 4.45 (m, 1H), 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, 2.7 Hz, 1H), 7.64 (d , J = 2.7 Hz, 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-(aminesulfonamide) Synthesis of arylamino)ethylidene)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 at room temperature for 5 hours, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and the aqueous layer was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered and evaporated. The residue obtained was purified by EtOAc EtOAc EtOAc(EtOAc(EtOAc) , 39%).

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, 1H), 4.06 (dd, J = 16.8, 5.0 Hz, 1H), 4.40 - 4.42 (m, 1H), 5.16 (s, 2H), 5.23-5.24 ( m,1H), 5.87-5.90 (m,1H), 6.93 (d, J=8.7 Hz, 1H), 6.95-6.99 (m, 1H), 7.03-7.05 (m, 1H), 7.14-7.18 (m, 2H), 7.33 (dd, J = 8.7, 2.3 Hz, 1H), 7.67 (d, J = 2.3 Hz, 1H), 8.20 (s, 1H).

ESI-MS: m/z = 564 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 65) (0.0587) was obtained as a white solid, m. g, 0.108 mmol, 93%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.48-1.56 (m, 2H), 1.71-1.78 (m, 3H), 1.96-2.04 (m, 2H), 2.08-2.13 (m, 2H), 2.32 ( s, 3H), 2.42-2.49 (m, 2H), 2.62-2.68 (m, 1H), 2.76-2.82 (m, 2H), 2.87-2.94 (m, 1H), 3.03 (ddd, J = 17.0, 10.4 , 4.2 Hz, 1H), 3.14-3.20 (m, 3H), 3.74 (s, 3H), 3.94-3.97 (m, 1H), 4.39-4.45 (m, 1H), 5.43-5.44 (m, 1H), 6.95 (d, J = 9.1 Hz, 1H), 6.97-7.00 (m, 1H), 7.04-7.06 (m, 1H), 7.14 - 7.19 (m, 2H), 7.60 (dd, J = 9.1, 2.7 Hz, 1H), 7.71 (d, J = 2.7 Hz, 1H), 8.29 (s, 1H).

ESI-MS: m/z = 542 (M+H) ⁺ .

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

The compound of Example 65 (0.0519 g, 0.0957 mmol) was dissolved in THF (1.00 mL) and methanol (1.00 mL), and 1M aqueous sodium hydroxide (1.01 mL, 1.01 mmol) was added at room temperature. After stirring at the same temperature for 2 hours, the reaction solution was concentrated. The obtained crude product was used in the subsequent reaction without purification.

The above crude product and ammonium chloride (0.0308 g, 0.575 mmol) were suspended in DMF (1.00 mL), and HATU (0.0547 g, 0.144 mmol) and diisopropylethylamine (0.0502 mL, 0.287) were added at room temperature. Mm). 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 a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) 82%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.39-1.56 (m, 2H), 1.63-1.76 (m, 3H), 1.96-2.13 (m, 4H), 2.32 (s, 3H), 2.40-2.60 ( m,3H), 2.76-2.81 (m, 2H), 2.93-2.97 (m, 2H), 3.15-3.20 (m, 3H), 3.95-3.99 (m, 1H), 4.39-4.43 (m, 1H), 5.38 (brs, 1H), 5.44-5.45 (m, 1H), 5.65 (brs, 1H), 6.93-6.99 (m, 2H), 7.04-7.06 (m, 1H), 7.15-7.19 (m, 2H), 7.55 (dd, J = 9.1, 2.7 Hz, 1H), 7.78 (d, J = 2.7 Hz, 1H), 8.42 (s, 1H).

ESI-MS: m/z = 527 (M+H) ⁺ .

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

White was obtained by the same procedure as in Example 46 except that 2-(oxaindole-3-yl)acetic acid was used instead of 2-(1H-1,2,3-triazol-1-yl)acetic acid. The title compound (hereinafter, the compound of Example 67) (0.0349 g, 0.0663 mmol, 71%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.49-1.62 (m, 2H), 1.72-1.81 (m, 2H), 1.93-2.04 (m, 3H), 2.06-2.13 (m, 2H), 2. 2.28 (m, 1H), 2.32 (s, 3H), 2.76-2.93 (m, 4H), 3.15-3.23 (m, 3H), 3.40-3.47 (m, 1H), 3.79-3.82 (m, 1H), 4.40-4.44(m,3H), 4.90-4.96(m,2H), 5.19-5.20(m,1H), 6.93(d,J=9.1Hz,1H),6.96-7.00(m,1H),7.04- 7.06 (m, 1H), 7.15-7.19 (m, 2H), 7.23 (dd, J = 9.1, 2.7 Hz, 1H), 7.62 (d, J = 2.7 Hz, 1H), 8.16 (s, 1H).

ESI-MS: m/z = 526 (M+H) ⁺ .

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

The compound of Example 57 (0.0400 g, 0.0825 mmol) was dissolved in dichloromethane (1. <RTI ID=0.0></RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; </RTI> <RTIgt; After stirring at the same temperature for 1 hour, methanol was added to the reaction solution, and concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc(EtOAc) ).

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, 1H), 4.41-4.45 (m, 1H), 5.26-5.27 (m, 1H), 6.51-6.53 (m, 1H), 6.94-7.00 (m, 2H), 7.04-7.06 (m, 1H), 7.15-7.19 (m, 2H), 7.37 (dd, J = 8.7, 2.7 Hz, 1H), 7.64 (d, J = 2.7 Hz, 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-(methylsulfonate) Synthesis of decylamine ethionylpiperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 69) (0.0267 g, 0.0474 mmol, 58%) was obtained as a white solid, m. .

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.70 (m, 2H), 1.73-1.91 (m, 3H), 1.96-2.13 (m, 4H), 2.27-2.32 (m, 1H), 2.32 ( s, 3H), 2.77-2.82 (m, 2H), 3.00 (s, 3H), 3.15-3.20 (m, 2H), 3.29-3.37 (m, 1H), 3.59-3.62 (m, 1H), 4.04 ( Dd, J = 16.9, 4.6 Hz, 1H), 4.08 (dd, J = 16.9, 4.6 Hz, 1H), 4.41-4.45 (m, 1H), 5.22 - 5.23 (m, 1H), 5.60 (t, J = 4.6 Hz, 1H), 6.95 (d, J = 8.9 Hz, 1H), 6.96-7.00 (m, 1H), 7.04-7.06 (m, 1H), 7.15-7.19 (m, 2H), 7.30 (dd, J =8.9, 2.5 Hz, 1H), 7.67 (d, J = 2.5 Hz, 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-cyanoethyl) Synthesis of mercapto) piperidine-2-carboxamide:

The title compound was obtained as a white solid (yield: m. m. , the compound of Example 70) (0.238 g, 0.481 mmol, 76%).

¹ H-NMR (400MHz, 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. 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, 1H), 5.18 (d, J = 5.0 Hz, 1H), 6.94-6.99 (m, 2H), 7.05 (d, J = 7.7 Hz, 1H), 7.14 - 7.19 (m, 2H), 7.26-7.29 (m, 1H), 7.65 (d, J = 2.7 Hz, 1H), 7.92 (brs, 1H).

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 was obtained as a yellow solid (yield: Reference Example 76). Compound) (0.128 g, 0.358 mmol, 70%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.00-2.15 (m, 4H), 3.45-3.50 (m, 2H), 3.57-3.63 (m, 2H), 4.79-4.83 (m, 1H), 6.91 ( d, J = 9.0 Hz, 2H), 7.03 (d, J = 9.0 Hz, 1H), 7.52 (d, J = 9.0 Hz, 2H), 8.16 (dd, J = 9.0, 2.7 Hz, 1H), 8.33 ( d, J = 2.7 Hz, 1H).

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) as a pale yellow solid was obtained by the procedure of the the the , 888%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.89-2.04 (m, 4H), 3.28-3.34 (m, 2H), 3.54 (s, 2H), 3.64 - 3.70 (m, 2H), 4.34 - 4.39 ( m, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.83 (d, J = 8.6 Hz, 1H), 6.88 (d, J = 9.1) Hz, 2H), 7.49 (d, J = 9.1 Hz, 2H).

ESI-MS: m/z = 328 (M+H) ⁺ .

(Reference 78) (R)-2-((3-Chloro-4-((1-(4-cyanophenyl)piperidin-4-yl)oxy)phenyl)aminecarboxamido) Synthesis of pyridine-1-carboxylic acid tert-butyl butyl ester:

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) were dissolved in DMF (1.00 mL) HATU (0.0840 g, 0.220 mmol) and diisopropylethylamine (0.0480 mL, 0.275 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 a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane-ethyl-ethylamine-ethylamine-ethylamine-ethylamine-ethyl-ethyl-ethyl-ethyl-------- ,Quantitative).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.43-1.48 (m, 2H), 1.52 (s, 9H), 1.58-1.70 (m, 3H), 1.92-2.06 (m, 4H), 2.31-2.34 ( m,1H), 2.79-2.86(m,1H),3.34-3.40(m,2H), 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, 2H), 6.93 (d, J = 8.6 Hz, 1H), 7.32 (dd, J = 8.6, 2.7 Hz, 1H), 7.49 (d, J) = 9.1 Hz, 2H), 7.63 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 539 (M+H) ⁺ .

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

The compound of Reference 78 (0.0990 g, 0.184 mmol) was dissolved in ethyl acetate (yield: EtOAc). After stirring at room temperature for 4 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. ).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.43-1.64 (m, 4H), 1.79-1.83 (m, 1H), 1.92-2.06 (m, 5H), 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 (dd, J = 8.6, 2.7 Hz, 1H), 7.49 (d, J = 9.1 Hz, 2H), 7.66 (d, J = 2.7 Hz, 1H), 8.84 (s, 1H).

ESI-MS: m/z = 439 (M+H) ⁺ .

(Example 71) (R)-1-Ethyl-N-(3-chloro-4-((1-(4-cyanophenyl)piperidin-4-yl)oxy)phenyl)piperidin Synthesis of pyridine-2-carbamide:

The compound of Reference Example 79 (0.0200 g, 0.0456 mmol) was dissolved in dichloromethane (1.45 mL), and triethylamine (0.00953 mL, 0.0683 mmol) and acetonitrile (0.00389 mL, 0.0547 mmol) were added at 0 °C. After stirring at the same temperature for 1 hour, methanol was added to the reaction solution, and concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) 97%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.49-1.61 (m, 2H), 1.72-1.78 (m, 2H), 1.90-2.04 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m,1H),3.12-3.19(m,1H),3.33-3.39(m,2H), 3.60-3.66(m,2H),3.75-3.78(m,1H),4.51-4.56(m,1H), 5.24-5.26 (m, 1H), 6.88 (d, J = 9.1 Hz, 2H), 6.91 (d, J = 8.6 Hz, 1H), 7.31 (dd, J = 8.6, 2.7 Hz, 1H), 7.49 (d) , J = 9.1 Hz, 2H), 7.64 (d, J = 2.7 Hz, 1H), 8.35 (s, 1H).

ESI-MS: m/z = 481 (M+H) ⁺ .

(Example 72) (R)-N-(3-Chloro-4-((1-(4-cyanophenyl)piperidin-4-yl)oxy)phenyl)-1-(methylsulfonate) Synthesis of mercapto) piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 72) (0.0208 g, 0.0402 mmol, 88%) was obtained as a white solid, m. .

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.57 (m, 1H), 1.60-1.67 (m, 2H), 1.69-1.74 (m, 1H), 1.78-1.80 (m, 1H), 1.93 2.03 (m, 4H), 2.45-2.48 (m, 1H), 3.02 (s, 3H), 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, 2H), 6.95 (d, J = 9.1 Hz, 1H), 7.33 (dd, J = 9.1, 2.7 Hz, 1H), 7.50 (d, J = 9.1 Hz, 2H), 7.69 (d, J = 2.7 Hz, 1H), 8.11 (s, 1H).

ESI-MS: m/z = 517 (M+H) ⁺ .

(Example 73) (R)-1-(2-(1H-imidazol-1-yl)ethenyl)-N-(3-chloro-4-((1-(4-cyanophenyl))piperidin Synthesis of pyridin-4-yl)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), and HATU (0.0208 g, 0.0547 mmol) and diisopropylethylamine (0.0119 mL, 0.0683 mmol). 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 a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) 81%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.85 (m, 4H), 1.91-2.05 (m, 5H), 2.22 - 2.26 (m, 1H), 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, 1H), 4.90 (d, J = 16.3 Hz, 1H), 5.15 -5.17 (m, 1H), 6.88 (d, J = 9.1 Hz, 2H), 6.90 (d, J = 8.6 Hz, 1H), 6.96 (s, 1H), 7.13 (s, 1H), 7.17 (dd, J = 8.6, 2.3 Hz, 1H), 7.49 (d, J = 9.1 Hz, 2H), 7.52 (s, 1H), 7.64 (d, J = 2.3 Hz, 1H), 8.12 (s, 1H).

ESI-MS: m/z = 547 (M+H) ⁺ .

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

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) were dissolved in DMF (1.00 mL) HATU (0.118 g, 0.310 mmol) and diisopropylethylamine (0.0677 mL, 0.388 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 sulfate and brine and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (hexane-ethyl acetate: EtOAc: EtOAc: EtOAc) M, 80%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.44-1.69 (m, 5H), 1.52 (s, 9H), 1.95-2.10 (m, 4H), 2.31-2.34 (m, 1H), 2.79-2.86 ( m,1H),3.11-3.17(m,2H),3.44-3.50(m,2H),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, 2H), 7.31 (dd, J = 8.6, 2.3 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H).

ESI-MS: m/z = 598 (M+H) ⁺ .

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

The compound of Reference Example 80 (0.120 g, 0.21 mmol) was dissolved in ethyl acetate ( 1.00 mL), and then hydrogen chloride-ethyl acetate solution (4.0 M, 1.00 mL, 4.01 mmol) was added at 0 °C. After stirring at room temperature for 2 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. %).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.42-1.63 (m, 4H), 1.79-1.83 (m, 1H), 1.95-2.11 (m, 5H), 2.72-2.79 (m, 1H), 3.03- 3.08 (m, 1H), 3.11-3.17 (m, 2H), 3.34 (dd, J = 9.5, 3.6 Hz, 1H), 3.45-3.51 (m, 2H), 4.45-4.50 (m, 1H), 6.92 ( d, J = 9.1 Hz, 2H), 6.95 (d, J = 9.1 Hz, 1H), 7.11 (d, J = 9.1 Hz, 2H), 7.45 (dd, J = 9.1, 2.3 Hz, 1H), 7.65 ( d, J = 2.3 Hz, 1H), 8.81 (s, 1H).

ESI-MS: m/z = 498 (M+H) ⁺ .

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

The compound of Reference Example 81 (11.0 g, 22.1 mmol) was dissolved in dichloromethane (45.0 mL), and triethylamine (3.69 mL, 26.5 mmol) and acetonitrile (1.73 mL, 24.3 mmol) were added at 0 °C. After stirring at the same temperature for 2 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The title compound (hereinafter, the compound of Example 74) (11.2 g, 20.8 mmol, 94%) was obtained as white crystals. As a result of analysis using a palmar column, the obtained compound of Example 74 had a retention time of 19.1 minutes, at which time the optical purity was 99.8% ee. The analysis conditions using the palmar string were the same as in Example 46.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.58 (m, 2H), 1.71-1.78 (m, 2H), 1.89-2.10 (m, 5H), 2.21 (s, 3H), 2.25-2.29 ( m,1H),3.10-3.21(m,3H),3.44-3.50(m,2H), 3.75-3.78(m,1H),4.44-4.49(m,1H),5.25-5.26(m,1H), 6.91-6.93 (m, 3H), 7.11 (d, J = 8.6 Hz, 2H), 7.31 (dd, J = 8.6, 2.3 Hz, 1H), 7.64 (d, J = 2.3 Hz, 1H), 8.36 (s) , 1H).

ESI-MS: m/z = 540 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 75) (0.0615 g, 0.107 mmol, 82%) was obtained as a white solid. .

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.80 (m, 5H), 1.96-2.11 (m, 4H), 2.44-2.47 (m, 1H), 3.02 (s, 3H), 3.12-3.22 ( m,3H), 3.44-3.50 (m, 2H), 3.90-3.93 (m, 1H), 4.47-4.52 (m, 1H), 4.59-4.60 (m, 1H), 6.92 (d, J = 9.1 Hz, 2H), 6.96 (d, J = 9.1 Hz, 1H), 7.11 (d, J = 9.1 Hz, 2H), 7.32 (dd, J = 9.1, 2.7 Hz, 1H), 7.68 (d, J = 2.7 Hz, 1H), 8.09 (s, 1H).

ESI-MS: m/z = 576 (M+H) ⁺ .

(Reference 82) (R)-2-((3-Chloro-4-((1-(4-(difluoromethoxy)phenyl)piperidin-4-yl)oxy)phenyl)amine Synthesis of methylidene) piperidine-1-carboxylic acid tert-butyl butyl ester:

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) were dissolved in DMF (1.00 mL) HATU (0.111 g, 0.293 mmol) and diisopropylethylamine (0.0639 mL, 0.366 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 a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = EtOAc / EtOAc / EtOAc (EtOAc) M, 96%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.69 (m, 5H), 1.52 (s, 9H), 1.95-2.11 (m, 4H), 2.31-2.34 (m, 1H), 2.79-2.86 ( m,1H),3.08-3.13(m,2H),3.42-3.48(m,2H),4.06(brs,1H),4.44-4.49(m,1H),4.84-4.85(m,1H),6.42( t, J = 74.8 Hz, 1H), 6.91-6.95 (m, 3H), 7.04 (d, J = 9.1 Hz, 2H), 7.32 (dd, J = 8.6, 2.7 Hz, 1H), 7.62 (d, J) =2.7Hz, 1H).

ESI-MS: m/z = 580 (M+H) ⁺ .

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

The title compound (0.120 g, 0.207 mmol) was dissolved in ethyl acetate (1.03 mL). After stirring at room temperature for 2 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. %).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.48-1.68 (m, 4H), 1.82-1.85 (m, 1H), 1.94-2.10 (m, 5H), 2.79-2.86 (m, 1H), 3.07- 3.18 (m, 3H), 3.41-3.47 (m, 2H), 3.57-3.60 (m, 1H), 4.43-4.48 (m, 1H), 6.42 (t, J = 74.5 Hz, 1H), 6.91-6.93 ( m, 3H), 7.04 (d, J = 9.1 Hz, 2H), 7.44 (dd, J = 8.8, 2.7 Hz, 1H), 7.71 (d, J = 2.7 Hz, 1H), 9.27 (s, 1H).

ESI-MS: m/z = 480 (M+H) ⁺ .

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

The compound of Reference Example 83 (0.0400 g, 0.0833 mmol) was dissolved in dichloromethane (1.00 mL), and triethylamine (0.0174 mL, 0.125 mmol) and ethyl acetate (0.00711 mL, 0.100 mmol) were added at 0 °C. After stirring at the same temperature for 1 hour, methanol was added to the reaction solution, and concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc(EtOAc) , 89%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.89-2.10 (m, 5H), 2.21 (s, 3H), 2.26-2.29 ( m,1H),3.07-3.20(m,3H),3.42-3.48(m,2H),3.75-3.78(m,1H),4.43-4.48(m,1H),5.24-5.26(m,1H), 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, 1H), 8.33 (s, 1H).

ESI-MS: m/z = 522 (M+H) ⁺ .

(Example 77) (R)-1-(2-(1H-tetrazol-1-yl)ethenyl)-N-(3-chloro-4-((1-(4-(difluoromethoxy)) Synthesis of phenyl)piperidin-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), and HATU (0.0380 g) was added at room temperature. , 0.100 mmol) and diisopropylethylamine (0.0218 mL, 0.125 mmol). 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 a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc 71%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.57-1.80 (m, 3H), 1.83-1.91 (m, 2H), 1.94-2.02 (m, 2H), 2.03-2.10 (m, 2H), 2.23 2.27 (m, 1H), 3.08-3.13 (m, 2H), 3.41-3.47 (m, 2H), 3.50-3.57 (m, 1H), 3.70-3.74 (m, 1H), 4.44-4.49 (m, 1H) ), 5.14 - 5.15 (m, 1H), 5.39 (d, J = 16.5 Hz, 1H), 5.44 (d, J = 16.5 Hz, 1H), 6.42 (t, J = 74.6 Hz, 1H), 6.90 - 6.94 (m, 3H), 7.04 (d, J = 8.7 Hz, 2H), 7.20 (dd, J = 8.9, 2.7 Hz, 1H), 7.65 (d, J = 2.7 Hz, 1H), 7.94 (s, 1H) , 8.83 (s, 1H).

ESI-MS: m/z = 590 (M+H) ⁺ .

(Reference 84) Synthesis of 3-(2-chloro-4-nitrophenoxy)piperidine-1-carboxylic acid tert-butyl butyl ester:

3-Hydroxypiperidine-1-carboxylic acid tert-butyl ketone (0.378 g, 1.88 mmol) and sodium hydride (55 wt% mineral oil dispersion, 0.0889 g, 2.05 mmol) were suspended in DMF (1.71 mL) at 0 ° C After stirring 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 brine, dried over anhydrous sodium sulfate and filtered. The residue obtained was purified by silica gel column chromatography (hexane / ethyl acetate=90/10-75/25) to give the title compound (yield of compound of reference 84) (0.566 g, 1.59) M, 91%).

¹ H-NMR (400 MHz, CDCl ₃ , constitutive mixture) δ: 1.35 - 1.43 (brm, 9H), 1.56-1.59 (m, 1H), 1.95-2.05 (m, 3H), 3.50 - 3.79 ( Brm, 4H), 4.46-4.48 (m, 1H), 7.04 (brs, 1H), 8.15 (dd, J = 9.1, 2.7 Hz, 1H), 8.30 (s, 1H).

ESI-MS: m/z = 379 (M+Na) ⁺ .

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

The title compound (0.200 g, 0.561 mmol) was dissolved in ethyl acetate (1.40 mL). After stirring at the same temperature for 2 hours, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained crude product was used in the subsequent reaction without purification.

The above crude product was dissolved in toluene (1.00 mL), and iodobenzene (0.0650 mL, 0.584 mmol), palladium(II) acetate (0.0175 g, 0.0780 mmol), tris-tert-butylphosphino-4 Fluoroborate (0.0226 g, 0.0780 mmol) and tertiary sodium butoxide (0.112 g, 1.17 mmol). After stirring at 120 ° C for 1 hour, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) M, 49%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.71-1.86 (m, 2H), 1.98-2.03 (m, 1H), 2.22-2.25 (m, 1H), 2.89-2.96 (m, 1H), 3.06 ( Dd, J = 12.2, 8.6 Hz, 1H), 3.50-3.54 (m, 1H), 3.78-3.82 (m, 1H), 4.60-4.66 (m, 1H), 6.86-6.90 (m, 1H), 6.92 6.94 (m, 2H), 7.07 (d, J = 9.1 Hz, 1H), 7.25-7.29 (m, 2H), 8.15 (dd, J = 9.1, 2.7 Hz, 1H), 8.31 (d, J = 2.7 Hz) , 1H).

ESI-MS: m/z = 333 (M+H) ⁺ .

(Reference 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), and iron powder (0.0755 g, 1.35 mmol) and ammonium chloride (0.0723 g, 1.35 mmol) were added at room temperature. ). After stirring at 80 ° C for 4 hours, the reaction solution was filtered, and distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=90/10 to 70/30) to give the title compound as a pale yellow solid (hereinafter, the compound of reference 86) (0.0592g, 0.196) M, 72%).

^{1 H-NMR (400MHz, 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, 1H), 2.94 ( Dd, J = 11.8, 9.1 Hz, 1H), 3.45-3.49 (m, 1H), 3.53 (brs, 2H), 3.74 - 3.79 (m, 1H), 4.18 - 4.24 (m, 1H), 6.52 (dd, J=8.6, 2.7 Hz, 1H), 6.74 (d, J=2.7 Hz, 1H), 6.81-6.86 (m, 1H), 6.88 (d, J=8.6 Hz, 1H), 6.90-6.93 (m, 2H) ), 7.22-7.26 (m, 2H).

ESI-MS: m/z = 303 (M+H) ⁺ .

(Example 78) Synthesis of 1-ethenyl-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-ethylhydrazinopiperidine-2-carboxylic acid (0.0204 g, 0.119 mmol) were dissolved in DMF (1.00 mL) and HATU (0.0490 g, 0.129) Methyl) and diisopropylethylamine (0.0260 mL, 0.149 mmol). After stirring at the same temperature for 19 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) , 81%).

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, 1H), 2.21. s, 3H), 2.26-2.29 (m, 1H), 2.83-2.89 (m, 1H), 2.95 (dd, J = 11.8, 8.6 Hz, 1H), 3.12-3.20 (m, 1H), 3.47-3.51 ( m,1H), 3.75-3.80 (m, 2H), 4.32-4.39 (m, 1H), 5.25 (d, J = 5.4 Hz, 1H), 6.83-6.86 (m, 1H), 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, 1H).

ESI-MS: m/z = 456 (M+H) ⁺ .

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

The same procedure as in Reference Example 84 was carried out except that (S)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester was used instead of 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester. The title compound (hereinafter, the compound of Reference 87) (0.403 g, 1.13 mmol, 76%).

¹ H-NMR (400 MHz, CDCl ₃ , constitutive mixture) δ: 1.35 - 1.43 (brm, 9H), 1.55-1.57 (m, 1H), 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, 1H), 8.30 (brs, 1H).

ESI-MS: m/z = 379 (M+Na) ⁺ .

(Reference 88) Synthesis of (R)-3-(2-chloro-4-nitrophenoxy)piperidine-1-carboxylic acid tert-butyl butyl ester:

The same procedure as in Reference Example 84 was carried out except that the (R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester was used instead of the 3-hydroxypiperidine-1-carboxylic acid tert-butyl ester. The title compound (hereinafter, the compound of Reference Example 88) (0.307 g, 0.860 mmol, 58%).

¹ H-NMR (400 MHz, CDCl ₃ , constitutive mixture) δ: 1.35-1.43 (brm, 9H), 1.55-1.58 (m, 1H), 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, 1H), 8.30 (brs, 1H).

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) was obtained as a pale yellow solid. , 78%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.71-1.86 (m, 2H), 1.98-2.03 (m, 1H), 2.22-2.25 (m, 1H), 2.89-2.96 (m, 1H), 3.06 ( Dd, J = 12.2, 8.6 Hz, 1H), 3.49-3.54 (m, 1H), 3.78-3.82 (m, 1H), 4.59-4.66 (m, 1H), 6.86-6.90 (m, 1H), 6.92 6.94 (m, 2H), 7.07 (d, J = 9.1 Hz, 1H), 7.25-7.29 (m, 2H), 8.14 (dd, J = 9.1, 2.7 Hz, 1H), 8.31 (d, J = 2.7 Hz) , 1H).

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) was obtained as a pale yellow solid. , 86%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.71-1.86 (m, 2H), 1.98-2.03 (m, 1H), 2.22-2.25 (m, 1H), 2.89-2.96 (m, 1H), 3.06 ( Dd, J = 11.8, 8.6 Hz, 1H), 3.50-3.54 (m, 1H), 3.78-3.82 (m, 1H), 4.59-4.66 (m, 1H), 6.86-6.90 (m, 1H), 6.92 6.94 (m, 2H), 7.07 (d, J = 9.1 Hz, 1H), 7.24 - 7.29 (m, 2H), 8.15 (dd, J = 9.1, 2.7 Hz, 1H), 8.31 (d, J = 2.7 Hz) , 1H).

ESI-MS: m/z = 333 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 91) (0.260 g, 0.859 mmol) was obtained as a pale yellow solid. ,Quantitative).

^{1 H-NMR (400MHz, 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, 1H), 2.94 ( Dd, J = 12.0, 8.8 Hz, 1H), 3.45-3.49 (m, 1H), 3.52 (brs, 2H), 3.74 - 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, 1H), 6.81-6.86 (m, 1H), 6.87 (d, J=86 Hz, 1H), 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:

The title compound (hereinafter, the compound of Reference Example 92) (0.215 g, 0.710 mmol) as a pale yellow solid was obtained by the procedure of the the the ,Quantitative).

^{1 H-NMR (400MHz, 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, 1H), 2.94 ( Dd, J = 11.8, 9.1 Hz, 1H), 3.45-3.49 (m, 1H), 3.52 (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, 1H), 6.82-6.85 (m, 1H), 6.87 (d, J=8.6 Hz, 1H), 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)aminecarboxamido)piperidine- Synthesis of 1-carboxylic acid tert-butyl butyl ester:

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) were dissolved in DMF (1.10 mL) HATU (0.0817 g, 0.215 mmol) and diisopropylethylamine (0.0433 mL, 0.248 mmol) were added at room temperature. After stirring at the same temperature for 15 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=90/10-75/25) to give the title compound as a white solid (hereinafter, the compound of Reference Example 93) (0.0750g, 0.146mmol , 88%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.54 (m, 2H), 1.52 (s, 9H), 1.60-1.79 (m, 5H), 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, 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 = 8.6 Hz, 1H), 7.23 - 7.27 (m, 2H), 7.30 (dd, J = 8.6, 2.5 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H).

ESI-MS: m/z = 514 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 94) (0.0750 g, 0.146 mmol) was obtained as a white solid. 88%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.42-1.58 (m, 2H), 1.52 (s, 9H), 1.59-1.79 (m, 5H), 1.93-1.99 (m, 1H), 2.17-2.20 ( m, 1H), 2.32-2.35 (m, 1H), 2.79-2.89 (m, 2H), 2.96 (dd, J = 12.0, 8.8 Hz, 1H), 3.47-3.51 (m, 1H), 3.77-3.81 ( m, 1H), 4.06 (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, 1H), 7.22 - 7.27 (m, 2H), 7.29 (dd, J = 9.1, 2.7 Hz, 1H), 7.65 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 514 (M+H) ⁺ .

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

The title compound (0.0750 g, 0.146 mmol) was dissolved in ethyl acetate (EtOAc) After stirring at room temperature for 3 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. ).

¹ H-NMR (400MHz, 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, 1H), 1.93 1.98 (m, 1H), 2.00-2.05 (m, 1H), 2.17-2.20 (m, 1H), 2.72-2.79 (m, 1H), 2.83-2.89 (m, 1H), 2.96 (dd, J = 11.8) , 9.1 Hz, 1H), 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, 1H), 4.33 4.40 (m, 1H), 6.82-6.86 (m, 1H), 6.91-6.93 (m, 2H), 6.99 (d, J = 9.1 Hz, 1H), 7.23 - 7.27 (m, 2H), 7.42 (dd, J = 9.1, 2.7 Hz, 1H), 7.68 (d, J = 2.7 Hz, 1H), 8.81 (brs, 1H).

ESI-MS: m/z = 414 (M+H) ⁺ .

(Reference Example 96) (R)-N-(3-Chloro-4-(((R)-1-phenylpiperidin-3-yl)oxy)phenyl)piperidine-2-carboxamide) synthesis:

The title compound (hereinafter, the compound of Reference Example 96) (0.0551 g, 0.133 mmol) was obtained as a white solid. 91%).

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, 1H), 1.93 1.98 (m, 1H), 2.00-2.05 (m, 1H), 2.17-2.20 (m, 1H), 2.72-2.79 (m, 1H), 2.83-2.89 (m, 1H), 2.96 (dd, J = 11.8) , 9.1 Hz, 1H), 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, 1H), 4.33 4.40 (m, 1H), 6.82-6.86 (m, 1H), 6.91-6.93 (m, 2H), 6.99 (d, J = 9.1 Hz, 1H), 7.23 - 7.27 (m, 2H), 7.42 (dd, J = 8.6, 2.7 Hz, 1H), 7.68 (d, J = 2.7 Hz, 1H), 8.81 (brs, 1H).

ESI-MS: m/z = 414 (M+H) ⁺ .

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

The compound of Reference Example 95 (0.0250 g, 0.0604 mmol) was dissolved in dichloromethane (1.00 mL), and triethylamine (0.0126 mL, 0.0906 mmol) and acetonitrile (0.00515 mL, 0.725 mmol) were added at 0 °C. After stirring at the same temperature for 1 hour, methanol was added to the reaction solution, and concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) , 75%). As a result of analysis using a palmar column, the obtained compound of Example 79 was maintained for 39.5 minutes, and the optical purity at this time was 99.5% ee. The analytical conditions using a palm string are as follows.

Measuring machine: Shimadzu Corporation High Speed Liquid Chromatography LC-2010CHT

Pipe column: DAICEL CHEMICAL INDUSTRIES Co., Ltd. CHIRALCEL OD-RH 0.46cmφ×15cm particle size 5μm

Column temperature: 40 ° C

Mobile phase: (A liquid) distilled water, (B liquid) acetonitrile

The composition of the mobile phase: liquid A: liquid B = 50:50, and liquid is supplied for 60 minutes.

Flow rate: 0.5mL/min

Detection: UV (210nm)

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, 1H), 2.21. s, 3H), 2.26-2.29 (m, 1H), 2.83-2.89 (m, 1H), 2.95 (dd, J = 11.8, 8.8 Hz, 1H), 3.12-3.20 (m, 1H), 3.47-3.51 ( m,1H), 3.74-3.80 (m, 2H), 4.32-4.39 (m, 1H), 5.25 (d, J = 5.0 Hz, 1H), 6.83-6.86 (m, 1H), 6.91-6.93 (m, 2H), 6.97 (d, J = 8.8 Hz, 1H), 7.23 - 7.25 (m, 2H), 7.31 (dd, J = 8.8, 2.5 Hz, 1H), 7.64 (d, J = 2.5 Hz, 1H), 8.32 (brs, 1H).

ESI-MS: m/z = 456 (M+H) ⁺ .

(Example 80) (R)-1-Ethyl-N-(3-chloro-4-(((R)-1-phenylpiperidin-3-yl)oxy)phenyl)piperidine- Synthesis of 2-formamide:

The title compound (hereinafter, the compound of Example 80) (0.0258 g, 0.0566 mmol) was obtained as a white solid. 94%). As a result of analysis using a palmar column, the obtained compound of Example 80 had a retention time of 39.4 minutes, and the optical purity at this time was 99.5% ee. The analysis conditions using the palmar string were 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, 1H), 2.21. s, 3H), 2.26-2.29 (m, 1H), 2.83-2.89 (m, 1H), 2.95 (dd, J = 11.8, 8.6 Hz, 1H), 3.12-3.20 (m, 1H), 3.47-3.51 ( m,1H), 3.74-3.80 (m, 2H), 4.32-4.39 (m, 1H), 5.25 (d, J = 5.0 Hz, 1H), 6.83-6.86 (m, 1H), 6.91-6.93 (m, 2H), 6.97 (d, J = 9.1 Hz, 1H), 7.23 - 7.25 (m, 2H), 7.29 (dd, J = 9.1, 2.5 Hz, 1H), 7.65 (d, J = 2.5 Hz, 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) Synthesis of piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 81) (0.0341 g, 0.0693 mmol, 96%) was obtained as a white solid, m. .

¹ H-NMR (400MHz, 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, 1H), 2.44- 2.46 (m, 1H), 2.83-2.90 (m, 1H), 2.96 (dd, J = 11.8, 9.1 Hz, 1H), 3.02 (s, 3H), 3.15-3.23 (m, 1H), 3.48-3.52 ( m,1H), 3.77-3.81 (m, 1H), 3.89-3.93 (m, 1H), 4.35-4.42 (m, 1H), 4.58-4.61 (m, 1H), 6.84-6.86 (m, 1H), 6.91-6.93 (m, 2H), 7.00 (d, J = 9.1 Hz, 1H), 7.23 - 7.27 (m, 2H), 7.32 (dd, J = 9.1, 2.3 Hz, 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) Synthesis of piperidine-2-carboxamide:

The title compound was obtained as a white solid (yield, Example 82), using the compound of Compound) (0.0334 g, 0.0679 mmol, 94%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.50-1.61 (m, 2H), 1.63-1.80 (m, 5H), 1.93-2.00 (m, 1H), 2.17-2.20 (m, 1H), 2.44- 2.46 (m, 1H), 2.83-2.90 (m, 1H), 2.96 (dd, J = 11.8, 8.6 Hz, 1H), 3.02 (s, 3H), 3.16-3.23 (m, 1H), 3.48-3.52 ( m,1H), 3.77-3.81 (m,1H), 3.89-3.93 (m,1H), 4.35-4.42 (m,1H), 4.59-4.60 (m,1H), 6.84-6.86 (m,1H), 6.91-6.93 (m, 2H), 7.00 (d, J = 9.1 Hz, 1H), 7.23 - 7.27 (m, 2H), 7.32 (dd, J = 9.1, 2.7 Hz, 1H), 7.69 (d, J = 2.7 Hz, 1H), 8.10 (s, 1H).

ESI-MS: m/z = 492 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 83) (0.0416 g, 0.0739 mmol) was obtained as a white solid. Quantitative).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.48-1.97 (m, 8H), 2.16-2.21 (m, 1H), 2.30-2.37 (m, 1H), 2.80-2.88 (m, 1H), 2.95 ( Dd, J = 11.8, 8.9 Hz, 1H), 3.03 (s, 6H), 3.20-3.27 (m, 1H), 3.46-3.52 (m, 1H), 3.66-3.73 (m, 1H), 3.75-3.81 ( m,1H), 4.15 (d, J = 16.8 Hz, 1H), 4.23 (d, J = 16.8 Hz, 1H), 4.34 - 4.38 (m, 1H), 5.22 (d, J = 4.6 Hz, 1H), 6.84 (t, J = 7.3 Hz, 1H), 6.91-6.93 (m, 2H), 6.97 (d, J = 8.8 Hz, 1H), 7.22-7.30 (m, 3H), 7.67 (d, J = 2.7 Hz) , 1H), 8.00 (brs, 1H).

ESI-MS: m/z = 564 (M+H) ⁺ .

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

The compound of Reference Example 95 was used instead of the compound of Reference Example 64, and 2-(1H-tetrazol-1-yl)acetic acid was used 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.

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.59-1.80 (m, 5H), 1.87-1.98 (m, 3H), 2.16-2.19 (m, 1H), 2.24 - 2.28 (m, 1H), 2.83 2.90 (m, 1H), 2.96 (dd, J = 11.8, 8.6 Hz, 1H), 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=16.8Hz,1H), 5.45(d,J=16.8Hz,1H),6.83-6.87(m,1H),6.91-6.93(m,2H),6.97 (d, J = 9.1 Hz, 1H), 7.22 - 7.26 (m, 3H), 7.65 (d, J = 2.7 Hz, 1H), 7.88 (s, 1H), 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 ester:

(S)-3-Hydroxypyrrolidine-1-carboxylic acid tert-butyl butyl ester (0.336 g, 1.79 mmol) and sodium hydride (55 wt% mineral oil dispersion, 0.0821 g, 1.88 mmol) were suspended in DMF (1.71 mL) After 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 brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) , 91%).

^{1 H-NMR (400MHz, DMSO} -D 6) δ: 1.40 (s, 9H), 2.10-2.21 (m, 2H), 3.33-3.37 (m, 1H), 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, 1H), 8.34 (d, J = 2.7 Hz, 1H) ).

ESI-MS: m/z = 365 (M+Na) ⁺ .

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

The title compound (0.200 g, 0.618 mmol) was dissolved in ethyl acetate (l. After stirring at the same temperature for 1 hour, a saturated aqueous solution of sodium hydrogencarbonate was added to the mixture, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered and evaporated. The obtained crude product was used in the subsequent reaction without purification.

The above crude product was dissolved in toluene (1.55 mL), and iodobenzene (0.103 mL, 0.927 mmol), palladium(II) acetate (0.0278 g, 0.124 mmol), tris-tert-butylphosphino-4 Fluoroborate (0.0360 g, 0.124 mmol) and tertiary sodium butoxide (0.178 g, 1.85 mmol). After stirring at 110 ° C for 1 hour, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) , 77%).

¹ H-NMR (400 MHz, DMSO-D ₆ ) δ: 2.22 - 2.26 (m, 1H), 2.37 - 2.46 (m, 1H), 3.38 - 3.42 (m, 3H), 3.74 (dd, J = 11.6, 4.8 Hz, 1H), 5.45-5.48 (m, 1H), 6.57-6.59 (m, 2H), 6.61-6.65 (m, 1H), 7.15-7.19 (m, 2H), 7.50 (d, J = 9.1 Hz, 1H), 8.25 (dd, J = 9.1, 2.7 Hz, 1H), 8.33 (d, J = 2.7 Hz, 1H).

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), and 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, and distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=90/10 to 70/30) to afford the title compound ( 0.436 mmol, 93%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.16-2.25 (m, 1H), 2.31-2.38 (m, 1H), 3.43 (ddd, J = 8.6, 8.6, 3.2 Hz, 1H), 3.50-3.63 ( m, 5H), 4.90-4.94 (m, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H), 6.57-6.60 (m, 2H), 6.67-6.71 (m, 1H), 6.73 (d, J = 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H), 7.22 - 7.26 (m, 2H).

ESI-MS: m/z = 289 (M+H) ⁺ .

(Reference Example 100) (R)-2-((3-Chloro-4-((S)-1-phenylpyrrolidin-3-yl)oxy)phenyl)aminecarboxamido)piperidine- Synthesis of 1-carboxylic acid tert-butyl butyl ester:

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) were dissolved in DMF (1.04 mL) HATU (0.103 g, 0.270 mmol) and diisopropylethylamine (0.0544 mL, 0.312 mmol) were added at room temperature. After stirring at the same temperature for 15 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate=90/10-75/25) to give the title compound as a white solid (hereinafter, the compound of Reference Example 100) (0.0865g, 0.173mmol) , 83%).

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, 1H), 4.07 (brs, 1H), 4.84 - 4.85 (m, 1H), 5.01-5.05 (m, 1H), 6.58-6.60 (m, 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, 1H), 7.59 (d, J = 2.3 Hz, 1H), 8.14 (brs, 1H).

ESI-MS: m/z = 500 (M+H) ⁺ .

(Reference 101) (R)-N-(3-Chloro-4-((())-1-phenylpyrrolidin-3-yl)oxy)phenyl)piperidine-2-carboxamide synthesis:

The compound of Reference Example 100 (0.0800 g, 0.160 mmol) was dissolved in ethyl acetate (yield: EtOAc, EtOAc) After stirring at room temperature for 1 hour, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. ).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.42-1.61 (m, 4H), 1.79-1.83 (m, 1H), 2.00-2.05 (m, 1H), 2.22-2.39 (m, 2H), 2.72- 2.79 (m, 1H), 3.03-3.08 (m, 1H), 3.34 (dd, J = 9.5, 3.2 Hz, 1H), 3.46 (ddd, J = 8.6, 8.6, 3.2 Hz, 1H), 3.50-3.59 ( m, 2H), 3.69 (dd, J = 10.9, 5.0 Hz, 1H), 5.02-5.05 (m, 1H), 6.58-6.60 (m, 2H), 6.68-6.72 (m, 1H), 6.91 (d, J = 8.6 Hz, 1H), 7.22 - 7.26 (m, 2H), 7.48 (dd, J = 8.6, 2.3 Hz, 1H), 7.62 (d, J = 2.3 Hz, 1H), 8.80 (s, 1H).

ESI-MS: m/z = 400 (M+H) ⁺ .

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

The compound of Reference Example 101 (0.0250 g, 0.0625 mmol) was dissolved in dichloromethane (1.00 mL), and triethylamine (0.0131 mL, 0.0938 mmol) and acetonitrile chloride (0.00533 mL, 0.0750 mmol) were added at 0 °C. After stirring at the same temperature for 1 hour, methanol was added to the reaction solution, and concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) , 98%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.89-2.01 (m, 1H), 2.21 (s, 3H), 2.23 - 2.38 ( m, 3H), 3.12-3.20 (m, 1H), 3.43-3.59 (m, 3H), 3.68 (dd, J = 10.9, 5.0 Hz, 1H), 3.75-3.78 (m, 1H), 5.01-5.04 ( m,1H), 5.25 (d, J = 5.4 Hz, 1H), 6.57-6.59 (m, 2H), 6.68-6.72 (m, 1H), 6.89 (d, J = 8.6 Hz, 1H), 7.22-7.26 (m, 2H), 7.35 (dd, J = 8.6, 2.7 Hz, 1H), 7.59 (d, J = 2.7 Hz, 1H), 8.33 (s, 1H).

ESI-MS: m/z = 442 (M+H) ⁺ .

(Example 86) (R)-N-(3-Chloro-4-((())-1-phenylpyrrolidin-3-yl)oxy)phenyl)-1-(2-(N-) Synthesis of methylmethylsulfonamide) ethionyl) piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 86) (0.0352 g, 0.0641 mmol) was obtained as a white solid. 63%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.56-1.75 (m, 5H), 2.24 - 2.34 (m, 3H), 3.03 (s, 3H), 3.03 (s, 3H), 3.20-3.27 (m, 1H), 3.43-3.59 (m, 3H), 3.65-3.73 (m, 2H), 4.14 (d, J = 16.8 Hz, 1H), 4.24 (d, J = 16.8 Hz, 1H), 5.00-5.05 (m) , 1H), 5.19-5.24 (m, 1H), 6.57-6.59 (m, 2H), 6.68-6.72 (m, 1H), 6.89 (d, J = 8.8 Hz, 1H), 7.22 - 7.34 (m, 3H) ), 7.63 (d, J = 2.4 Hz, 1H), 8.00 (s, 1H).

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). After stirring at the same temperature for 3 hours, the reaction mixture was evaporated. mjjjjjjjjjj

^{1 H-NMR (400MHz, DMSO} -d 6) δ: 2.16-2.22 (m, 1H), 2.25-2.34 (m, 1H), 3.23-3.31 (m, 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, 1H), 8.25 (dd, J = 9.1, 2.7 Hz, 1H), 8.37 (d, J = 2.7 Hz, 1H), 9.27 (brs, 2H).

ESI-MS: m/z = 243 (M+H) ⁺ .

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

Reference compound 102 (0.200 g, 0.717 mmol), palladium (II) acetate (0.0322 g, 0.143 mmol), tris-tert-butylphosphinotetrafluoroborate (0.0416 g, 0.143 mmol) and tertiary Sodium alkoxide (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 obtained crude product was used in the subsequent reaction without purification.

The above crude product was dissolved in THF (3.12 mL), ethanol (6.18 mL) and distilled water (3.12 mL), and iron powder (0.160 g, 2.87 mmol) and ammonium chloride (0.384 g, 7.17 mmol) were added at room temperature. . After stirring at 70 ° C for 2 hours, the reaction solution was filtered, and distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=90/10 to 70/30) to give the title compound as a yellow solid (hereinafter, the compound of Reference Example 103) (0.0370g, 0.121mmol) , 17%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.12 - 2.21 (m, 1H), 2.26 - 2.31 (m, 1H), 3.44 - 3.51 (m, 3H), 3.55 - 3.59 (m, 1H), 3. 3.69 (m, 1H), 3.82 (ddd, J = 11.6, 5.2, 3.2 Hz, 1H), 4.85-4.89 (m, 1H), 6.53 (dd, J = 8.8, 2.8 Hz, 1H), 6.66-6.71 ( m, 2H), 6.73 (d, J = 2.8 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.95-7.02 (m, 2H).

ESI-MS: m/z = 307 (M+H) ⁺ .

(Reference 104) (R)-2-((3-Chloro-4-((S)-1-(2-fluorophenyl)pyrrolidin-3-yl)oxy)phenyl)aminecarboxamide Synthesis of benzylidene piperidine-1-carboxylic acid tert-butyl butyl ester:

The title compound (hereinafter, the compound of Reference Example 104) (0.0512 g, 0.0988 mmol) was obtained as a white solid. 82%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.42-1.54 (m, 11H), 1.59-1.69 (m, 3H), 2.18-2.34 (m, 3H), 2.78-2.86 (m, 1H), 3.46- 3.50 (m, 1H), 3.56 (brd, J = 11.6 Hz, 1H), 3.60-3.67 (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, 1H), 4.96-5.00 (m, 1H), 6.67-6.74 (m, 2H), 6.89 (d, J = 8.8 Hz, 1H), 6.96-7.03 (m, 2H) , 7.33 (dd, J = 8.8, 2.8 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 8.12 (brs, 1H).

ESI-MS: m/z = 518 (M+H) ⁺ .

(Example 87) (R)-1-Ethyl-N-(3-chloro-4-((S)-1-(2-fluorophenyl)pyrrolidin-3-yl)oxy)benzene Synthesis of piperidine-2-carboxamide:

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. After stirring at room temperature for 2 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained crude product was used in 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 anhydrous acetic acid (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 residue was purified by EtOAc EtOAc EtOAc (EtOAc) , 83%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.60 (m, 2H), 1.70-1.78 (m, 2H), 1.87-1.99 (m, 1H), 2.20 (s, 3H), 2.21-2.31 ( m, 3H), 3.19 (ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 3.45-3.50 (m, 1H), 3.55 (brd, J = 11.6 Hz, 1H), 3.60-3.66 (m, 1H) , 3.76 (brd, J = 13.2 Hz, 1H), 3.89 (ddd, J = 11.6, 4.8, 3.2 Hz, 1H), 4.95 - 4.98 (m, 1H), 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 = 8.8, 2.4 Hz, 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 was obtained as a pale yellow oil (yield: Reference Example 105), except that 1-bromo-3- fluorobenzene was used instead of 1-fluoro-2-iodobenzene. Compound) (0.176 g, 0.574 mmol, 80%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15-2.24 (m, 1H), 2.32 - 2.39 (m, 1H), 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, 1H), 6.32 (dd, J = 8.8, 2.4, 0.8 Hz, 1H), 6.37 (dddd, J=8.4, 8.4, 2.4, 0.8 Hz, 1H), 6.53 (dd, J=8.4, 2.8 Hz, 1H), 6.73 (d, J=2.8 Hz, 1H), 6.80 (d, J=8.4 Hz, 1H) ), 7.15 (ddd, J = 8.8, 8.4, 7.6 Hz, 1H).

ESI-MS: m/z = 307 (M+H) ⁺ .

(Reference Example 106) (R)-2-((3-Chloro-4-((S)-1-(3-fluorophenyl)pyrrolidin-3-yl)oxy)phenyl)aminecarboxamide Synthesis of benzylidene piperidine-1-carboxylic acid tert-butyl butyl ester:

The title compound (hereinafter, the compound of Reference Example 106) (0.254 g, 0.490 mmol,) was obtained as a white solid. 88%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.44-1.69 (m, 14H), 2.21-2.39 (m, 3H), 2.79-2.86 (m, 1H), 3.44 (ddd, J = 8.8, 8.8, 2.8 Hz, 1H), 3.50 (brd, J = 11.2 Hz, 1H), 3.56 (ddd, J = 9.2, 9.2, 6.8 Hz, 1H), 3.65 (dd, J = 9.2, 5.2 Hz, 1H), 4.02-4.10 (m, 1H), 4.84-4.86 (m, 1H), 5.01-5.05 (m, 1H), 6.26 (ddd, J = 12.4, 2.4, 2.4 Hz, 1H), 6.33 (ddd, J = 8.4, 2.4, 0.8Hz, 1H), 6.38 (dddd, J=8.4, 8.4, 2.4, 0.8Hz, 1H), 6.91 (d, J=8.8Hz, 1H), 7.15 (ddd, J=8.4, 8.4, 6.8Hz, 1H) ), 7.36 (dd, J = 8.8, 2.4 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 8.15 (brs, 1H).

ESI-MS: m/z = 518 (M+H) ⁺ .

(Example 88) (R)-1-Ethyl-N-(3-chloro-4-((S)-1-(3-fluorophenyl)pyrrolidin-3-yl)oxy)benzene Synthesis of piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 88) (0.202 g, 0.439 mmol) was obtained as a white solid. 90%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.62 (m, 2H), 1.72-1.78 (m, 2H), 1.90-2.01 (m, 1H), 2.21 (s, 3H), 2.24 - 2.29 ( m, 2H), 2.33-2.39 (m, 1H), 3.16 (ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 3.43 (ddd, J = 8.8, 8.8, 3.2 Hz, 1H), 3.49 (brd, J = 10.8 Hz, 1H), 3.56 (ddd, J = 9.2, 9.2, 6.8 Hz, 1H), 3.64 (dd, J = 10.8, 4.8 Hz, 1H), 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, 2.4 Hz, 1H), 6.32 (dd, J = 8.4, 2.0 Hz, 1H) , 6.38 (ddd, J = 8.4, 8.4, 2.0 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 7.15 (ddd, J = 8.4, 8.4, 7.2 Hz, 1H), 7.35 (dd, J =8.8, 2.4 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 8.35 (brs, 1H).

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 was obtained as a pale yellow oil (yield: Reference Example 107), except that 1-fluoro-4-iodobenzene was used instead of 1-fluoro-2-iodobenzene. Compound) (0.0900 g, 0.293 mmol, 71%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.16-2.25 (m, 1H), 2.31-2.37 (m, 1H), 3.38 (ddd, J = 8.5, 8.5, 3.2 Hz, 1H), 3.44 - 3.47 ( m, 1H), 3.50-3.54 (m, 3H), 3.58 (dd, J = 10.5, 4.9 Hz, 1H), 4.89 - 4.92 (m, 1H), 6.49 (dd, J = 9.0, 4.4 Hz, 2H) , 6.53 (dd, J = 8.5, 2.9 Hz, 1H), 6.73 (d, J = 2.9 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 6.92-6.97 (m, 2H).

ESI-MS: m/z = 307 (M+H) ⁺ .

(Reference 108) (R)-2-((3-Chloro-4-((S)-1-(4-fluorophenyl)pyrrolidin-3-yl)oxy)phenyl)aminecarboxamide Synthesis of benzylidene piperidine-1-carboxylic acid tert-butyl butyl ester:

The title compound (hereinafter, the compound of Reference Example 108) (0.150 g, 0.290 mmol) was obtained as a pale yellow solid. , 99%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.52-1.74 (m, 5H), 1.52 (s, 9H), 2.20-2.40 (m, 3H), 2.80-2.86 (m, 1H), 3.40 (ddd, J = 8.4, 8.4, 3.3 Hz, 1H), 3.44 - 3.47 (m, 1H), 3.49 - 3.55 (m, 1H), 3.66 (dd, J = 10.6, 5.0 Hz, 1H), 4.00 - 4.13 (m, 1H), 4.84-4.85 (m, 1H), 5.01-5.04 (m, 1H), 6.49 (dd, J = 9.0, 4.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 6.93-6.97 (m, 2H), 7.34 (dd, J = 8.8, 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H).

ESI-MS: m/z = 519 (M+H) ⁺ .

(Example 89) (R)-1-Ethyl-N-(3-chloro-4-((S)-1-(4-fluorophenyl)pyrrolidin-3-yl)oxy)benzene Synthesis of piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 89) (0.113 g, 0.246 mmol) was obtained as a white solid. 85%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.87-1.98 (m, 1H), 2.20 (s, 3H), 2.22-2.36 ( m, 3H), 3.20 (ddd, J = 13.1, 13.1, 2.6 Hz, 1H), 3.39 (ddd, J = 8.4, 8.4, 3.4 Hz, 1H), 3.43 - 3.46 (m, 1H), 3.48-3.55 ( m,1H), 3.65 (dd, J=10.6, 5.0 Hz, 1H), 3.74-3.78 (m, 1H), 4.99-5.02 (m, 1H), 5.24-5.26 (m, 1H), 6.49 (dd, J=9.0, 4.1 Hz, 2H), 6.87 (d, J=8.8 Hz, 1H), 6.92-6.97 (m, 2H), 7.33 (dd, J=8.8, 2.7 Hz, 1H), 7.60 (d, J) =2.7 Hz, 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, reference compound 109) was obtained as a yellow oil. ) (0.0200 g, 0.0619 mmol, 15%).

^{1 H-NMR (400MHz, 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, 1H), 6.72 (d, J=2.8 Hz, 1H), 6.78 (d, J) = 8.7 Hz, 1H), 6.79-6.84 (m, 1H), 6.95 (dd, J = 8.3, 1.2 Hz, 1H), 7.14 - 7.18 (m, 1H), 7.30 (dd, J = 8.0, 1.5 Hz, 1H).

ESI-MS: m/z = 324 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 110) (0.0250 g, 0.0468 mmol) was obtained as a white solid. 76%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.47-1.69 (m, 5H), 1.51 (s, 9H), 2.25-2.33 (m, 3H), 2.79-2.85 (m, 1H), 3.40-3.45 ( m, 2H), 3.59-3.65 (m, 1H), 4.03 (dd, J = 11.2, 5.4 Hz, 1H), 4.06 (brs, 1H), 4.83-4.85 (m, 1H), 4.96-5.00 (m, 1H), 6.81-6.86 (m, 1H), 6.88 (d, J = 8.8 Hz, 1H), 6.96 (dd, J = 8.0, 1.5 Hz, 1H), 7.15-7.19 (m, 1H), 7.28-7.33 (m, 2H), 7.60 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 535 (M+H) ⁺ .

(Example 90) (R)-1-Ethyl-N-(3-chloro-4-((S)-1-(2-chlorophenyl)pyrrolidin-3-yl)oxy)benzene Synthesis of piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 90) (0.0178 g, 0.0373 mmol) was obtained as a white solid. 80%).

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, 3H), 2.24 - 2.29 ( m,3H),3.12-3.19(m,1H),3.41-3.44(m,2H),3.59-3.65(m,1H),3.74-3.77(m,1H),4.02(dd,J=11.0,5.4 Hz, 1H), 4.95-4.99 (m, 1H), 5.24-5.25 (m, 1H), 6.81-6.83 (m, 1H), 6.86 (d, J = 9.0 Hz, 1H), 6.95-6.97 (m, 1H), 7.15-7.19 (m, 1H), 7.29-7.34 (m, 2H), 7.60 (d, J = 2.4 Hz, 1H), 8.31 (s, 1H).

ESI-MS: m/z = 477 (M+H) ⁺ .

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

The title compound was obtained as a yellow oil (yield, the compound of Reference Example 111), except that 1-chloro-3-iodobenzene was used instead of 1-fluoro-2-iodobenzene. ) (0.0400 g, 0.124 mmol, 30%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.14 - 2.23 (m, 1H), 2.33 - 2.38 (m, 1H), 3.38 - 3.43 (m, 1H), 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, 1H), 6.79 (d, J = 8.5 Hz, 1H), 7.10-7.14 (m, 1H).

ESI-MS: m/z = 324 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 112) (0.0550 g, 0.103 mmol) was obtained as a pale yellow solid. , 83%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.69 (m, 5H), 1.45 (s, 9H), 2.20-2.39 (m, 3H), 2.81-2.87 (m, 1H), 3.41-3.59 ( m,3H), 3.64 (dd, J=11.0, 4.9 Hz, 1H), 4.06 (brs, 1H), 4.84-4.85 (m, 1H), 5.01-5.03 (m, 1H), 6.44 (dd, J = 8.3, 2.0 Hz, 1H), 6.53-6.54 (m, 1H), 6.64-6.67 (m, 1H), 6.90 (d, J = 8.8 Hz, 1H), 7.11-7.15 (m, 1H), 7.34 (dd , J = 8.8, 2.7 Hz, 1H), 7.60 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 535 (M+H) ⁺ .

(Example 91) (R)-1-Ethyl-N-(3-chloro-4-((S)-1-(3-chlorophenyl)pyrrolidin-3-yl)oxy)benzene Synthesis of piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 91) (0.0400 g, 0.0840 mmol) as a pale yellow solid was obtained by the same procedure as the compound of , 81%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.58 (m, 2H), 1.70-1.78 (m, 2H), 1.90-1.97 (m, 1H), 2.21 (s, 3H), 2.22-2.29 ( m, 2H), 2.33 - 2.38 (m, 1H), 3.13 - 3.20 (m, 1H), 3.41-3.46 (m, 1H), 3.47-3.50 (m, 1H), 3.52-3.58 (m, 1H), 3.63 (dd, J = 10.9, 4.8 Hz, 1H), 3.75-3.78 (m, 1H), 5.01-5.03 (m, 1H), 5.24-5.26 (m, 1H), 6.42-6.45 (m, 1H), 6.53-6.54 (m, 1H), 6.64-6.67 (m, 1H), 6.88 (d, J = 8.8 Hz, 1H), 7.11-7.14 (m, 1H), 7.35 (dd, J = 8.8, 2.6 Hz, 1H), 7.60 (d, J = 2.6 Hz, 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:

The title compound (hereinafter, the compound of Reference Example 113) was obtained as a pale yellow solid by the procedure of the same procedure. (2.00 g, 6.19 mmol, 43%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15-2.24 (m, 1H), 2.32 - 2.37 (m, 1H), 3.37 - 3.58 (m, 6H), 4.89 - 4.92 (m, 1H), 6.48 ( d, J = 9.0 Hz, 2H), 6.53 (dd, J = 8.5, 2.8 Hz, 1H), 6.72 (d, J = 2.8 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 7.16 ( d, J = 9.0 Hz, 2H).

ESI-MS: m/z = 323 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 114) (3.25 g, 6.08 mmol) was obtained as a pale yellow solid. , 98%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.45-1.67 (m, 5H), 1.52 (s, 9H), 2.21-2.38 (m, 3H), 2.83-2.89 (m, 1H), 3.39-3.56 ( m,3H), 3.63 (dd, J = 10.7, 4.9 Hz, 1H), 4.06 (brs, 1H), 4.84-4.86 (m, 1H), 5.00-5.03 (m, 1H), 6.48 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 1H), 7.17 (d, J = 8.8 Hz, 2H), 7.31 (dd, J = 8.8, 2.2 Hz, 1H), 7.60 (d, J = 2.2Hz, 1H), 8.25 (brs, 1H).

ESI-MS: m/z = 534 (M+H) ⁺ .

(Example 92) (R)-1-Ethyl-N-(3-chloro-4-((S)-1-(4-chlorophenyl)pyrrolidin-3-yl)oxy)benzene Synthesis of piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 92) (2.40 g, 5.04 mmol) was obtained as a pale yellow solid. , 83%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.62 (m, 2H), 1.70-1.78 (m, 2H), 1.85-1.95 (m, 1H), 2.18 (s, 3H), 2.21-2.37 ( m, 3H), 3.19-3.26 (m, 1H), 3.38-3.56 (m, 3H), 3.63 (dd, J = 10.7, 4.9 Hz, 1H), 3.74-3.78 (m, 1H), 4.99-5.02 ( m, 1H), 5.25 (d, J = 4.9 Hz, 1H), 6.47 (d, J = 9.0 Hz, 2H), 6.86 (d, J = 8.8 Hz, 1H), 7.16 (d, J = 9.0 Hz, 2H), 7.32 (dd, J = 8.8, 2.5 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 8.48 (s, 1H).

ESI-MS: m/z = 476 (M+H) ⁺ .

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

The title compound was obtained as a pale yellow solid (yield: Reference Example 115). Compound) (0.0570 g, 0.179 mmol, 43%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.15-2.24 (m, 1H), 2.31-2.36 (m, 1H), 3.39-3.45 (m, 1H), 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, 1H), 6.26-6.29 (m, 1H), 6.52 (dd, J = 8.6, 2.7 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H), 6.79 (d, J = 8.6 Hz, 1H), 7.12 - 7.16 (m, 1H).

ESI-MS: m/z = 319 (M+H) ⁺ .

(Reference 116) (R)-2-((3-Chloro-4-(((S)-1-(3-methoxyphenyl)pyrrolidin-3-yl)oxy)phenyl)amine) Synthesis of methylidene) piperidine-1-carboxylic acid tert-butyl butyl ester:

The title compound (hereinafter, the compound of Reference Example 116) (0.0500 g, 0.151 mmol) was obtained as a white solid. 96%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.40-1.52 (m, 2H), 1.52 (s, 9H), 1.53-1.69 (m, 3H), 2.21-2.37 (m, 3H), 2.81-2.87 ( m,1H), 3.44 (ddd, J=8.6, 8.6, 3.2 Hz, 1H), 3.48-3.51 (m, 1H), 3.52-3.58 (m, 1H), 3.67 (dd, J = 10.9, 5.0 Hz, 1H), 3.80 (s, 3H), 4.06 (brs, 1H), 4.84-4.85 (m, 1H), 5.00-5.03 (m, 1H), 6.12-6.13 (m, 1H), 6.21 (dd, J = 8.0, 2.0 Hz, 1H), 6.28 (dd, J = 7.9, 2.3 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 7.12-7.16 (m, 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-Ethyl-N-(3-chloro-4-((S)-1-(3-methoxyphenyl)pyrrolidin-3-yl)oxy Synthesis of phenyl) piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 93) (0.0460 g, 0.0975 mmol) as a pale yellow solid was obtained by the same procedure as the compound of , 65%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.63 (m, 2H), 1.71-1.78 (m, 2H), 1.87-1.99 (m, 1H), 2.20 (s, 3H), 2.23 - 2.36 ( m, 3H), 3.15-3.23 (m, 1H), 3.41-3.47 (m, 1H), 3.47-3.50 (m, 1H), 3.52-3.58 (m, 1H), 3.66 (dd, J = 10.9, 5.0 Hz, 1H), 3.74-3.78 (m, 1H), 3.80 (s, 3H), 4.99-5.02 (m, 1H), 5.24-5.26 (m, 1H), 6.11-6.13 (m, 1H), 6.20 ( Dd, J = 8.2, 1.8 Hz, 1H), 6.28 (dd, J = 8.2, 2.3 Hz, 1H), 6.87 (d, J = 9.1 Hz, 1H), 7.14 (dd, J = 8.2, 8.2 Hz, 1H) ), 7.33 (dd, J = 9.1, 2.3 Hz, 1H), 7.59 (d, J = 2.3 Hz, 1H), 8.40 (s, 1H).

ESI-MS: m/z = 472 (M+H) ⁺ .

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

The title compound was obtained as a pale-yellow solid (yield of Reference Example 117). Compound) (0.0570 g, 0.179 mmol, 43%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.19-2.27 (m, 1H), 2.29-2.34 (m, 1H), 3.34-3.39 (m, 1H), 3.43-3.54 (m, 4H), 3.59 ( Dd, J = 10.5, 5.1 Hz, 1H), 3.76 (s, 3H), 4.89 - 4.91 (m, 1H), 6.51-6.56 (m, 3H), 6.73 (d, J = 2.7 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 9.0 Hz, 2H).

ESI-MS: m/z = 319 (M+H) ⁺ .

(Reference 118) (R)-2-((3-Chloro-4-(((S)-1-(4-methoxyphenyl)pyrrolidin-3-yl)oxy)phenyl)amine) Synthesis of methylidene) piperidine-1-carboxylic acid tert-butyl butyl ester:

The title compound (hereinafter, the compound of Reference Example 118) (0.0800 g, 0.151 mmol) was obtained as a white solid. 96%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.43-1.51 (m, 2H), 1.51 (s, 9H), 1.54-1.69 (m, 3H), 2.26-2.32 (m, 3H), 2.81-2.88 ( m, 1H), 3.36-3.41 (m, 1H), 3.42-3.45 (m, 1H), 3.47-3.53 (m, 1H), 3.67 (dd, J = 10.6, 5.2 Hz, 1H), 3.76 (s, 3H), 4.05 (brs, 1H), 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, 2H) ), 6.88 (d, J = 9.0 Hz, 1H), 7.32 (dd, J = 9.0, 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H).

ESI-MS: m/z = 531 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 94) (0.0530 g, 0.112 mmol) was obtained as a white solid. 74%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.61 (m, 2H), 1.71-1.77 (m, 2H), 1.89-1.95 (m, 1H), 2.20 (s, 3H), 2.25-2.32 ( m, 3H), 3.14-3.22 (m, 1H), 3.36-3.41 (m, 1H), 3.42-3.45 (m, 1H), 3.46-3.53 (m, 1H), 3.66 (dd, J = 10.6, 5.2 Hz, 1H), 3.74-3.78 (m, 1H), 3.76 (s, 3H), 4.99-5.01 (m, 1H), 5.24-5.26 (m, 1H), 6.55 (d, J = 9.0 Hz, 2H) , 6.84-6.88 (m, 3H), 7.33 (dd, J = 8.9, 2.7 Hz, 1H), 7.59 (d, J = 2.7 Hz, 1H), 8.37 (s, 1H).

ESI-MS: m/z = 472 (M+H) ⁺ .

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

The title compound was obtained as a yellow oil (yield from Reference Example 119). Compound) (0.150 g, 0.495 mmol, 69%).

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, 1H), 3.33 (dd, J = 10.8, 2.8 Hz, 1H), 3.47-3.53 (m, 3H), 3.59 (dd, J = 10.8, 5.6 Hz, 1H), 4.84-4.89 (m, 1H), 6.52 (dd, J = 8.8, 2.8 Hz , 1H), 6.74 (d, J = 2.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.87 (ddd, J = 7.2, 7.2, 0.8 Hz, 1H), 6.94 (dd, J = 8.8, 0.8 Hz, 1H), 7.11-7.15 (m, 2H).

ESI-MS: m/z = 303 (M+H) ⁺ .

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

The title compound (hereinafter, referred to as the compound of Reference Example 120) (0.212 g, 0.412 mmol) was obtained as a white solid. 83%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.43-1.73 (m, 14H), 2.20-2.25 (m, 1H), 2.28-2.35 (m, 5H), 2.78-2.86 (m, 1H), 3.23 ( Ddd, J = 8.8, 7.6, 4.4 Hz, 1H), 3.34 (dd, J = 10.8, 2.8 Hz, 1H), 3.47 (ddd, J = 9.6, 8.0, 8.0 Hz, 1H), 3.63 (dd, J = 10.8, 5.6 Hz, 1H), 4.04-4.10 (m, 1H), 4.83-4.85 (m, 1H), 4.94-4.99 (m, 1H), 6.86-6.91 (m, 2H), 6.95 (dd, J = 8.8, 1.6 Hz, 1H), 7.12-7.15 (m, 2H), 7.33 (dd, J = 9.2, 2.8 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 8.10 (brs, 1H).

ESI-MS: m/z = 514 (M+H) ⁺ .

(Example 95) (R)-1-Ethyl-N-(3-chloro-4-((S)-1-(o-tolyl)pyrrolidin-3-yl)oxy)phenyl) Synthesis of piperidine-2-carbamide:

The title compound (hereinafter, the compound of Example 95) (0.185 g, 0.406 mmol) was obtained as a white solid. 98%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.51-1.62 (m, 2H), 1.70-1.79 (m, 2H), 1.89-1.98 (m, 1H), 2.18-2.33 (m, 9H), 3.15 ( Ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 3.22 (ddd, J = 8.4, 7.2, 4.4 Hz, 1H), 3.33 (dd, J = 10.8, 2.8 Hz, 1H), 3.47 (ddd, J = 8.8, 7.6, 7.6 Hz, 1H), 3.62 (dd, J = 10.8, 6.0 Hz, 1H), 3.73-3.79 (m, 1H), 4.94-4.98 (m, 1H), 5.24-5.26 (m, 1H) , 6.84-6.90 (m, 2H), 6.94 (dd, J = 8.8, 1.2 Hz, 1H), 7.12 - 7.15 (m, 2H), 7.32 (dd, J = 8.8, 2.8 Hz, 1H), 7.60 (d , J = 2.8 Hz, 1H), 8.29 (brs, 1H).

ESI-MS: m/z = 456 (M+H) ⁺ .

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

The title compound was obtained as a yellow oil (yield from Reference Example 121), except that 1-bromo-3-methylbenzene was used instead of 1-fluoro-2-iodobenzene. Compound) (0.100 g, 0.330 mmol, 46%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.20 (ddd, J = 13.6, 8.8, 5.2 Hz, 1H), 2.30-2.36 (m, 4H), 3.42 (ddd, J = 8.8, 8.8, 3.2 Hz, 1H), 3.48-3.52 (m, 3H), 3.56 (dd, J = 9.2, 2.0 Hz, 1H), 3.60 (dd, J = 11.2, 5.2 Hz, 1H), 4.89 - 4.93 (m, 1H), 6.40 -6.41 (m, 2H), 6.51-6.55 (m, 2H), 6.73 (d, J = 2.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 7.13 (dd, J = 8.8, 8.0 Hz, 1H).

ESI-MS: m/z = 303 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 122) (0.151 g, 0.294 mmol) was obtained as a white solid. 89%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.35-1.69 (m, 14H), 2.23 - 2.38 (m, 6H), 2.82 (ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 3.42-3.58 ( m,3H), 3.68 (dd, J = 10.8, 5.2 Hz, 1H), 4.04-4.08 (m, 1H), 4.84-4.86 (m, 1H), 5.01-5.04 (m, 1H), 6.40-6.41 ( m, 2H), 6.53 (d, J = 7.7 Hz, 1H), 6.90 (d, J = 8.8 Hz, 1H), 7.13 (dd, J = 8.6, 7.7 Hz, 1H), 7.36 (dd, J = 8.8 , 2.8 Hz, 1H), 7.58 (d, J = 2.8 Hz, 1H), 8.16 (brs, 1H).

ESI-MS: m/z = 514 (M+H) ⁺ .

(Example 96) (R)-1-Ethyl-N-(3-chloro-4-((())-1-(m-tolyl)pyrrolidin-3-yl)oxy)phenyl) Synthesis of piperidine-2-carbamide:

The title compound (hereinafter, the compound of Example 96) was obtained as a white solid (0.119 g, 0.261 mmol, m. 89%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.51-1.57 (m, 2H), 1.70-1.79 (m, 2H), 1.90-1.98 (m, 1H), 2.21 (s, 3H), 2.23 - 2.37 ( m,6H), 3.16 (ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 3.42-3.58 (m, 3H), 3.65-3.70 (m, 1H), 3.74-3.79 (m, 1H), 5.00- 5.04 (m, 1H), 5.25 (brd, J = 4.8 Hz, 1H), 6.40-6.41 (m, 2H), 6.53 (dd, J = 7.6, 0.8 Hz, 1H), 6.89 (d, J = 8.8 Hz) , 1H), 7.13 (dd, J = 8.8, 7.6 Hz, 1H), 7.35 (dd, J = 8.8, 2.8 Hz, 1H), 7.59 (d, J = 2.8 Hz, 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 was obtained as a yellow oil (yield from Reference Example 123), except that 1-bromo-4-methylbenzene was used instead of 1-fluoro-2-iodobenzene. Compound) (0.160 g, 0.528 mmol, 74%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.16-2.24 (m, 1H), 2.25 (s, 3H), 2.29-2.35 (m, 1H), 3.39 (ddd, J = 8.8, 8.8, 3.6 Hz, 1H), 3.46-3.56 (m, 4H), 3.59 (dd, J = 10.4, 5.2 Hz, 1H), 4.89-4.93 (m, 1H), 6.49-6.54 (m, 3H), 6.73 (d, J = 2.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 8.0 Hz, 2H).

ESI-MS: m/z = 303 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 124) (0.129 g, 0.251 mmol) was obtained as a white solid. 48%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.42-1.71 (m, 14H), 2.25-2.37 (m, 6H), 2.78-2.86 (m, 1H), 3.42 (ddd, J = 8.8,8.8,3.6 Hz, 1H), 3.47 (brd, J = 11.8 Hz, 1H), 3.52 (ddd, J = 8.8, 8.8, 7.2 Hz, 1H), 3.67 (dd, J = 10.8, 5.2 Hz, 1H), 4.04-4.09 (m, 1H), 4.84-4.85 (m, 1H), 5.00-5.04 (m, 1H), 6.51 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.8 Hz, 1H), 7.05 ( d, J = 8.4 Hz, 2H), 7.35 (dd, J = 8.8, 2.4 Hz, 1H), 7.58 (d, J = 2.4 Hz, 1H), 8.12 (brs, 1H).

ESI-MS: m/z = 514 (M+H) ⁺ .

(Example 97) (R)-1-Ethyl-N-(3-chloro-4-((S)-1-(p-tolyl)pyrrolidin-3-yl)oxy)phenyl) Synthesis of piperidine-2-carbamide:

The title compound (hereinafter, the compound of Example 97) (0.107 g, 0.235 mmol) was obtained as a white solid. 93%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.60 (m, 2H), 1.71-1.78 (m, 2H), 1.89-1.97 (m, 1H), 2.21 (s, 3H), 2.25-2.37 ( m, 6H), 3.18 (ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 3.39-3.55 (m, 3H), 3.67 (dd, J = 10.8, 5.2 Hz, 1H), 3.76 (brd, J = 13.2 Hz, 1H), 4.99-5.03 (m, 1H), 5.25 (brd, J = 5.2 Hz, 1H), 6.51 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 1H) , 7.05 (d, J = 8.8 Hz, 2H), 7.34 (dd, J = 8.8, 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 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:

The title compound was obtained as a yellow oil (yield, m.p.). Reference compound of Example 125) (0.0796 g, 0.223 mmol, 31%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.13 - 2.21 (m, 1H), 2.24 - 2.30 (m, 1H), 3.35 (ddd, J = 8.8, 8.8, 3.6 Hz, 1H), 3.42 (brd, J = 10.8 Hz, 1H), 3.51 (brs, 2H), 3.67 (ddd, J = 9.6, 9.6, 6.8 Hz, 1H), 3.76 (dd, J = 11.6, 5.2 Hz, 1H), 4.85 - 4.89 (m) , 1H), 6.52 (dd, J = 8.8, 2.8 Hz, 1H), 6.73 (d, J = 2.8 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 6.93 (dd, J = 8.0, 8.0 Hz, 1H), 7.12 (d, J = 8.0 Hz, 1H), 7.41 (ddd, J = 8.0, 8.0, 2.0 Hz, 1H), 7.58 (dd, J = 8.0, 1.6 Hz, 1H).

ESI-MS: m/z = 357 (M+H) ⁺ .

(Reference 126) (R)-2-((3-Chloro-4-((S)-1-(2-(trifluoromethyl)phenyl)pyrrolidin-3-yl)oxy)benzene) Synthesis of 3-aminobutyl carbamic acid piperidine-1-carboxylic acid:

The title compound (hereinafter, the compound of Reference Example 126) (0.124 g, 0.218 mmol) was obtained as a white solid. 97%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.69 (m, 14H), 2.22 - 2.34 (m, 3H), 2.82 (ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 3.36 (ddd, J = 9.6, 6.8, 3.6 Hz, 1H), 3.41 (brd, J = 11.2 Hz, 1H), 3.60-3.66 (m, 1H), 3.82 (dd, J = 10.8, 5.2 Hz, 1H), 4.03-4.08 (m, 1H), 4.83-4.85 (m, 1H), 4.96-5.00 (m, 1H), 6.88 (d, J = 9.2 Hz, 1H), 6.96 (dd, J = 8.0, 7.2 Hz, 1H), 7.15 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 9.2, 2.8 Hz, 1H), 7.40-7.44 (m, 1H), 7.59 (dd, J = 8.0, 1.6 Hz, 1H), 7.62 (d, J = 2.8 Hz, 1H), 8.14 (brs, 1H).

ESI-MS: m/z = 568 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 98) (0.0990 g, 0.194 mmol) was obtained as a white solid. 89%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.57 (m, 2H), 1.70-1.78 (m, 2H), 1.90-1.98 (m, 1H), 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, 1H), 6.96 (dd, J = 8.0, 7.6 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H), 7.32 (dd, J = 9.2, 2.8 Hz) , 1H), 7.40-7.44 (m, 1H), 7.58 (dd, J = 8.0, 1.6 Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H), 8.30 (brs, 1H).

ESI-MS: m/z = 510 (M+H) ⁺ .

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

The title compound was obtained as a yellow oil (yield, m.p. Reference compound 127 (0.154 g, 0.432 mmol, 60%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.16-2.25 (m, 1H), 2.35-2.42 (m, 1H), 3.46 (ddd, J = 8.4, 8.4, 3.2 Hz, 1H), 3.52-3.56 ( m, 3H), 3.58-3.65 (m, 2H), 4.92-4.95 (m, 1H), 6.54 (dd, J = 8.8, 2.8 Hz, 1H), 6.70 (J = 8.0, 2.4 Hz, 1H), 6.73 -6.75 (m, 2H), 6.81 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 8.0 Hz, 1H), 7.30 (dd, J = 8.0, 8.0 Hz, 1H).

ESI-MS: m/z = 357 (M+H) ⁺ .

(Reference Example 128) (R)-2-((3-Chloro-4-((S)-1-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)oxy)benzene) Synthesis of 3-aminobutyl carbamic acid piperidine-1-carboxylic acid:

The title compound (hereinafter, the compound of Reference Example 128) (0.230 g, 0.405 mmol) was obtained as a white solid. 94%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.44-1.71 (m, 14H), 2.23 - 2.42 (m, 3H), 2.82 (ddd, J = 13.2, 13.2, 2.4 Hz, 1H), 3.49 (ddd, J = 8.8, 8.8, 2.8 Hz, 1H), 3.54 (brd, J = 10.8 Hz, 1H), 3.61 (ddd, J = 9.2, 9.2, 6.8 Hz, 1H), 3.69 (dd, J = 10.8, 4.8 Hz) , 1H), 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, 1H) ), 6.91-6.93 (m, 2H), 7.31 (dd, J = 8.4, 7.6 Hz, 1H) 7.37 (dd, J = 8.8, 2.8 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 8.16 (brs, 1H).

ESI-MS: m/z = 568 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 99) (0.0920 g, 0.180 mmol) was obtained as a white solid. 89%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.61 (m, 2H), 1.71-1.79 (m, 2H), 1.90-2.02 (m, 1H), 2.21 (s, 3H), 2.23 - 2.31 ( m, 2H), 2.36-2.42 (m, 1H), 3.15 (ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 3.49 (ddd, J = 8.8, 8.8, 2.8 Hz, 1H), 3.53 (brd, J = 10.8 Hz, 1H), 3.60 (ddd, J = 9.2, 9.2, 6.8 Hz, 1H), 3.68 (dd, J = 10.8, 5.2 Hz, 1H), 3.74 - 3.79 (m, 1H), 5.03-5.07 (m, 1H), 5.25 (brd, J = 5.2 Hz, 1H), 6.70 (dd, J = 8.8, 2.8 Hz, 1H), 6.74 (brs, 1H), 6.89-6.93 (m, 2H), 7.29- 7.33 (m, 1H), 7.36 (dd, J = 8.8, 2.8 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 8.34 (brs, 1H).

ESI-MS: m/z = 532 (M+Na) ⁺ .

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

The title compound was obtained as a yellow oil (yield, m.p.). Reference compound 129) (0.0300 g, 0.0841 mmol, 20%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15-2.24 (m, 1H), 2.36-2.41 (m, 1H), 3.45-3.66 (m, 6H), 4.91-4.95 (m, 1H), 6. Dd, J = 8.5, 2.9 Hz, 1H), 6.57 (d, J = 8.8 Hz, 2H), 6.73 (d, J = 2.9 Hz, 1H), 6.80 (d, J = 8.5 Hz, 1H), 7.45 ( d, J = 8.8 Hz, 2H).

ESI-MS: m/z = 357 (M+H) ⁺ .

(Reference Example 130) (R)-2-((3-Chloro-4-((S)-1-(4-(trifluoromethyl)phenyl)pyrrolidin-3-yl)oxy)benzene) Synthesis of 3-aminobutyl carbamic acid piperidine-1-carboxylic acid:

The title compound (hereinafter, the compound of Reference Example 130) (0.0300 g, 0.0528 mmol,) was obtained as a white solid. 63%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.69 (m, 5H), 1.51 (s, 9H), 2.21-2.42 (m, 3H), 2.81-2.88 (m, 1H), 3.47-3.69 ( m, 4H), 4.06 (brs, 1H), 4.85-4.85 (m, 1H), 5.03-5.06 (m, 1H), 6.57 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 9.0 Hz) , 1H), 7.34 (dd, J = 9.0, 2.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H).

ESI-MS: m/z = 568 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 100) (0.0250 g, 0.0490 mmol) as a pale yellow solid was obtained by the same procedure as the compound of , 92%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.89-1.96 (m, 1H), 2.21 (s, 3H), 2.23-2.30 ( m, 2H), 2.36-2.41 (m, 1H), 3.13-3.20 (m, 1H), 3.47-3.52 (m, 1H), 3.53-3.56 (m, 1H), 3.58-3.69 (m, 2H), 3.75-3.78 (m, 1H), 5.03-5.05 (m, 1H), 5.24-5.25 (m, 1H), 6.57 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 1H) , 7.35 (dd, J = 8.8, 2.4 Hz, 1H), 7.45 (d, J = 8.8 Hz, 2H), 7.60 (d, J = 2.4 Hz, 1H), 8.39 (s, 1H).

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:

The title compound was obtained as a yellow oil (yield: m. , the compound of Reference Example 131) (0.0814 g, 0.218 mmol, 4.6%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.09-2.18 (m, 1H), 2.26-2.32 (m, 1H), 3.42-3.54 (m, 4H), 3.69 (ddd, J=9.2, 9.2, 6.8 Hz, 1H), 3.82 (dd, J = 10.8, 4.8 Hz, 1H), 4.85-4.88 (m, 1H), 6.52 (dd, J = 8.8, 2.8 Hz, 1H), 6.71-6.75 (m, 2H) , 6.77-6.80 (m, 2H), 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) Synthesis of phenyl)aminomethane) piperidine-1-carboxylic acid tert-butyl ester:

The title compound (hereinafter, the compound of Reference Example 132) (0.125 g, 0.214 mmol) was obtained as a white solid. 98%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.43-1.72 (m, 14H), 2.15-2.24 (m, 1H), 2.27-2.34 (m, 2H), 2.78-2.85 (m, 1H), 3.46 ( Ddd, J = 8.4, 8.4, 2.8 Hz, 1H), 3.52 (brd, J = 11.2 Hz, 1H), 3.67 (ddd, J = 9.2, 9.2, 6.4 Hz, 1H), 3.89 (dd, J = 11.2, 4.8 Hz, 1H), 4.03-4.08 (m, 1H), 4.83-4.85 (m, 1H), 4.96-5.00 (m, 1H), 6.73-6.80 (m, 2H), 6.90 (d, J = 8.8 Hz) , 1H), 7.14 - 7.17 (m, 2H), 7.33 (dd, J = 8.8, 2.8 Hz, 1H), 7.60 (d, J = 2.8 Hz, 1H), 8.14 (brs, 1H).

ESI-MS: m/z = 584 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 101) (0.101 g, 0.192 mmol) was obtained as a white solid. 88%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.60 (m, 2H), 1.71-1.77 (m, 2H), 1.89-1.99 (m, 1H), 2, 15-2, 31 (m, 6H) ), 3.15 (ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 3.46 (ddd, J = 8.8, 8.8, 2.8 Hz, 1H), 3.51 (brd, J = 11.2 Hz, 1H), 3.66 (ddd, J = 9.6, 9.6, 6.4 Hz, 1H), 3.73 - 3.79 (m, 1H), 3.89 (dd, J = 11.2, 5.2 Hz, 1H), 4.96 - 4.99 (m, 1H), 5.24 - 5.25 (m, 1H), 6.75 (dd, J = 8.4, 7.2 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.8 Hz, 1H), 7.13-7.17 (m, 2H), 7.33 (dd, J = 8.8, 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 8.31 (brs, 1H).

ESI-MS: m/z = 526 (M+H) ⁺ .

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

The title compound was obtained as a yellow oil (yield: m. , the compound of Reference Example 133) (0.108 g, 0.290 mmol, 40%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15-2.24 (m, 1H), 2.33-2.40 (m, 1H), 3.43 (ddd, J = 9.2, 9.2, 3.2 Hz, 1H), 3.49-3.61 ( m, 5H), 4.90-4.94 (m, 1H), 6.37 (brs, 1H), 6.47 (dd, J = 8.0, 2.4 Hz, 1H), 6.52-6.55 (m, 2H), 6.73 (d, J = 2.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 7.20 (dd, J = 8.0, 8.0 Hz, 1H).

ESI-MS: m/z = 373 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 134) (0.166 g, 0.284 mmol) was obtained as a white solid. 98%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.43-1.72 (m, 14H), 2.21-2.40 (m, 3H), 2.78-2.86 (m, 1H), 3.45 (ddd, J = 8.8, 8.8, 2.8 Hz, 1H), 3.51 (brd, J = 10.8 Hz, 1H), 3.57 (ddd, J = 9.2, 9.2, 6.8 Hz, 1H), 3.66 (dd, J = 10.8, 4.8 Hz, 1H), 4.03-4.10 (m, 1H), 4.84-4.86 (m, 1H), 5.02-5.05 (m, 1H), 6.37 (brs, 1H), 6.47 (dd, J = 8.4, 2.4 Hz, 1H), 6.54 (brd, J = 8.4 Hz, 1H), 6.91 (d, J = 9.2 Hz, 1H), 7.20 (dd, J = 8.4, 8.4 Hz, 1H), 7.36 (dd, J = 9.2, 2.8 Hz, 1H), 7.60 (d) , J = 2.8 Hz, 1H), 8.15 (brs, 1H).

ESI-MS: m/z = 606 (M+Na) ⁺ .

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

The title compound (hereinafter, the compound of Example 102) (0.139 g, 0.264 mmol) was obtained as a white solid. 93%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.51-1.59 (m, 2H), 1.71-1.79 (m, 2H), 1.89-1.98 (m, 1H), 2.21 (s, 3H), 2.29-2.31 ( m, 2H), 2.34-2.40 (m, 1H), 3.15 (ddd, J = 13.2, 13.2, 3.2 Hz, 1H), 3.45 (ddd, J = 8.8, 8.8, 3.2 Hz, 1H), 3.50 (brd, J = 10.8 Hz, 1H), 3.57 (ddd, J = 8.8, 8.8, 6.8 Hz, 1H), 3.65 (dd, J = 10.8, 5.2 Hz, 1H), 3.74 - 3.80 (m, 1H), 5.01-5.05 (m, 1H), 5.25 (brd, J = 5.6 Hz, 1H), 6.37 (brs, 1H), 6.47 (dd, J = 8.4, 2.4 Hz, 1H), 6.54 (brd, J = 8.4 Hz, 1H) , 6.89 (d, J = 8.8 Hz, 1H), 7.20 (dd, J = 8.4, 8.4 Hz, 1H), 7.36 (dd, J = 8.8, 2.4 Hz, 1H), 7.60 (d, J = 2.4 Hz, 1H), 8.34 (brs, 1H).

ESI-MS: m/z = 526 (M+H) ⁺ .

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

The title compound was obtained as a yellow oil (yield: m. , the compound of Reference Example 135) (0.0950 g, 0.255 mmol, 62%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.15-2.24 (m, 1H), 2.33 - 2.38 (m, 1H), 3.41 (ddd, J = 8.6, 8.6, 2.9 Hz, 1H), 3.48-3.60 ( m, 5H), 4.91-4.93 (m, 1H), 6.51 (d, J = 9.1 Hz, 2H), 6.53 - 6.55 (m, 1H), 6.73 (d, J = 2.7 Hz, 1H), 6.80 (d , J = 8.6 Hz, 1H), 7.09 (d, J = 9.1 Hz, 2H).

ESI-MS: m/z = 373 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 136) (0.130 g, 0.223 mmol) was obtained as a white solid. 92%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.43-1.48 (m, 2H), 1.52 (s, 9H), 1.56-1.69 (m, 3H), 2.21-2.39 (m, 3H), 2.82-2.89 ( m, 1H), 3.44 (ddd, J=8.6, 8.6, 2.9 Hz, 1H), 3.49 (d, J = 10.9 Hz, 1H), 3.53-3.59 (m, 1H), 3.66 (dd, J = 10.9, 5.0 Hz, 1H), 4.07 (brs, 1H), 4.85-4.86 (m, 1H), 5.01-5.04 (m, 1H), 6.51 (d, J = 9.1 Hz, 2H), 6.89 (d, J = 9.1) Hz, 1H), 7.09 (d, J = 9.1 Hz, 2H), 7.32 (dd, J = 9.1, 2.3 Hz, 1H), 7.61 (d, J = 2.3 Hz, 1H).

ESI-MS: m/z = 584 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 103) (0.0650 g, 0.124 mmol) as a pale yellow solid was obtained by the same procedure as the compound of , 56%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.65 (m, 2H), 1.71-1.78 (m, 2H), 1.88-1.98 (m, 1H), 2.20 (s, 3H), 2.23-2.29 ( m, 2H), 2.33 - 2.38 (m, 1H), 3.16-3.23 (m, 1H), 3.43 (ddd, J = 8.6, 8.6, 2.9 Hz, 1H), 3.47-3.50 (m, 1H), 3.52- 3.59 (m, 1H), 3.65 (dd, J = 10.7, 4.9 Hz, 1H), 3.74 - 3.78 (m, 1H), 5.01-5.03 (m, 1H), 5.24 - 5.26 (m, 1H), 6.51 ( d, J = 9.0 Hz, 2H), 6.87 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 9.0 Hz, 2H), 7.33 (dd, J = 8.8, 2.4 Hz, 1H), 7.60 ( d, J = 2.4 Hz, 1H), 8.43 (s, 1H).

ESI-MS: m/z = 526 (M+H) ⁺ .

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

The title compound was obtained as a pale yellow solid (m. Compound 137) (0.0080 g, 0.024 mmol, 6%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.14 - 2.23 (m, 1H), 2.32 (s, 3H), 2.32 - 2.36 (m, 1H), 3.38 (ddd, J = 8.7, 8.7, 3.0 Hz, 1H), 3.45-3.47 (m, 1H), 3.50-3.58 (m, 4H), 4.89-4.91 (m, 1H), 6.34 (dd, J = 8.8, 2.7 Hz, 1H), 6.41 (d, J = 2.7 Hz, 1H), 6.53 (dd, J = 8.5, 2.7 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H), 6.79 (d, J = 8.5 Hz, 1H), 7.15 (d, J = 8.8Hz, 1H).

ESI-MS: m/z = 337 (M+H) ⁺ .

(Reference 138) (R)-2-((3-Chloro-4-((S)-1-(4-chloro-3-methylphenyl)pyrrolidin-3-yl)oxy)benzene Synthesis of 3-aminobutyl carbamic acid piperidine-1-carboxylic acid:

The title compound (hereinafter, the compound of Reference Example 138) (0.0110 g, 0.0201 mmol) was obtained as a white solid. 85%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.43-1.69 (m, 5H), 1.51 (s, 9H), 2.21-2.38 (m, 3H), 2.32 (s, 3H), 2.81-2.87 (m, 1H), 3.41 (ddd, J = 8.6, 8.6, 3.1 Hz, 1H), 3.44 - 3.47 (m, 1H), 3.52 (ddd, J = 8.9, 8.9, 7.0 Hz, 1H), 3.63 (dd, J = 10.9, 5.0 Hz, 1H), 4.06 (brs, 1H), 4.84-4.85 (m, 1H), 5.00-5.03 (m, 1H), 6.34 (dd, J = 8.8, 2.9 Hz, 1H), 6.42 (d , J = 2.9 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 7.34 (dd, J = 8.8, 2.4 Hz, 1H), 7.59 (d , J = 2.4Hz, 1H).

ESI-MS: m/z = 548 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 104) (0.0070 g, 0.014 mmol) as a pale yellow solid was obtained by the same procedure as the compound of , 71%).

^{1 H-NMR (400MHz, 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, 3H), 2.20 ( s, 3H), 2.32 (s, 3H), 3.15-3.22 (m, 1H), 3.38-3.55 (m, 3H), 3.63 (dd, J = 10.9, 5.0 Hz, 1H), 3.74-3.78 (m, 1H), 5.00-5.02 (m, 1H), 5.24-5.26 (m, 1H), 6.34 (dd, J = 8.7, 2.8 Hz, 1H), 6.41 (d, J = 2.8 Hz, 1H), 6.87 (d , J = 8.6 Hz, 1H), 7.15 (d, J = 8.7 Hz, 1H), 7.34 (dd, J = 8.6, 2.4 Hz, 1H), 7.59 (d, J = 2.4 Hz, 1H), 8.39 (s) , 1H).

ESI-MS: m/z = 491 (M+H) ⁺ .

(Reference 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) was obtained as a yellow solid. M, 16%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.14 - 2.23 (m, 1H), 2.34 - 2.39 (m, 1H), 3.53 (brs, 2H), 3.60-3.65 (m, 1H), 3.67-3.73 ( m, 2H), 3.76-3.79 (m, 1H), 4.89-4.92 (m, 1H), 6.38 (d, J = 8.5 Hz, 1H), 6.50-6.56 (m, 2H), 6.71 (d, J = 2.7 Hz, 1H), 6.81 (d, J = 8.5 Hz, 1H), 7.44 (ddd, J = 8.5, 7.1, 2.0 Hz, 1H), 8.16 (dd, J = 5.0, 2.0 Hz, 1H).

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)aminecarboxamide Synthesis of benzylidene piperidine-1-carboxylic acid tert-butyl butyl ester:

The title compound (hereinafter, the compound of Reference Example 140) (0.0350 g, 0.0699 mmol) as a pale yellow solid was obtained by the same procedure as the the the ,Quantitative).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.45-1.69 (m, 5H), 1.51 (s, 9H), 2.21-2.42 (m, 3H), 2.82-2.85 (m, 1H), 3.62-3.73 ( m, 2H), 3.78 (d, J = 3.2 Hz, 2H), 4.07 (brs, 1H), 4.84 - 4.85 (m, 1H), 5.01-5.04 (m, 1H), 6.39 (d, J = 8.5 Hz) , 1H), 6.55 (dd, J = 7.1, 5.0 Hz, 1H), 6.92 (d, J = 8.8 Hz, 1H), 7.32 (dd, J = 8.8, 2.7 Hz, 1H), 7.45 (ddd, J = 8.5, 7.1, 2.0 Hz, 1H), 7.61 (d, J = 2.7 Hz, 1H), 8.02 (brs, 1H), 8.16 (dd, J = 5.0, 2.0 Hz, 1H).

ESI-MS: m/z = 501 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 105) (0.0250 g, 0.0564 mmol) as a pale yellow solid was obtained by the same procedure as the compound of , 86%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.67 (m, 2H), 1.70-1.78 (m, 2H), 1.89-1.98 (m, 1H), 2.21 (s, 3H), 2.22-2.29 ( m, 2H), 2.35-2.41 (m, 1H), 3.13-3.20 (m, 1H), 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=8.5Hz, 1H), 6.55 (dd, J=7.1, 5.4Hz, 1H), 6.90 (d, J=8.8Hz, 1H), 7.32 (dd , J = 8.8, 2.7 Hz, 1H), 7.45 (ddd, J = 8.5, 7.1, 2.0 Hz, 1H), 7.61 (d, J = 2.7 Hz, 1H), 8.16 (dd, J = 5.4, 2.0 Hz, 1H), 8.33 (s, 1H).

ESI-MS: m/z = 443 (M+H) ⁺ .

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

The title compound was obtained as a yellow oil (yield, the compound of Reference Example 141) was obtained by the procedure of the same procedure as the above. ) (0.0250 g, 0.0771 mmol, 19%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.14 - 2.23 (m, 1H), 2.34 - 2.41 (m, 1H), 3.53 (brs, 2H), 3.57 - 3.62 (m, 1H), 3.63 - 3.71 ( m, 2H), 3.74-3.77 (m, 1H), 4.89-4.91 (m, 1H), 6.32 (d, J = 9.0 Hz, 1H), 6.53 (dd, J = 8.7, 2.8 Hz, 1H), 6.72 (d, J = 2.8 Hz, 1H), 6.81 (d, J = 8.7 Hz, 1H), 7.39 (dd, J = 9.0, 2.7 Hz, 1H), 8.08 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 324 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 142) (0.0390 g, 0.0728 mmol) was obtained as a white solid. 95%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.69 (m, 5H), 1.52 (s, 9H), 2.20-2.41 (m, 3H), 2.79-2.86 (m, 1H), 3.59-3.78 ( m, 4H), 4.05 (brs, 1H), 4.84-4.85 (m, 1H), 5.00-5.03 (m, 1H), 6.33 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 9.0 Hz) , 1H), 7.32 (dd, J = 9.0, 2.0 Hz, 1H), 7.40 (dd, J = 8.8, 2.4 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 8.08 (d, J = 2.4Hz, 1H).

ESI-MS: m/z = 536 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 106) (0.0170 g, 0.0356 mmol) was obtained as a white solid. 49%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.61 (m, 2H), 1.70-1.78 (m, 2H), 1.87-1.98 (m, 1H), 2.19-2.28 (m, 2H), 2.20 ( s, 3H), 2.35-2.40 (m, 1H), 3.16-3.24 (m, 1H), 3.58-3.78 (m, 5H), 4.99-5.02 (m, 1H), 5.24-5.26 (m, 1H), 6.32 (d, J = 9.0 Hz, 1H), 6.88 (d, J = 8.9 Hz, 1H), 7.31 (dd, J = 8.9, 2.6 Hz, 1H), 7.39 (dd, J = 9.0, 2.6 Hz, 1H) ), 7.61 (d, J = 2.6 Hz, 1H), 8.08 (d, J = 2.6 Hz, 1H), 8.43 (brs, 1H).

ESI-MS: m/z = 477 (M+H) ⁺ .

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

Reference compound 102 (0.250 g, 0.896 mmol), palladium (II) acetate (0.0402 g, 0.179 mmol), tris-tert-butylphosphinotetrafluoroborate (0.0520 g, 0.179 mmo) and tertiary butyl Sodium alkoxide (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 (yield: hexane/ethyl acetate=100/0~85/15) to give the title compound as a yellow solid (the compound of reference 143 below) (0.202g, 0.582mmol) , 65%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.28 (s, 6H), 2.34 - 2.41 (m, 2H), 3.48-3.58 (m, 3H), 3.80 (dd, J = 10.9, 5.0 Hz, 1H) , 5.17-5.20 (m, 1H), 6.24 (s, 2H), 6.41 (s, 1H), 7.00 (d, J = 9.1 Hz, 1H), 8.17 (dd, J = 9.1, 2.7 Hz, 1H), 8.30 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 347 (M+H) ⁺ .

(Reference 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) was 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) were added at room temperature. mL, 5.82 mmol). After stirring at 70 ° C for 1 hour, the reaction solution was filtered, and distilled water was added to the filtrate, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 100/0 to 70/30) to give the title compound ( 0.436 mmol, 75%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.14 - 2.23 (m, 1H), 2.27 (s, 6H), 2.29-2.35 (m, 1H), 3.41 (ddd, J = 8.6, 8.6, 3.5 Hz, 1H), 3.49-3.54 (m, 4H), 3.59 (dd, J = 10.6, 5.2 Hz, 1H), 4.88-4.92 (m, 1H), 6.22 (s, 2H), 6.37 (s, 1H), 6.53 (dd, J = 8.6, 2.7 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H).

ESI-MS: m/z = 317 (M+H) ⁺ .

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

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) were dissolved in DMF (4.36 mL) HATU (0.199 g, 0.523 mmol) and diisopropylethylamine (0.0990 mL, 0.566 mmol) were added at room temperature. After stirring at the same temperature for 19 hours, distilled water was added to the reaction solution, and the aqueous layer was extracted with diethyl ether. The organic layer was washed with a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The obtained residue was purified by EtOAc EtOAc EtOAc (EtOAc(EtOAc) , 91%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.42-1.72 (m, 14H), 2.20-2.37 (m, 9H), 2.82 (ddd, J = 13.6, 11.8, 1.4 Hz, 1H), 3.46-3.52 ( m,3H), 3.67 (dd, J = 10.9, 5.0 Hz, 1H), 4.04-4.09 (m, 1H), 4.84-4.85 (m, 1H), 5.00-5.04 (m, 1H), 6.23 (s, 2H), 6.38 (s, 1H), 6.90 (d, J = 9.1 Hz, 1H), 7.36 (dd, J = 9.1, 2.7 Hz, 1H), 7.57 (d, J = 2.7 Hz, 1H), 8.13 ( Brs, 1H).

ESI-MS: m/z = 528 (M+H) ⁺ .

(Reference 146) (R)-N-(3-Chloro-4-(((S)-1-(3,5-dimethylphenyl)pyrrolidin-3-yl)oxy)phenyl) Synthesis of piperidine-2-carbamide:

The compound of Reference Example 145 (0.210 g, 0.398 mmol) was dissolved in dichloromethane (3.98mL), and trifluoroacetic acid (0.994mL, 12.9mmol) was added at 0 °C. After stirring at room temperature for 1.5 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. ).

¹ H-NMR (400MHz, 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, 8H), 2.72 2.79 (m, 1H), 3.06 (ddd, J = 12.2, 4.3, 3.4 Hz, 1H), 3.34 (dd, J = 9.5, 3.6 Hz, 1H), 3.41-3.57 (m, 3H), 3.67 (dd, J = 10.9, 5.0 Hz, 1H), 5.00-5.04 (m, 1H), 6.23 (s, 2H), 6.38 (s, 1H), 6.91 (d, J = 9.1 Hz, 1H), 7.49 (dd, J = 9.1, 2.7 Hz, 1H), 7.61 (d, J = 2.7 Hz, 1H), 8.80 (s, 1H).

ESI-MS: m/z = 428 (M+H) ⁺ .

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

The compound of Reference Example 146 (0.165 g, 0.386 mmol) was dissolved in dichloromethane (3.98mL), and triethylamine (0.0720mL, 0.517mmol) and anhydrous acetic acid (0.0450mL, 0.478mmol) were added at 0 °C. After stirring at room temperature for 4 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) , 71%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.45-1.63 (m, 2H), 1.70-1.78 (m, 2H), 1.89-1.98 (m, 1H), 2.21 (s, 3H), 2.22-2.37 ( m, 9H), 3.16 (ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 3.41-3.56 (m, 3H), 3.66 (dd, J = 10.9, 5.0 Hz, 1H), 3.74 - 3.79 (m, 1H), 4.99-5.03 (m, 1H), 5.25 (brd, J = 5.9 Hz, 1H), 6.22 (s, 2H), 6.38 (s, 1H), 6.88 (d, J = 9.1 Hz, 1H), 7.36 (dd, J = 9.1, 2.7 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 8.32 (brs, 1H).

ESI-MS: m/z = 470 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 108) (0.125 g, 0.247 mmol, 71%) was obtained as a white solid.

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.49-1.74 (m, 4H), 1.76-1.82 (m, 1H), 2.22-2.37 (m, 8H), 2.44-2.47 (m, 1H), 3.02 ( s, 3H), 3.15-3.22 (m, 1H), 3.42-3.57 (m, 3H), 3.68 (dd, J = 10.6, 5.2 Hz, 1H), 3.88-3.94 (m, 1H), 4.59-4.60 ( m,1H), 5.01-5.05 (m, 1H), 6.23 (s, 2H), 6.38 (s, 1H), 6.91 (d, J = 8.6 Hz, 1H), 7.36 (dd, J = 8.6, 2.7 Hz) , 1H), 7.64 (d, J = 2.7 Hz, 1H), 8.09 (brs, 1H).

ESI-MS: m/z = 506 (M+H) ⁺ .

(Example 109) (R)-1-(2-(1H-1,2,3-triazol-1-yl)ethenyl)-N-(3-chloro-4-(((S)-) Synthesis of 1-(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) were dissolved in DMF (3.51 mL) HATU (0.160 g, 0.421 mmol) and diisopropylethylamine (0.0918 mL, 0.526 mmol) were added. 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 a saturated aqueous solution of sodium hydrogen sulfate and brine and dried over anhydrous sodium sulfate. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) , 78%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.48-1.67 (m, 2H), 1.74-1.83 (m, 3H), 2.18-2.43 (m, 9H), 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, 1H), 3.67 (dd, J = 10.6, 5.2 Hz, 1H), 3.70-3.75 (m, 1H), 4.99-5.03 (m, 1H), 5.28 (brd, J = 5.2 Hz, 1H), 5.30 (d, J = 15.6 Hz, 1H), 5.39 (d, J = 15.6 Hz, 1H), 6.23 ( s, 2H), 6.38 (s, 1H), 6.90 (d, J = 9.1 Hz, 1H), 7.41 (dd, J = 9.1, 2.7 Hz, 1H), 7.73 (d, J = 2.7 Hz, 1H), 7.74 (d, J = 0.9 Hz, 1H), 7.81 (d, J = 0.9 Hz, 1H), 8.28 (brs, 1H).

ESI-MS: m/z = 537 (M+H) ⁺ .

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

The same procedure as in Example 109 was carried out except that 2-(1H-tetrazol-1-yl)acetic acid was used instead of 2-(1H-1,2,3-triazol-1-yl)acetic acid. The title compound (hereinafter, compound of Example 110) (0.168 g, 0.312 mmol, 89%)

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.52-1.92 (m, 5H), 2.18-2.32 (m, 9H), 3.39-3.56 (m, 4H), 3.63-3.70 (m, 2H), 4.96- 4.99 (m, 1H), 5.13 (brd, J = 3.2 Hz, 1H), 5.36 (d, J = 17.2 Hz, 1H), 5.41 (d, J = 17.2 Hz, 1H), 6.21 (s, 2H), 6.37 (s, 1H), 6.84 (d, J = 9.1 Hz, 1H), 7.21 (dd, J = 9.1, 2.3 Hz, 1H), 7.58 (d, J = 2.3 Hz, 1H), 8.09 (brs, 1H) ), 8.81 (s, 1H).

ESI-MS: m/z = 538 (M+H) ⁺ .

(Example 111) (R)-N-(3-Chloro-4-(((S)-1-(3,5-dimethylphenyl)pyrrolidin-3-yl)oxy)phenyl) Synthesis of 1-(2-cyanoethyl)piperidin-2-carboxamide:

The title compound was obtained as a white solid (yield: m. , Compound of Example 111) (0.101 g, 0.204 mmol, 58%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.63-1.69 (m, 2H), 1.74-1.86 (m, 2H), 1.89-2.00 (m, 1H), 2.20-2.36 (m, 9H), 3.37- 3.57 (m, 4H), 360-3.69 (m, 4H), 4.99-5.03 (m, 1H), 5.18 (brd, J = 5.4 Hz, 1H), 6.22 (s, 2H), 6.38 (s, 1H) , 6.88 (d, J = 91 Hz, 1H), 7.30 (dd, J = 9.1, 2.7 Hz, 1H), 7.60 (d, J = 2.7 Hz, 1H), 7.96 (brs, 1H).

ESI-MS: m/z = 495 (M+H) ⁺ .

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

The title compound was obtained as a yellow oil (yield: m.m. , the compound of Reference Example 147) (0.222 g, 0.615 mmol, 69%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.25 (d, J = 6.8 Hz, 6H), 2.38-2.41 (m, 2H), 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, 1H), 7.01 (d, J = 9.1 Hz, 1H), 7.19 (dd, J = 7.7, 7.7 Hz, 1H), 8.17 (dd, J = 9.1, 2.7 Hz, 1H), 8.30 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 361 (M+H) ⁺ .

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

The title compound (hereinafter, referred to as the compound of Reference Example 148) (0.148 g, m.p. 0.447 mmol, 73%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.25 (d, J = 6.9 Hz, 6H), 2.18-2.21 (m, 1H), 2.31-2.36 (m, 1H), 2.80-2.90 (m, 1H) , 3.44 (ddd, J=8.7, 8.7, 3.2 Hz, 1H), 3.50-3.58 (m, 4H), 3.63 (dd, J = 11.2, 5.2 Hz, 1H), 4.90-4.93 (m, 1H), 6.41 -6.45 (m, 2H), 6.53 (dd, J = 8.7, 2.7 Hz, 1H), 6.59 (brd, J = 7.8 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 7.17 (dd, J = 7.8, 7.8 Hz, 1H).

ESI-MS: m/z = 331 (M+H) ⁺ .

(Reference 149) (R)-2-((3-Chloro-4-((S)-1-(3-isopropylphenyl)pyrrolidin-3-yl)oxy)phenyl)amine Synthesis of methylidene) piperidine-1-carboxylic acid tert-butyl butyl ester:

The title compound (hereinafter, referred to as the compound of Reference Example 149) (0.230 g, 0.424 mmol) was obtained as a white solid. 95%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (d, J = 7.2 Hz, 6H), 1.40-1.72 (m, 14H), 2.24 - 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, 1H), 4.84 - 4.86 (m, 1H), 5.01-5.05 (m, 1H) , 6.42-6.44 (m, 2H), 6.60 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 9.1 Hz, 1H), 7.17 (dd, J = 7.7, 7.7 Hz, 1H), 7.36 ( Dd, J = 9.1, 2.7 Hz, 1H), 7.58 (d, J = 2.7 Hz, 1H), 8.14 (s, 1H).

ESI-MS: m/z = 542 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 112) (0.154 g, 0.318 mmol) was obtained as a white solid. 75%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.25 (d, J = 6.8 Hz, 6H), 1.45-1.62 (m, 2H), 1.70-1.79 (m, 2H), 1.89-1.98 (m, 1H) , 2.21 (s, 3H), 2.22 - 2.37 (m, 3H), 2.80 - 2.90 (m, 1H), 3.16 (ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 3.44 - 3.59 (m, 3H) , 3.70 (dd, J = 10.6, 5.2 Hz, 1H), 3.74 - 3.79 (m, 1H), 5.00 - 5.04 (m, 1H), 5.25 (brd, J = 5.4 Hz, 1H), 6.41-6.45 (m , 2H), 6.60 (d, J = 7.7 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 7.17 (dd, J = 7.7, 7.7 Hz, 1H), 7.36 (dd, J = 8.6, 2.7 Hz, 1H), 7.59 (d, J = 2.7 Hz, 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:

The title compound was obtained as a yellow oil (yield: m. Hereinafter, the compound of Reference Example 150) (0.220 g, 0.620 mmol, 55%).

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, 1H), 5.20-5.23 (m, 1H), 6.02-6.10 (m, 2H), 6.17 (tt, J = 9.1, 2.2 Hz, 1H), 7.01 (d, J = 9.1 Hz, 1H), 8.18 (dd, J = 9.1, 2.7 Hz, 1H) ), 8.32 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 355 (M+H) ⁺ .

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

The title compound (hereinafter, referred to as the compound of Reference Example 151) (0.141 g, 0.434) was obtained as a yellow oil. M, 70%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.14 - 2.23 (m, 1H), 2.33 - 2.40 (m, 1H), 3.39 (ddd, J = 8.8, 8.8, 2.7 Hz, 1H), 3.47 (ddd, J=11.2, 1.6, 1.6 Hz, 1H), 3.52 (d, J=4.5 Hz, 1H), 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, 1H), 6.54 (dd, J = 8.6, 2.7 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H), 6.80 (d, J = 8.6 Hz, 1H).

ESI-MS: m/z = 325 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 152) (0.206 g, 0.384 mmol) was obtained as a white solid. 89%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.42-1.49 (m, 2H), 1.52 (s, 9H), 1.64-1.69 (m, 3H), 2.20-2.29 (m, 1H), 2.30-2.41 ( m, 2H), 2.78-2.86 (m, 1H), 3.42 (ddd, J = 8.8, 8.8, 2.7 Hz, 1H), 3.47 (brd, J = 11.3 Hz, 1H), 3.55 (ddd, J = 9.3, 9.3, 6.8 Hz, 1H), 3.61 (dd, J = 11.1, 4.8 Hz, 1H), 4.01-4.12 (m, 1H), 4.83-4.87 (m, 1H), 5.01-5.04 (m, 1H), 6.00 -6.07 (m, 2H), 6.13 (tt, J = 9.3, 2.2 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 7.36 (dd, J = 8.6, 2.7 Hz, 1H), 7.61 ( d, J = 2.7 Hz, 1H), 8.21 (brs, 1H).

ESI-MS: m/z = 558 (M+Na) ⁺ .

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

The title compound (hereinafter, the compound of Example 113) (0.0783 g, 0.164 mmol) was obtained as a white solid. 85%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.64-1.48 (m, 2H), 1.71-1.79 (m, 2H), 1.89-1.98 (m, 1H), 2.17-2.30 (m, 5H), 2.34- 2.40 (m, 1H), 3.16 (ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 3.41 (ddd, J = 8.8, 8.8, 2.7 Hz, 1H), 3.47 (brd, J = 10.9 Hz, 1H) , 3.52-3.62 (m, 2H), 3.74-3.79 (m, 1H), 5.00-5.04 (m, 1H), 5.25 (brd, J = 5.0 Hz, 1H), 6.00-6.07 (m, 2H), 6.13 (tt, J = 9.1, 2.2 Hz, 1H), 6.88 (d, J = 8.6 Hz, 1H), 7.36 (dd, J = 8.6, 2.7 Hz, 1H), 7.61 (d, J = 2.7 Hz, 1H) , 8.37 (brs, 1H).

ESI-MS: m/z = 500 (M+Na) ⁺ .

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

The same procedure as in Reference Example 143 was carried out except that 4-bromo-2-methyl-1-(trifluoromethoxy)benzene was used instead of 1-bromo-3,5-dimethylbenzene. The title compound (hereinafter, the compound of Reference Example 153) (0.487 g, 1.17 mmol, 65%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.28 (s, 3H), 2.38-2.43 (m, 2H), 3.47-3.59 (m, 3H), 3.80 (dd, J = 11.1,4.8Hz, 1H) , 5.19-5.22 (m, 1H), 6.37-6.41 (m, 2H), 7.01 (d, J = 9.1 Hz, 1H), 7.08 (brd, J = 8.6 Hz, 1H), 8.18 (dd, J = 9.1 , 2.7 Hz, 1H), 8.31 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 417 (M+H) ⁺ .

(Reference 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) was obtained as a brown oil. M, 83%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.17-2.21 (m, 1H), 2.27 (s, 3H), 2.32 - 2.37 (m, 1H), 3.40 (ddd, J = 8.6, 8.6, 3.0 Hz, 1H), 3.47-3.60 (m, 5H), 4.89-4.93 (m, 1H), 6.35-6.37 (m, 2H), 6.54 (dd, J = 8.7, 2.7 Hz, 1H), 6.74 (d, J = 2.7 Hz, 1H), 6.80 (d, J = 8.7 Hz, 1H), 7.05 (dd, J = 8.7, 1.4 Hz, 1H).

ESI-MS: m/z = 387 (M+H) ⁺ .

(Reference 155) (R)-2-((3-Chloro-4-((S)-1-(3-methyl-4-(trifluoromethoxy)phenyl)pyrrolidin-3- Synthesis of benzyl)oxy)phenyl)amine-carbamoyl)piperidine-1-carboxylic acid tert-butyl butyl ester:

The title compound (hereinafter, referred to as the compound of Reference Example 155) (0.525 g, 0.878 mmol) was obtained as a brown solid. 91%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.42-1.49 (m, 2H), 1.52 (s, 9H), 1.64-1.67 (m, 3H), 2.20-2.39 (m, 6H), 2.83 (ddd, J = 13.2, 13.2, 2.4 Hz, 1H), 3.43 (ddd, J = 8.6, 8.6, 2.9 Hz, 1H), 3.48 (brd, J = 11.0 Hz, 1H), 3.55 (ddd, J = 9.0, 9.0, 6.7 Hz, 1H), 3.65 (dd, J = 11.0, 5.0 Hz, 1H), 4.04-4.08 (m, 1H), 4.84-4.86 (m, 1H), 5.01-5.04 (m, 1H), 6.34-6.38 (m, 2H), 6.90 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 8.7 Hz, 1H), 7.35 (dd, J = 8.7, 2.7 Hz, 1H), 7.59 (d, J = 2.7 Hz, 1H), 8.19 (brs, 1H).

ESI-MS: m/z = 598 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Example 114) (0.0580 g, 0.107 mmol) was obtained as a white solid. 54%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.50-1.57 (m, 2H), 1.73-1.76 (m, 2H), 1.89-2.00 (m, 1H), 2.21 (s, 3H), 2.22-2.29 ( m, 5H), 2.33 - 2.38 (m, 1H), 3.16 (ddd, J = 13.2, 13.2, 2.8 Hz, 1H), 3.43 (ddd, J = 8.6, 8.6, 3.2 Hz, 1H), 3.48 (brd, J = 11.3 Hz, 1H), 3.54 (ddd, J = 9.1, 9.1, 6.8 Hz, 1H), 3.65 (dd, J = 10.9, 5.0 Hz, 1H), 3.74 - 3.79 (m, 1H), 5.01-5.04 (m, 1H), 5.25 (brd, J = 5.9 Hz, 1H), 6.34 - 6.38 (m, 2H), 6.88 (d, J = 9.1 Hz, 1H), 7.06 (brd, J = 7.7 Hz, 1H) , 7.35 (dd, J = 9.1, 2.7 Hz, 1H), 7.59 (d, J = 2.7 Hz, 1H), 8.34 (brs, 1H).

ESI-MS: m/z = 540 (M+H) ⁺ .

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

Pyrrolidin-3-ol hydrochloride (2.00 g, 16.2 mmol) and sodium tert-butoxide (4.36 g, 38.8 mmol) were suspended in toluene (40.5 mL) and 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 ginseng (dibenzylideneacetone) Palladium (0) (0.741 g, 0.809 mmol). 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 brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=98/2 to 70/30) to give the title compound as a pale yellow solid (hereinafter, the compound of reference 156) (2.10g, 11.0) M, 68%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.01-2.07 (m, 1H), 2.11-2.20 (m, 1H), 2.28 (s, 6H), 3.26 (brd, J = 10.4 Hz, 1H), 3.33 (ddd, J=9.2, 9.2, 3.6 Hz, 1H), 3.45-3.52 (m, 2H), 4.55-4.59 (m, 1H), 6.22 (s, 2H), 6.37 (s, 1H).

ESI-MS: m/z = 192 (M+H) ⁺ .

(Reference 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 sieve 4A (1.50 g) was added at room temperature. Next, add N-methyl at 0 ° C N-methylmorpholine N-oxide (1.38 g, 11.8 mmol) and tetrapropylammonium perruthenate (0.276 g, 0.784 mmol). After stirring at room temperature for 30 minutes, the reaction solution was filtered, and the filtrate was concentrated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc(EtOAc) , 52%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.31 (6H, s), 2.71 (t, J = 7.2Hz, 2H), 3.65-3.69 (m, 4H), 6.31 (s, 2H), 6.51 (s , 1H).

ESI-MS: m/z = 190 (M+H) ⁺ .

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

The compound of Reference Example 157 (0.100 g, 0.528 mmol) was dissolved in THF (5.28 mL), and EtOAc (M. After stirring at the same temperature for 30 minutes, a saturated aqueous solution of ammonium chloride was added to the mixture and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and evaporated. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) 0.404 mmol, 76%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.17 (s, 1H), 2.27-2.36 (m, 8H), 2.57 (s, 1H), 3.41-3.54 (m, 3H), 3.66 (d, J = 10.4 Hz, 1H), 6.19 (s, 2H), 6.39 (s, 1H).

ESI-MS: m/z = 216 (M+H) ⁺ .

(Reference 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 (1.01mL), and sodium hydride (60% by weight mineral oil dispersion, 0.0223 g, 0.557 mmol) was added at 0 °C. After stirring at the same temperature for 20 minutes, 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, a saturated aqueous solution of ammonium chloride was added to the mixture and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc (EtOAc) 0.423 mmol, 84%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.27 (s, 6H), 2.60 (ddd, J = 13.6,8.8,8.8Hz, 1H), 2.78 (ddd, J = 13.6,6.0,4.4Hz, 1H) , 2.84 (s, 1H), 3.54-3.58 (m, 2H), 3.90 (s, 2H), 6.19 (s, 2H), 6.41 (s, 1H), 7.63 (d, J = 9.1 Hz, 1H), 8.16 (dd, J = 9.1, 2.7 Hz, 1H), 8.28 (d, J = 2.7 Hz, 1H).

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) was dissolved in THF (1.84 mL), and ethanol (3.65 mL), water (1.84 mL), iron powder (0.0946 g, 1.69 mmol) and acetic acid (0.242) were added at room temperature. mL, 4.23 mmol). After stirring at 50 ° C for 2 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=93/7 to 70/30) to give the title compound ( 0.352 mmol, 83%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.27 (s, 6H), 2.42 (ddd, J = 13.2, 8.4, 8.4 Hz, 1H), 2.62-2.69 (m, 2H), 3.48 (ddd, J = 8.4, 8.4, 4.4 Hz, 1H), 3.56 (brs, 2H), 3.61 (ddd, J = 8.4, 8.4, 6.8 Hz, 1H), 3.69 (d, J = 10.4 Hz, 1H), 3.77 (d, J) = 10.4 Hz, 1H), 6.16 (s, 2H), 6.37 (s, 1H), 6.52 (dd, J = 8.6, 2.7 Hz, 1H), 6.69 (d, J = 2.7 Hz, 1H), 7.34 (d) , J = 8.6 Hz, 1H).

ESI-MS: m/z = 341 (M+H) ⁺ .

(Reference 161) 8-Chloro-1'-(3,5-dimethylphenyl) snail [ Synthesis of ene-2,3'-pyrrolidinium-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 was concentrated under reduced pressure, and the obtained residue was purified to silica gel elution elution elution Compound) (0.0596 g, 0.175 mmol, 60%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.97 (ddd, J = 13.6,10.0,8.8Hz, 1H), 2.27 (s, 6H), 2.45-2.51 (m, 1H), 3.43-3.50 (m, 4H), 3.60 (ddd, J = 10.0, 10.0, 6.4 Hz, 1H), 3.69 (dd, J = 11.2, 1.6 Hz, 1H), 5.80 (d, J = 9.5 Hz, 1H), 6.20 (s, 2H) ), 6.31 (d, J = 2.7 Hz, 1H), 6.37 (s, 1H), 6.39 (d, J = 9.5 Hz, 1H), 6.56 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 341 (M+H) ⁺ .

(Reference 162) (2R)-2-((8-chloro-1'-(3,5-dimethylphenyl)) snail [ Synthesis of tert-butyl butyl-2,3'-pyrrolidin]-6-yl)amine carbhydryl)piperidine-1-carboxylate:

The compound of Reference Example 161 (0.100 g, 0.293 mmol) was dissolved in DMF (2.93 mL), and diisopropylethylamine (0.0666 mL, 0.381 mmol), (R)-1-(3) Oxycarbonyl)-2-piperidinecarboxylic acid (0.0740 g, 0.323 mmol) and HATU (0.134 g, 0.352 mmol). 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 brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc (EtOAc/EtOAc/EtOAc (EtOAc) 61%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.42-1.70 (m, 13H), 2.00 (ddd, J = 13.2,6.4,6.4Hz, 1H), 2.27-2.35 (m, 8H), 2.48 (dd, J=13.2, 6.4 Hz, 1H), 2.78-2.85 (m, 1H), 3.45-3.51 (m, 2H), 3.61 (ddd, J=9.6, 9.6, 6.4 Hz, 1H), 3.70 (brd, J= 10.8 Hz, 1H), 3.99-4.14 (m, 1H), 4.82-4.87 (m, 1H), 5.83 (d, J = 10.0 Hz, 1H), 6.20 (s, 2H), 6.38 (s, 1H), 6.45 (d, J = 10.0 Hz, 1H), 7.22-7.23 (m, 1H), 7.26-7.28 (m, 1H), 8.11 (brs, 1H).

ESI-MS: m/z = 552 (M+H) ⁺ .

(Example 115) (2R)-1-Ethyl-N-(8-chloro-1'-(3,5-dimethylphenyl) snail [ Synthesis of ene-2,3'-pyrrolidin]-6-yl)piperidine-2-carboxamide:

The compound of Reference Example 162 (0.0991 g, 0.179 mmol) was dissolved in dichloromethane (1. After stirring at room temperature for 1.5 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained crude product was used in 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 anhydrous acetic acid (0.0203 mL, 0.215 mmol) were added at 0 °C. After stirring at room temperature for 16 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc(EtOAc) 84%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.60 (m, 2H), 1.70-1.79 (m, 2H), 1.89-2.04 (m, 2H), 2.21 (s, 3H), 2.24-2.30 ( m, 7H), 2.44 - 2.50 (m, 1H), 3.11-3.18 (m, 1H), 3.44 - 3.51 (m, 2H), 3.61 (ddd, J = 9.2, 9.2, 6.4 Hz, 1H), 3.70 ( Brd,J=10.4Hz,1H),3.73-3.80(m,1H),5.22-5.26(m,1H),5.82(d,J=10.0Hz,1H),6.20(s,2H),6.37(s , 1H), 6.44 (d, J = 10.0 Hz, 1H), 7.16-7.20 (m, 1H), 7.31 - 7.35 (m, 1H), 8.28 (s, 1H).

ESI-MS: m/z = 494 (M+H) ⁺ .

(Example 116) (2R)-1-Ethyl-N-(8-chloro-1'-(3,5-dimethylphenyl) snail [ Synthesis of alkane-2,3'-pyrrolidin]-6-yl)piperidine-2-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 at the same temperature for 9 hours under a hydrogen atmosphere, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by EtOAc EtOAc EtOAc EtOAc (EtOAc) M, 88%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.56 (m, 2H), 1.70-1.79 (m, 2H), 1.88-2.12 (m, 4H), 2.21 (s, 3H), 2.25-2.31 ( m, 8H), 2.87 (dd, J = 6.4, 6.4 Hz, 2H), 3.12-3.19 (m, 1H), 3.41-3.52 (m, 3H), 3.57 (ddd, J = 9.2, 9.2, 6.4 Hz, 1H), 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, 1H), 8.22 (s, 1H).

ESI-MS: m/z = 496 (M+H) ⁺ .

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

1,4-Dioxo-8-azaspiro[4.5]decane (2.00 g, 14.0 mmol) and potassium tert-butoxide (2.19 g, 19.6 mmol) were suspended in toluene (34.9 mL) and added at room temperature. -Bromo-2-methylbenzene (2.63 g, 15.4 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0.261 g, 0.419 mmol) and bis(dibenzylidene) Acetone) dipalladium (0) (0.128 g, 0.140 mmol). 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 brine, dried over anhydrous sodium sulfate and filtered. The obtained crude product was used in 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. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained residue, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was recrystallized from ethyl acetate (yield: ield: ield:

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.39 (s, 3H), 2.61 (t, J = 5.9 Hz, 4H), 3.22 (t, J = 5.9 Hz, 4H), 7.02-7.05 (m, 2H) ), 7.18 (ddd, J = 7.7, 7.7, 1.2 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H),

ESI-MS: m/z = 190 (M+H) ⁺ .

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

The compound of Reference Example 163 (0.500 g, 2.64 mmol) was dissolved in THF (26.0 mL), EtOAc (EtOAc, EtOAc, EtOAc) After stirring at the same temperature for 30 minutes, a saturated aqueous solution of ammonium chloride was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The residue obtained was purified by silica gel column chromatography (hexane / ethyl acetate = 95/5 to 80/20) to give the title compound (yield of compound of reference 164) (0.441 g, 2.05 M, 78%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.95-2.01 (m, 2H), 2.06-2.12 (m, 2H), 2.30 (s, 3H), 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, 1H), 7.14 - 7.19 (m, 2H).

ESI-MS: m/z = 216 (M+H) ⁺ .

(Reference 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 (4.10mL), and sodium hydride (60% by weight mineral oil dispersion, 0.0900 g, 2.25 mmol) was added at 0 °C. After stirring at the same temperature for 20 minutes, 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, a saturated aqueous solution of ammonium chloride was added to the mixture and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate = 98/2 to 90/10) to give the title compound (yield of the compound of reference 165) (0.471 g, 1.27 M, 62%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.31 (s, 3H), 2.35-2.42 (m, 4H), 2.87 (s, 1H), 2.95-3.01 (m, 2H), 3.08-3.13 (m, 2H), 7.01 (ddd, J=7.7, 7.7, 1.1 Hz, 1H), 7.06 (d, J = 7.7 Hz, 1H), 7.16-7.20 (m, 2H), 7.82 (d, J = 9.1 Hz, 1H) ), 8.13 (dd, J = 9.1, 2.7 Hz, 1H), 8.33 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 371 (M+H) ⁺ .

(Reference 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) was dissolved in THF (3.03 mL), and ethanol (6.07 mL), water (3.03 mL), iron powder (0.271 g, 4.85 mmol) and acetic acid (0.695) were added at room temperature. mL, 12.1 mmol). After stirring at 50 ° C for 3 hours, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. A saturated aqueous solution of sodium hydrogencarbonate was added to the obtained residue, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (hexane-ethyl-ethyl acetate-ethyl-ethyl-diethylamine) M, 99%).

¹ H-NMR (400MHz, 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, 1H), 6.98 (dd, J = 7.7 Hz, 1H), 7.07 (d, J = 7.7 Hz, 1H), 7.14 - 7.19 (m, 2H), 7.40 (d, J = 8.8 Hz, 1H).

ESI-MS: m/z = 341 (M+H) ⁺ .

(Reference 167) 8-Chloro-1'-(o-tolyl) snail [ Synthesis of ene-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 was concentrated under reduced pressure, and the residue obtained was purified by EtOAc EtOAc EtOAc EtOAc ) (0.307 g, 0.901 mmol, 75%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.81-1.88 (m, 2H), 2.09-2.15 (m, 2H), 2.31 (s, 3H), 2.89-2.93 (m, 2H), 3.23 (ddd, J = 12.0, 12.0, 1.6 Hz, 2H), 3.43 (brs, 2H), 5.71 (d, J = 10.0 Hz, 1H), 6.30 (d, J = 2.7 Hz, 1H), 6.31 (d, J = 10.0) Hz, 1H), 6.58 (d, J = 2.7 Hz, 1H), 6.98 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 7.12-7.14 (m, 1H), 7.17-7.19 (m, 2H) .

ESI-MS: m/z = 341 (M+H) ⁺ .

(Reference 168) (R)-2-((8-chloro-1'-(o-tolyl)) snail [ Synthesis of tert-butyl butyl-2,4'-piperidine]-6-yl)amine-carbamoylpiperidine-1-carboxylate:

The compound of Reference Example 167 (0.207 g, 0.607 mmol) was dissolved in DMF (6.07 mL), and diisopropylethylamine (0.138 mL, 0.790 mmol), (R)-1-(3) Oxycarbonyl)-2-piperidinecarboxylic acid (0.153 g, 0.668 mmol) and HATU (0.277 g, 0.729 mmol). 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 brine, dried over anhydrous sodium sulfate and filtered. The residue obtained was purified by EtOAc EtOAc EtOAc (EtOAc) , 98%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.41-1.72 (m, 14H), 1.83-1.91 (m, 2H), 2.12 (brd, J = 12.7 Hz, 2H), 2.27-2.37 (m, 4H) , 2.78-2.85 (m, 1H), 2.92 (ddd, J = 12.03.3.2, 3.2 Hz, 2H), 3.23 (ddd, J = 12.0, 12.0, 1.6 Hz, 2H), 3.99-4.14 (m, 1H) , 4.82-4.88 (m, 1H), 5.73 (d, J = 9.5 Hz, 1H), 6.37 (d, J = 9.5 Hz, 1H), 6.99 (ddd, J = 7.2, 7.2, 0.8 Hz, 1H), 7.13 (d, J = 7.2 Hz, 1H), 7.18-7.21 (m, 3H), 7.33 (d, J = 1.8 Hz, 1H), 8.11 (brs, 1H).

ESI-MS: m/z = 552 (M+H) ⁺ .

(Example 117) (R)-1-Ethyl-N-(8-chloro-1'-(o-tolyl) snail [ Synthesis of ene-2,4'-piperidin]-6-yl)piperidine-2-carboxamide:

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 at room temperature for 0.5 hour, the reaction solution was poured into a saturated aqueous solution of sodium hydrogencarbonate and extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained crude product was used in the subsequent reaction without purification.

The above crude product was dissolved in dichloromethane (240 mL), and triethylamine (13.8 mL, 99.1 mmol) and anhydrous acetic acid (8.63 mL, 91.4 mmol) were added at 0 °C. After stirring at room temperature for 18 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the mixture was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (chlorobenzene / methanol = 100 / 0 to 80 / 20) to afford crystals of crystal Compound 117) (24.2 g, 49.0 mmol, 64%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.60 (m, 2H), 1.70-1.78 (m, 2H), 1.84-1.98 (m, 3H), 2.09-2.14 (m, 2H), 2.21. s, 3H), 2.24-2.30 (m, 1H), 2.31 (s, 3H), 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, 1H), 6.35 (d, J = 10.0 Hz, 1H), 6.98 (ddd, J = 7.2, 7.2, 1.2 Hz, 1H), 7.12-7.19 (m, 4H), 7.37 (d, J = 2.3 Hz, 1H), 8.26 (brs, 1H).

ESI-MS: m/z = 494 (M+H) ⁺ .

(Example 118) (R)-1-Ethyl-N-(8-chloro-1'-(o-tolyl) snail [ Synthesis of alkane-2,4'-piperidin]-6-yl)piperidine-2-carboxamide:

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 residue was purified by EtOAc EtOAc EtOAc (EtOAc) , 76%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.48-1.56 (m, 2H), 1.73-1.83 (m, 4H), 1.86-1.89 (m, 2H), 1.90-1.94 (m, 3H), 2.20 ( s, 3H), 2.24-2.30 (m, 1H), 2.31 (s, 3H), 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, 1H), 6.98 (ddd, J = 7.7, 7.7, 1.2 Hz, 1H), 7.11 (d, J = 7.7 Hz, 1H), 7.17-7.20 (m, 3H), 7.36 (d, J = 2.4 Hz, 1H), 8.21 (brs, 1H).

ESI-MS: m/z = 496 (M+H) ⁺ .

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

The title compound was obtained as a yellow oil (yield: 169, 169). Compound) (1.15 g, 6.08 mmol, 44%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.34 (s, 3H), 2.55 (t, J = 5.9Hz, 4H), 3.60 (t, J = 5.9Hz, 4H), 6.72 (d, J = 7.7 Hz, 1H), 6.79-6.81 (m, 2H), 7.19 (dd, J = 7.7, 7, 7 Hz, 1H).

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) as a pale yellow solid was obtained by the same procedure as the compound of , 64%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.90-1.97 (m, 2H), 2.02 (s, 1H), 2.03-2.09 (m, 2H), 2.31 (s, 3H), 2.55 (s, 1H) , 3.12-3.18 (m, 2H), 3.46-3.52 (m, 2H), 6.67 (d, J = 7.2 Hz, 1H), 6.75-6.79 (m, 2H), 7.15 (dd, J = 7.2, 7.2 Hz) , 1H).

ESI-MS: m/z = 216 (M+H) ⁺ .

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

The title compound (hereinafter, the compound of Reference Example 171) (0.763 g, 2.06 mmol) was obtained as a pale yellow solid. , 53%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.28-2.39 (m, 7H), 2.84 (s, 1H), 3.27-3.33 (m, 2H), 3.37-3.44 (m, 2H), 6.71 (d, J = 7.7 Hz, 1H), 6.75-6.77 (m, 2H), 7.14 - 7.19 (m, 1H), 7.80 (d, J = 9.1 Hz, 1H), 8.12 (dd, J = 9.1, 2.7 Hz, 1H) ), 8.31 (d, J = 2.7 Hz, 1H).

ESI-MS: m/z = 371 (M+H) ⁺ .

(Reference 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) was obtained as a pale red solid. , 94%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.13-2.19 (m, 2H), 2.22-2.29 (m, 2H), 2.31 (s, 3H), 2.65 (s, 1H), 3.11-3.17 (m, 2H), 3.51-3.56 (m, 4H), 6.51 (dd, J = 8.8, 2.8 Hz, 1H), 6.68 (d, J = 7.6 Hz, 1H), 6.72 (d, J = 2.8 Hz, 1H), 6.75-6.77 (m, 2H), 7.15 (dd, J = 7.6, 7.6 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H).

ESI-MS: m/z = 341 (M+H) ⁺ .

(Reference Example 173) 8-Chloro-1'-(m-tolyl) snail [ Synthesis of ene-2,4'-piperidine]-6-amine:

The title compound (hereinafter, the compound of Reference Example 173) (0.436 g, 1.28 mmol) was obtained as a white solid. 66%).

^{1 H-NMR (400MHz, 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, 1H), 6.67 (d, J) =7.7 Hz, 1H), 6.78-6.81 (m, 2H), 7.14-7.18 (m, 1H).

ESI-MS: m/z = 341 (M+H) ⁺ .

(Reference 174) (R)-2-((8-chloro-1'-(m-tolyl)) snail [ Synthesis of tert-butyl butyl-2,4'-piperidine]-6-yl)amine-carbamoylpiperidine-1-carboxylate:

The title compound (hereinafter, the compound of Reference Example 174) (0.541 g, 0.980 mmol,) was obtained as a white solid. 99%).

^{1 H-NMR (400MHz, 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 = 10.0 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H), 6.77-6.81 (m, 2H), 7.14 - 7.18 (m, 2H), 7.31 (d) , J = 2.3 Hz, 1H), 8.09 (brs, 1H).

ESI-MS: m/z = 552 (M+H) ⁺ .

(Example 119) (R)-1-Ethyl-N-(8-chloro-1'-(m-tolyl) snail [ Synthesis of ene-2,4'-piperidin]-6-yl)piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 119) (0.438 g, 0.887 mmol) was obtained as a white solid. 90%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.52-1.60 (m, 2H), 1.71-1.86 (m, 4H), 1.88-2.01 (m, 1H), 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, 1H), 3.29-3.36 (m, 2H), 3.45-3.50 (m, 2H), 3.73 3.79 (m, 1H), 5.23-5.25 (m, 1H), 5.65 (d, J = 10.0 Hz, 1H), 6.34 (d, J = 10.0 Hz, 1H), 6.68 (d, J = 7.2 Hz, 1H) ), 6.78-6.81 (m, 2H), 7.13-7.18 (m, 2H), 7.36 (d, J = 2.7 Hz, 1H), 8.26 (s, 1H).

ESI-MS: m/z = 494 (M+H) ⁺ .

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

The title compound was obtained as a yellow oil (yield: 175). Compound) (2.25 g, 11.9 mmol, 85%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 2.29 (s, 3H), 2.55 (t, J = 6.1 Hz, 4H), 3.55 (t, J = 6.1 Hz, 4H), 6.91 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H).

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) was obtained as a pale red solid. , 59%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.91-1.98 (m, 2H), 2.01 (brs, 1H), 2.03-2.10 (m, 2H), 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, 2H), 7.07 (d, J = 8.6 Hz, 2H).

ESI-MS: m/z = 216 (M+H) ⁺

(Reference 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) was obtained as a pale yellow solid (yield). , 76%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 2.28 (s, 3H), 2.29-2.40 (m, 4H), 2.84 (s, 1H), 3.22-3.28 (m, 2H), 3.33-3.39 (m, 2H), 6.87 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 9.1 Hz, 1H), 8.12 (dd, J = 9.1, 2.7 Hz, 1H), 8.31 (d, J = 2.7 Hz, 1H).

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) was obtained as a yellow solid. 98%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 2.13-2.19 (m, 2H), 2.23-2.29 (m, 5H), 2.65 (s, 1H), 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, 1H), 6.87 (d, J = 8.6 Hz, 2H), 7.07 (d, J = 8.6 Hz, 2H), 7.39 (d, J = 8.6 Hz, 1H).

ESI-MS: m/z = 341 (M+H) ⁺ .

(Reference Example 179) 8-Chloro-1'-(p-tolyl) snail [ Synthesis of ene-2,4'-piperidine]-6-amine:

The title compound (hereinafter, the compound of Reference Example 179) (1.05 g, 3.08 mmol) was obtained as a pale yellow solid (yield). , 73%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.78-1.86 (m, 2H), 2.07-2.12 (m, 2H), 2.28 (s, 3H), 3.26-3.33 (m, 2H), 3.38-3.44 ( m, 4H), 5.64 (d, J = 10.0 Hz, 1H), 6.28-6.31 (m, 2H), 6.56 (d, J = 2.7 Hz, 1H), 6.91 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H).

ESI-MS: m/z = 341 (M+H) ⁺ .

(Reference Example 180) (R)-2-((8-chloro-1'-(p-tolyl)) snail [ Synthesis of tert-butyl butyl-2,4'-piperidine]-6-yl)amine-carbamoylpiperidine-1-carboxylate:

The title compound (hereinafter, the compound of Reference Example 180) (0.759 g, 1.37 mmol) was obtained as a white solid. 94%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.41-1.72 (m, 14H), 1.81-1.88 (m, 2H), 2.07-2.13 (m, 2H), 2.28 (s, 3H), 2.30-2.36 ( m, 1H), 2.77-2.85 (m, 1H), 3.26-3.33 (m, 2H), 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, 1H), 6.91 (d, J = 8.6 Hz, 2H), 7.09 (d, J = 8.6 Hz, 2H), 7.17 ( d, J = 2.7 Hz, 1H), 7.31 (d, J = 2.7 Hz, 1H), 8.07 (brs, 1H).

ESI-MS: m/z = 552 (M+H

(Example 120) (R)-1-Ethyl-N-(8-chloro-1'-(p-tolyl) snail [ Synthesis of ene-2,4'-piperidin]-6-yl)piperidine-2-carboxamide:

The title compound (hereinafter, the compound of Example 120) (0.631 g, 1.28 mmol) was obtained as a white solid. 93%).

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, 1H), 2.07- 2.12 (m, 2H), 2.21 (s, 3H), 2.23-2.28 (m, 4H), 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, 1H), 5.65 (d, J = 10.0 Hz, 1H), 6.34 (d, J = 10.0 Hz, 1H), 6.91 (d, J = 8.6 Hz) , 2H), 7.09 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 2.3 Hz, 1H), 7.36 (d, J = 2.3 Hz, 1H), 8.26 (s, 1H).

ESI-MS: m/z = 494 (M+H) ⁺ .

(Reference 181) Synthesis of 4-ethynyl-4-hydroxypiperidine-1-carboxylic acid tert-butyl butyl ester:

After cooling the ethynylmagnesium bromide-THF solution (0.5 M, 65.2 mL, 32.6 mmol) to -20 ° C, the 4-side Oxypiperidine-1-carboxylic acid tert-butyl was dissolved in THF (50 mL) at the same temperature. Ester (5.00 g, 25.1 mmol). After stirring at the same temperature for 1 hour, a saturated aqueous solution of ammonium chloride was added to the mixture and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=90/10 to 70/30) to give the title compound as a white solid (hereinafter, the compound of reference 181) (2.89 g, 12.8 mmol , 51%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.46 (s, 9H), 1.68-1.75 (m, 2H), 1.87-1.93 (m, 2H), 2.01 (brs, 1H), 2.54 (s, 1H) , 3.24-3.30 (m, 2H), 3.71-3.84 (m, 2H).

(Reference 182) Synthesis of 4-(2-chloro-4-cyanophenoxy)-4-ethynylpiperidine-1-carboxylic acid tert-butyl ester:

The compound of Reference Example 181 (2.89 g, 12.8 mmol) was dissolved in DMF (25.7mL), and sodium hydride (60% by weight mineral oil dispersion, 0.564 g, 14.1 mmol) was added at 0 °C. After stirring at the same temperature for 30 minutes, 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, a saturated aqueous solution of ammonium chloride was added to the mixture and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) , 74%).

^{1 H-NMR (400MHz, CDCl} 3) δ: 1.46 (s, 9H), 2.06-2.18 (m, 4H), 2.82 (s, 1H), 3.48-3.55 (m, 2H), 3.58-3.65 (m, 2H), 7.50 (dd, J = 8.6, 2.3 Hz, 1H), 7.69 (d, J = 2.3 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H).

ESI-MS: m/z = 359 (MH) ^- .

(Reference 183) 8-Chloro-6-cyano snail [ Synthesis of tert-butyl 2,4'-piperidine]-1'-carboxylic acid:

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. N-hexane was added to the reaction solution, followed by extraction with acetonitrile. The acetonitrile layer was washed with brine, dried over anhydrous sodium sulfate and filtered, The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = EtOAc / EtOAc / ) (2.16 g, 5.99 mmol, 64%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.48 (s, 9H), 1.61-1.68 (m, 2H), 1.95-2.03 (m, 2H), 3.23 - 3.37 (m, 2H), 3.86-4.05 ( m, 2H), 5.69 (d, J = 10.0 Hz, 1H), 6.37 (d, J = 10.0 Hz, 1H), 7.19 (d, J = 1.8 Hz, 1H), 7.49 (d, J = 1.8 Hz, 1H).

ESI-MS: m/z = 359 (MH) ^- .

(Reference 184) 8-chlorospiro [ Synthesis of ene-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, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate (MgSO4).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.64-1.72 (m, 2H), 1.97-2.02 (m, 2H), 2.87-2.92 (m, 2H), 3.14-3.21 (m, 2H), 5.74 ( d, J = 10.0 Hz, 1H), 6.33 (d, J = 10.0 Hz, 1H), 7.17 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 1H).

ESI-MS: m/z = 261 (M+H) ⁺ .

(Reference Example 185) 8-Chloro-1'-phenyl snail [ Synthesis of ene-2,4'-piperidine]-6-carbonitrile:

The compound of Reference Example 184 (0.200 g, 0.767 mmol) and sodium tris-butoxide (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 ginsyl (dibenzylideneacetone) dipalladium (0) (0.00702 g, 0.00767 mmol). 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 brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=90/10 to 70/30) to give the title compound as a white solid (hereinafter, the compound of Reference 185) (0.175 g, 0.520 mmol) , 68%).

^{1 H-NMR (400MHz, 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, 1H), 6.38 (d, J = 10.0 Hz, 1H), 6.86-6.90 (m, 1H), 6.99 (d, J = 8.6 Hz, 2H), 7.19 (d, J = 2.3) Hz, 1H), 7.29 (dd, J = 8.6, 7.2 Hz, 2H), 7.49 (d, J = 2.3 Hz, 1H).

ESI-MS: m/z = 337 (M+H) ⁺ .

(Reference 186) (8-chloro-1'-phenyl spiro [ Synthesis of tert-butyl butyl-2,4'-piperidine]-6-yl)carboxylic acid:

The compound of Reference Example 185 (0.175 g, 0.520 mmol) was suspended in toluene (5.20mL), and methanol (5.20mL) and sodium hydroxide (0.416g, 10.4mmol) 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 brine, dried over anhydrous sodium sulfate and filtered. The obtained crude product was used in the subsequent reaction without purification.

The above crude product was suspended in tertiary butanol (26.0 mL), and triethylamine (0.109 mL, 0.780 mmol) and diphenyl phosphoryl azide (0.157 g, 0.572 mmol) were added at room temperature. ). After stirring at 80 ° C for 17 hours, the reaction solution was diluted with THF. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = EtOAc / EtOAc / , 13%).

¹ H-NMR (400MHz, CDCl ₃ ) δ: 1.51 (s, 9H), 1.79-1.87 (m, 2H), 2.08-2.13 (m, 2H), 3.31-3.38 (m, 2H), 3.47-3.51 ( m, 2H), 5.65 (d, J = 10.0 Hz, 1H), 6.29 (brs, 1H), 6.36 (d, J = 10.0 Hz, 1H), 6.82 - 6.87 (m, 1H), 6.98 - 7.03 (m , 3H), 7.16 (d, J = 23 Hz, 1H), 7.25-7.30 (m, 2H).

ESI-MS: m/z = 427 (M+H) ⁺ .

(Reference 187) (R)-2-((8-chloro-1'-phenylspiro[ Synthesis of tert-butyl butyl-2,4'-piperidine]-6-yl)amine-carbamoylpiperidine-1-carboxylate:

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, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained crude product was used in the subsequent reaction without purification.

The above crude product was dissolved in DMF (0.700 mL), and diisopropylethylamine (0.0159 mL, 0.0910 mmol), (R)-1-(tert-butoxycarbonyl)-2- Piperidinecarboxylic acid (0.0177 g, 0.0770 mmol) and HATU (0.0319 g, 0.0840 mmol). 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 brine, dried over anhydrous sodium sulfate and filtered. The obtained residue was purified by silica gel column chromatography (yield: hexane/ethyl acetate=90/10 to 60/40) to give the title compound as a white solid (hereinafter, the compound of Reference 187) (0.0340g, 0.0632mmol) , 90%).

^{1 H-NMR (400MHz, 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, 1H), 2.80- 2.87 (m, 1H), 3.31-3.38 (m, 2H), 3.47-3.52 (m, 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, 1H), 6.84 - 6.87 (m, 1H), 6.99 (d, J = 8.6 Hz, 2H), 7.17 (d, J = 2.7 Hz, 1H), 7.26-7.32 (m, 3H), 8.09 (brs, 1H).

ESI-MS: m/z = 538 (M+H) ⁺ .

(Example 121) (R)-1-Ethyl-N-(8-chloro-1'-phenylspiro[ Synthesis of ene-2,4'-piperidin]-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, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The obtained crude product was used in 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 anhydrous acetic acid (0.00691 mL, 0.0732 mmol) were added at 0 °C. After stirring at room temperature for 4 hours, a saturated aqueous solution of sodium hydrogencarbonate was added and the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The residue was purified by EtOAc EtOAc EtOAc (EtOAc) , 93%).

¹ H-NMR (400 MHz, CDCl ₃ ) δ: 1.46-1.57 (m, 2H), 1.70-1.87 (m, 4H), 1.89-2.01 (m, 1H), 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, 2H), 3.46-3.51 (m, 2H), 3.73-3.79 (m, 1H), 5.23-5.25(m,1H), 5.65(d,J=10.0Hz,1H), 6.34(d,J=10.0Hz,1H),6.83-6.87(m,1H),6.99(d,J=8.6Hz , 2H), 7.13 (d, J = 2.7 Hz, 1H), 7.25-7.29 (m, 2H), 7.36 (d, J = 2.3 Hz, 1H), 8.30 (s, 1H).

ESI-MS: m/z = 480 (M+H) ⁺ .

(Example 122) RORγ- coactivator binding activity: LanthaScreen invitrogen use Company using time-resolved fluorescence energy transfer (TR-FRET) in the ^{TM TR-FRET Retinoid-Related Orphan} Receptor (ROR) gamma Coactivator Assay set, To evaluate the ligand binding domain (hereinafter, RORγ-LBD) of the cyclic amine derivative (I), its stereoisomer or the hydrate thereof, or the pharmacologically acceptable salt thereof to RORγ Inhibition of the binding of activators.

After the test compound was dissolved in DMSO, it was diluted with TR-FRET Coregulator Buffer D (invigor) containing 5 mmol/L DTT so that the final concentration of DMSO was 1%. To each well of a 384-well black plate (Corning), 4 nmol/L of GST-fused RORγ-LBD (invigen) diluted with the above buffer and the test compound were added. Further, a well in which the test compound was not added and GST fusion RORγ-LBD was not added (background), and a well in which the test compound was not added and GST fusion RORγ-LBD was added (control) was set. Next, 150 nmol/L of fluorescein (Flurescein)-labeled TRAP220/DRIP-2 (invitogen) diluted with the above buffer, and 32 nmol/L of sputum-labeled anti-GST antibody (invitogen) were added to each well. After the plate was incubated at room temperature for 16 to 24 hours, fluorescence at 495 nm and 520 nm at 320 nm excitation was measured for each well, and the ratio (fluorescence value at 520 nm / fluorescence value at 495 nm) was calculated.

Calculate the Fold change when the test compound is added (the ratio of the ratio of the test compound to the background/background ratio), the fold change of the control (the ratio of the control ratio to the background), and the change in the fold of the background (the ratio of the background) After the ratio of the background ratio, the binding inhibition ratio (hereinafter, RORγ-co-activator binding inhibition ratio) (%) of RORγ-LBD to the co-activator was calculated by the following formula 1.

RORγ-co-activator binding inhibition rate (%) = (1 - ((fold change in the test compound addition) - (fold change in background)) / ((multiple change in control) - (fold change in background)) ) ×100‧‧‧Form 1

The RORγ-co-activator binding inhibition ratio (%) at 33 μmol/L of the test compound is shown in Table 2-1 to Table 2-3.

From this result, it is clear that the cyclic amine derivative (I), its stereoisomer or the hydrate thereof, or the pharmacologically acceptable salts thereof, significantly inhibits RORγ-LBD and the co-activator. Combine.

(Example 123) Inhibition of IL-17 production in mouse spleen cells: Using mouse spleen cells, the method described in The Journal of Biological Chemistry, 2003, Vol. 278, No. 3, p. 1910-1914 Partially modified to evaluate the production of IL-17 by the stimulation of IL-23 by the cyclic amine derivative (I), its stereoisomers or hydrates thereof, or their pharmacologically acceptable salts. Inhibition.

Spleen cells were prepared from a spleen of C57BL/6J mice (male, 6 to 26 weeks old) (Charles River Japan Co., Ltd.) using a single cell floating solution using Histopaque-1083 (Sigma). The culture medium was added to RPMI1640 medium (Gibco), 10% FBS (Gibco), 50 U/mL penicillin, ‧50 μg/mL streptomycin (Gibco), 50 μmol/L 2-indole ethanol (Gibco), and 100 U. /mL Human IL-2 (Cell Science Institute, Inc.) is used. After the test compound was dissolved in DMSO, it was diluted with the culture medium so that the final concentration of DMSO became 0.1%. The spleen cells (3 × 10 ⁵ /well) prepared by the culture medium were inoculated into the wells of a 96-well flat bottom plate (Corning), and the test compound and 10 ng/mL of human IL-23 (R&D systems) were added. The cells were cultured for 3 days at 37 ° C under 5% CO ₂ . Further, wells to which human IL-23 was not added and to which the test compound was not added, and pores to which human IL-23 was added and the test compound was not added were set. After the completion of the culture, the culture supernatant was taken, and the amount of IL-17 produced in the supernatant was quantified by an ELISA method (R&D Systems).

The IL-17 production inhibition rate (%) was calculated by the following formula 2.

IL-17 production inhibition rate (%) = (1 - ((IL-23 addition and IL-17 production when the test compound is added) - (IL-17 is not added and the test compound is not added when IL-17 The amount of production)) / ((IL-23 is added when IL-23 is added and the compound is not added) - (IL-17 is not added and the IL-17 is not added when the test compound is not added))) × 100 ‧‧‧式2

The IL-17 production inhibition rate (%) at 5 μmol/L of the test compound is shown in Table 3-1 to Table 3-3.

From this result, it is clear that the cyclic amine derivative (I), its stereoisomer or the hydrate thereof, or the pharmacologically acceptable salts thereof inhibit the production of IL-17.

(Example 124) Symptom inhibitory effect on imiquimod-induced dryness mode in mice: an increase in the thickness of the ear shell was used as an indicator of symptom deterioration, and the cyclic amine derivative in the mouse dryness mode induced by imiquimod was evaluated ( I), its stereoisomers or the action of such hydrates, or their pharmacologically acceptable salts. The imiquimod-induced mouse cognac mode was produced by partially changing the method of Schaper et al. (The Journal of Dermatological Science, 2013, Vol. 71, No. 1, p. 29-36).

BALB/c mice (male, 7 weeks old) (Charles River Japan Co., Ltd.) were prepared for breeding and used at 8 weeks of age. In order to induce dryness-like symptoms, 5 mg of BESELNA was applied to the outer side of the left and right ear shells of the mouse from the first day of the administration of imiquimod (hereinafter, the induction day) to the 7th day after the 7th day after the induction. CREAM 5% (imiquimod dose 0.5 mg / individual / day).

The test compound was administered to the mice at a dose of 10 mg/kg once a day from the 3rd day after the induction to the 7th day after the induction. As the test compound, the compound of Example 46, the compound of Example 74, the compound of Example 109, and the compound of Example 117 were used. Further, the compound of Example 46, the compound of Example 74, the compound of Example 109 and the compound of Example 117 were each suspended in a 0.5 w/v% methylcellulose solution and orally administered. The group in which the compound of Example 46 was administered to the mouse was designated as the compound administration group of Example 46, and the group to which the compound of Example 74 was administered was designated as the compound administration group of Example 74, and the administration example was administered. The group of the compound of 109 was set as the compound administration group of Example 109, and the group which gave the compound of Example 117 was set as the compound administration group of Example 117. In the vehicle-administered group, the vehicle (0.5 w/v% methylcellulose solution) of each test compound was administered in the same manner.

Using a digital micrometer (Mitutoyo Co., Ltd.), the thickness of the ear shell around the imiquimod before induction (before induction) and the thickness of the ear shell around the eighth day after induction were measured. The average value of the thickness of the left and right ear shells was taken as the thickness of the ear shell, and the change (the thickness of the ear shell on the 8th day after induction - the thickness of the ear shell before induction) was used as an index for evaluation of the efficacy.

The results are shown in Fig. 1, Fig. 2, Fig. 3 and Fig. 4. The vertical axis represents the change in thickness of the ear shell (mm) (mean ± standard error, n = 6). The "solvent" on the horizontal axis indicates the solvent-administered group, the "compound of the example 46" indicates the compound-administered group of the embodiment 46, and the "compound of the example 74" indicates the compound-administered group of the example 74, "Example 109 The compound of Example 117 represents the compound administration group of Example 109, and the "compound of Example 117" represents the compound administration group of Example 117. * Marker indicates that the comparison with the vehicle administration group (Student's t-test) was statistically significant (*: P < 0.05).

By the imiquimod induction, the thickness of the ear shell on the 8th day after induction of the vehicle administration group was increased by 0.25 mm to 0.27 mm with respect to the thickness of the ear shell before induction. The increase in the thickness of the ear shell was statistically significantly inhibited by 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, it is clear that the cyclic amine derivative (I), its stereoisomer or the hydrate thereof, or the pharmacologically acceptable salt thereof exhibits a remarkable symptom-inhibiting effect on cognac.

(Example 125) Symptom suppression effect on experimental autoimmune encephalomyelitis model in mice: Evaluation of experimental autologous autoimmune encephalomyelitis model in mice by increasing the score of neurological symptoms as an indicator of symptom deterioration The cyclic amine derivative (I), its stereoisomer or the hydrate of these, or their pharmacologically acceptable salts. The mouse experimental autoimmune encephalomyelitis model was prepared by partially modifying the method of Hindinger et al. (Journal of Neuroscience Research, 2006, Vol. 84, p. 1225-1234).

A partially synthesized peptide (MOG35-55; CS Bio) containing a concentration of myelin oligodendrocyte glycoprotein at a concentration of 4 mg/mL in PBS and Freund's complete adjuvant The MOG35-55 administration solution was mixed in equal amounts and inoculated into the skin of both sides of the lateral abdomen of C57BL/6J mice (male, 8 weeks old) (Charles River Japan Co., Ltd.) totaling 0.1 mL (one side 0.05) mL). Further, on the day of inoculation of the MOG35-55 administration solution and 2 days later, 200 μL of pertussis toxin (Sigma) prepared at a concentration of 1 μg/mL was administered intraperitoneally in the mouse.

After inoculation of the MOG35-55 administration solution, the test compound was administered to the mice. For the test compound, the compound of Example 74 was used. Further, the compound of Example 74 was suspended in a 0.5 w/v% methylcellulose solution, and 13 days after the inoculation of the MOG35-55 administration solution, it was orally administered once every day for 1 mg/kg. The group in which the compound of Example 74 was administered to mice was designated as the compound administration group of Example 74. For the vehicle administration group, the vehicle (0.5 w/v% methylcellulose solution) of each test compound was administered in the same manner.

After the inoculation of the MOG35-55 administration solution, the neurological symptom scores of the group administered with the test compound and the corresponding vehicle administration group were scored (0: normal, 1: tail slack or hind limb weakness, 2: tail slack) And hind limb weakness, 3: partial paralysis of the hind limbs, 4: complete paralysis of the hind limbs, 5: sudden death). The scoring method uses the method described in Current Protocols in Immunology (John Wiley & Sons. Inc, 2000, p. 15.1.1-15.1.20).

The results are shown in Fig. 5. The vertical axis represents the neurological symptom score (mean ± standard error, n = 10). The "solvent" on the horizontal axis indicates the solvent-administered group, and the "compound of the example 74" indicates the compound-administered group of Example 74. Fig. 5 is a graph showing the neurological symptom score after 29 days of inoculation of the MOG35-55 administration solution. * Marker indicates that the comparison with the vehicle administration group (Wilcoxon assay) was statistically significant (*: P < 0.05).

The neurological symptom score of the vehicle administration group was increased to 2.1 by the inoculation of the MOG35-55 administration solution. This increase in neurological symptom score was statistically significantly inhibited by administration of the compound of Example 74.

From the results, it is clear that the cyclic amine derivative (I), its stereoisomer or the hydrate thereof, or the pharmacologically acceptable salts thereof exhibit significant symptom-suppressing effects on multiple sclerosis. .

(Example 126) Symptom inhibitory effect on DNFB-induced allergic dermatitis mode in mice: an increase in the rate of swelling of the ear shell was used as an indicator of symptom deterioration, and the cyclic amine derivative in the model of allergic dermatitis induced by DNFB in mice was evaluated. The action of the substance (I), its stereoisomers or hydrates thereof, or their pharmacologically acceptable salts. The DNFB-induced mouse allergic dermatitis pattern was produced by partially changing the method of Curzytek et al. (Pharmacological Reports, 2013, Vol. 65, p. 1237-1246).

BALB/c mice (female, 6 weeks old) (Charles River Japan Co., Ltd.) were prepared and used at 7 or 8 weeks of age. 25 μL of a 0.5 v/v% DNFB solution dissolved in acetone: olive oil (4:1) was applied to the back of the mouse. The mice were sensitized by repeating the same procedure the next day. Four days after sensitization, 10 μL of a 0.2 v/v% DNFB solution dissolved in acetone: olive oil (4:1) was applied to both sides of the right ear shell of the sensitized mouse to cause inflammation.

The test compound was administered to the mice at a dose of 10 mg/kg before causing 1 hour. As the test compound, the compound of Example 46, the compound of Example 74, the compound of Example 109, and the compound of Example 117 were used. Further, the compound of Example 46, the compound of Example 74, the compound of Example 109 and the compound of Example 117 were each suspended in a 0.5 w/v% methylcellulose solution and orally administered. The group in which the compound of Example 46 was administered to the mouse was designated as the compound administration group of Example 46, and the group to which the compound of Example 74 was administered was designated as the compound administration group of Example 74, and the administration example was administered. The group of the compound of 109 was set as the compound administration group of Example 109, and the group which gave the compound of Example 117 was set as the compound administration group of Example 117. In the vehicle administration group, the vehicle (0.5 w/v% methylcellulose solution) of the test compound was administered in the same manner.

Using a digital micrometer (Mitutoyo Co., Ltd.), the thickness of the right ear shell before and after application of the DNFB solution causing the day was measured, and the thickness of the right ear shell after 24 hours was caused. The swelling rate of the ear shell was calculated by the following formula 3 as an index for evaluation of the efficacy.

Ear swelling rate (%) = ((the thickness of the right ear shell after 24 hours) - (the thickness of the right ear shell caused by the front) / / the thickness of the right ear shell × 100‧‧‧3

The results are shown in Fig. 6, Fig. 7, Fig. 8, and Fig. 9. The vertical axis indicates the swelling rate (%) of the ear shell (mean ± standard error, n = 6 to 7). The "solvent" on the horizontal axis indicates the solvent-administered group, the "compound of the example 46" indicates the compound-administered group of the embodiment 46, and the "compound of the example 74" indicates the compound-administered group of the example 74, "Example 109 The compound of Example 117 represents the compound administration group of Example 109, and the "compound of Example 117" represents the compound administration group of Example 117. * Marker indicates that the comparison with the vehicle administration group (Student's t-test) was statistically significant (*: P < 0.05).

By the ear shell coating of the DNFB solution, the swelling rate of the ear shell of the vehicle administration group was increased by 30.9% to 41.6%. The increase in swelling rate of the ear shell was statistically significantly inhibited by 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, it is clear that the cyclic amine derivative (I), its stereoisomers or hydrates thereof, or their pharmacologically acceptable salts, are allergic to dermatitis, especially to contact. Sexual dermatitis shows a significant symptom-suppressing effect.

(Example 127) For Oxazolinone-induced symptom inhibition effect in atopic dermatitis model in mice: increasing the thickness of the ear shell as an indicator of symptom deterioration, evaluation The oxazolinone induces the action of the cyclic amine derivative (I), its stereoisomers or hydrates thereof, or their pharmacologically acceptable salts in a mouse model of atopic dermatitis. The oxazolinone-induced mouse atopic dermatitis pattern was produced by partially changing the method of Nakajima et al. (Journal of Investigative Dermatology, 2014, Vol. 134, p. 2122-2130).

BALB/c mice (female, 7 weeks old) (Charles River Japan Co., Ltd.) were prepared for breeding and used at 8 weeks of age. Apply 25 μL of 3w/v% dissolved in ethanol to the back of the mouse The solution was sensitized to the oxazolinone solution. After 5 days from sensitization to 13 days, 10 μL of 0.6 w/v% dissolved in ethanol was applied to both sides of the right ear shell of the sensitized mice every other day. An oxazolinone solution that causes inflammation.

From the sensitization day to the 15th day after the sensitization, the test compound was administered to the mice once a day at a dose of 10 mg/kg. As the test compound, the compound of Example 46, the compound of Example 74, the compound of Example 109, and the compound of Example 117 were used. Further, 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 in which the compound of Example 46 was administered to the mouse was designated as the compound administration group of Example 46, and the group to which the compound of Example 74 was administered was designated as the compound administration group of Example 74, and the administration example was administered. The group of the compound of 109 was set as the compound administration group of Example 109, and the group which gave the compound of Example 117 was set as the compound administration group of Example 117. For the vehicle administration group, the vehicle (0.5 w/v% methylcellulose solution) of each test compound was administered in the same manner.

Determination of sensitization day using a digital micrometer (Mitutoyo) The thickness of the right ear shell before application (before sensitization) of the oxazolinone solution, and finally the thickness of the right ear shell the next day. The change in the thickness of the ear shell (which ultimately causes the thickness of the right ear shell on the next day - the thickness of the right ear shell before sensitization) is used as an indicator of the efficacy evaluation.

The results are shown in Fig. 10, Fig. 11, Fig. 12, and Fig. 13. The vertical axis represents the change in thickness of the ear shell (mm) (mean ± standard error, n = 6 to 7). The "solvent" on the horizontal axis indicates the solvent-administered group, the "compound of the example 46" indicates the compound-administered group of the embodiment 46, and the "compound of the example 74" indicates the compound-administered group of the example 74, "Example 109 The compound of Example 117 represents the compound administration group of Example 109, and the "compound of Example 117" represents the compound administration group of Example 117. * Marker indicates that the comparison with the vehicle administration group (Student's t-test) was statistically significant (*: P < 0.05).

By The ear shell coating of the oxazolinone solution, the concentration of the ear shell of the next day caused by the solvent administration group increased by 0.68 mm to 0.70 mm with respect to the thickness of the ear shell before sensitization. The increase in the thickness of the ear shell was statistically significantly inhibited by 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, it is clear that the cyclic amine derivative (I), its stereoisomer or the hydrate thereof, or their pharmacologically acceptable salts, to allergic dermatitis, especially to ectopic Sexual dermatitis shows a significant symptom-suppressing effect.

Industrial availability

The cyclic amine derivative (I) of the present invention, a stereoisomer thereof or a hydrate of the above, or a pharmacologically acceptable salt thereof, can be utilized as a lend because of its excellent RORγ antagonist activity. A medicine that can anticipate a disease condition improvement or a symptom relief by a function of suppressing RORγ. In particular, a therapeutic or prophylactic agent for an allergic disease such as an autoimmune disease such as multiple sclerosis or dryness, or allergic dermatitis such as contact dermatitis or atopic dermatitis can be used.

Claims (11)

a cyclic amine derivative represented by the following formula (I), a stereoisomer thereof or a hydrate of the above, or a pharmacologically acceptable salt thereof; Wherein A represents a group represented by the following formula (II-1), (II-2), (II-3), (II-4) or (II-5): (wherein R ¹ represents an aryl group or a heteroaryl group in which one to three arbitrary hydrogen atoms may be substituted with a group selected from the group consisting of a halogen 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 (one or three hydrogen atoms of the alkyl group may be substituted by a halogen atom) and a carbon number of 1 Alkoxy group of ~3 (the alkoxy group may have one to three arbitrary hydrogen atoms which may be substituted by a halogen atom); R ² represents a halogen atom, and R ³ represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms; The double line of the line and the dotted line indicates a single bond or a double bond, and the wavy line indicates the bond point with the general formula (I); X represents -C(=O)-(CH ₂ ) _n -R ⁴ or -S(= O) _{2 -} R ⁵ , n represents an integer of 0 to 5, and R ⁴ represents a cyano group, a hydroxyl 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 , ring constitutes a cyclic ether group of 4 to 6 atoms, and an alkyl group having 1 to 3 carbon atoms (this Any one or two of the hydrogen atoms of the alkyl group may be substituted by a halogen atom, or one or two hydrogen atoms may be substituted with a carbon number of 1 to 3, and R ⁵ represents a carbon number. alkyl of 1 to 3, R ⁶ represents a hydrogen atom or a carbon atoms of 1 to 3 alkyl group (the alkyl group 1 to 3 of the hydrogen atoms may be substituted by any of halogen atom), R ⁷ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, the carbon atoms or acyl of 2 to 4 carbon atoms, alkylsulfonyl of 1 to 3, Base, Y represents an oxygen atom, a sulfur atom or =N-CN]. A cyclic amine derivative according to claim 1, a stereoisomer thereof or a hydrate of the above, or a pharmacologically acceptable salt thereof, wherein R ¹ is 1 or 2 of any hydrogen atom a phenyl, pyridyl or pyrimidinyl group selected from the group consisting of a fluorine atom, a chlorine atom, a cyano group, a hydroxymethyl group, a -C(=O)-OR ^{3 group} , and an alkyl group having 1 to 3 carbon atoms a sulfonyl group, an alkyl group having 1 to 3 carbon atoms (the alkyl group is one or three of any hydrogen atom may be substituted by a fluorine atom or a chlorine atom) and an alkoxy group having a carbon number of 1 to 3 (the alkoxy group) Any one hydrogen atom of one to three groups may be substituted by a fluorine atom or a chlorine atom; R ² is a fluorine atom or a chlorine atom, R ³ is an alkyl group having 1 to 3 carbon atoms, and n is an integer of 0 to 4; R ⁴ is cyano, hydroxy, -N(R ⁶ )R ⁷ , -NH-C(=Y)-NHR ⁶ , -NH-S(=O) ₂ -NHR ⁶ , -C(=O)-OR ⁶ , -C(=O)-NHR ⁶ , an oxo-3-yl group, an alkyl group having 1 to 3 carbon atoms (any one hydrogen atom of the alkyl group may be substituted by a fluorine atom or a chlorine atom) Or one or two heteroaryl groups in which any hydrogen atom may be substituted by a methyl group, and R ⁶ is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms (the alkyl group may be any one of 3 to 3 hydrogen atoms) Take the fluorine atom or chlorine atom generation). A cyclic amine derivative according to claim 1, a stereoisomer thereof or a hydrate of the above, or a pharmacologically acceptable salt thereof, wherein R ¹ is 1 or 2 of any hydrogen atom a phenyl group selected from the group consisting of a fluorine atom, a chlorine atom, a cyano group, an isopropyl group, a methyl group of one to three, and a methyl group substituted by a fluorine atom, and one to three a methoxy group in which any hydrogen atom may be substituted by a fluorine atom; 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 , oxo-3-yl, or one or two of any hydrogen atom which may be substituted with a methyl group, imidazolyl or pyrazolyl , triazolyl, 1,3,4- A oxazolyl, tetrazolyl or pyridyl group, R ⁵ is a methyl group, R ⁶ is a hydrogen atom or a methyl group, and R ⁷ is a hydrogen atom, a methyl group, an ethyl sulfonyl group or a methylsulfonyl group. A cyclic amine derivative according to claim 1, a stereoisomer thereof or a hydrate of the above, or a pharmacologically acceptable salt thereof, wherein R ¹ is 1 or 2 of any hydrogen atom a phenyl group 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; and R ² is a chlorine atom. n is an integer of 0 to 2, and R ⁴ is methyl, cyano, -N(R ⁶ )R ⁷ , -NH-C(=Y)-NHR ⁶ , -NH-S(=O) ₂ -NHR ⁶ Or one or two of any hydrogen atom may be substituted by a methyl group, a triazolyl group, 1,3,4- A oxazolyl or tetrazolyl 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 ethyl sulfonyl group or a methylsulfonyl group, and Y is an oxygen atom or =N- CN.  A medicine comprising the cyclic amine derivative according to any one of claims 1 to 4, a stereoisomer thereof or a hydrate of the above, or a pharmacologically acceptable salt thereof as an active ingredient.    A retinoid-associated orphan receptor gamma antagonist comprising the cyclic amine derivative of any one of claims 1 to 4, a stereoisomer thereof or a hydrate thereof, or the like A pharmacologically acceptable salt is used as an active ingredient.    A therapeutic or prophylactic agent for an autoimmune disease, which comprises the cyclic amine derivative according to any one of claims 1 to 4, a stereoisomer thereof or a hydrate thereof, or a pharmacologically equivalent thereof An acceptable salt is used as an active ingredient.    A therapeutic or prophylactic agent for multiple sclerosis or dryness, which comprises the cyclic amine derivative according to any one of claims 1 to 4, a stereoisomer thereof or a hydrate thereof, or a pharmacological agent thereof Academically acceptable salts are used as active ingredients.    A therapeutic or prophylactic agent for an allergic disease, which comprises the cyclic amine derivative according to any one of claims 1 to 4, a stereoisomer thereof or a hydrate thereof, or a pharmacologically acceptable one thereof The permissible salt is used as an active ingredient.    A therapeutic or prophylactic agent for allergic dermatitis, which comprises the cyclic amine derivative according to any one of claims 1 to 4, a stereoisomer thereof or a hydrate thereof, or the pharmacologically An acceptable salt is used as an active ingredient.    A therapeutic or prophylactic agent for contact dermatitis or atopic dermatitis, which comprises the cyclic amine derivative of any one of claims 1 to 4, a stereoisomer thereof or a hydrate thereof, or Their pharmacologically acceptable salts are used as active ingredients.