WO2019044940A1 - Cyclic amine derivative and use thereof for medical purposes - Google Patents

Cyclic amine derivative and use thereof for medical purposes Download PDF

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WO2019044940A1
WO2019044940A1 PCT/JP2018/032045 JP2018032045W WO2019044940A1 WO 2019044940 A1 WO2019044940 A1 WO 2019044940A1 JP 2018032045 W JP2018032045 W JP 2018032045W WO 2019044940 A1 WO2019044940 A1 WO 2019044940A1
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雄輝 松村
英喜 高橋
新之助 林
バレットマーシャル
真幸 星
拓実 青木
和也 大角
慎也 横坂
目黒　裕之
こずえ 高垣
戒能　美枝
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東レ株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/92—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with a hetero atom directly attached to the ring nitrogen atom
    • C07D211/96—Sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to cyclic amine derivatives and their pharmaceutical uses.
  • Autoimmune disease is a general term for diseases in which excessive immune reaction causes symptoms by attacking normal cells and tissues of the patient.
  • diseases in which excessive immune reaction causes symptoms by attacking normal cells and tissues of the patient.
  • multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory Intestinal diseases, ankylosing spondylitis, uveitis or polymyalgia rheumatica can be mentioned.
  • Non-patent Documents 1 and 2 Various mechanisms have been proposed for the onset and progression of autoimmune diseases, and one of them is Th17 cells, which is a subset of helper T cells, and IL-17, which is an inflammatory cytokine that it produces. It is known to play 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 is involved in induction of inflammatory cytokines, chemokines, metalloproteases and other inflammatory mediators and neutrophil migration. ing. Therefore, if it is possible to suppress the production or function of IL-17, a strong anti-inflammatory effect is considered to be exerted, and clinical trials of anti-IL-17 antibodies with indications for various autoimmune diseases are conducted. It is done.
  • ROR ⁇ nuclear receptor retinoid-related orphan receptor ⁇
  • Non-patent Document 5 In patients with autoimmune diseases (multiple sclerosis, psoriasis, systemic lupus erythematosus etc.), it has been reported that the expression level of ROR ⁇ in peripheral blood mononuclear cells shows a high value as compared with healthy people (Non-patent Document 5) And 6). It is reported that in ROR ⁇ knockout mice, the pathological condition of mouse experimental autoimmune encephalomyelitis model, which is an animal model of multiple sclerosis, is suppressed, and symptoms of autoimmune diseases such as colitis are suppressed. (Non-Patent Documents 3 and 7).
  • ROR ⁇ antagonists which are compounds that inhibit the binding of ROR ⁇ to coactivators, are expected to be useful as therapeutic or prophylactic agents for autoimmune diseases.
  • N- (5- (N- (4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) phenyl) sulfamoyl) has hitherto been described.
  • Non-patent Document 9 6- (2-chloro-4-methylphenyl) -3- (4-cyclopropyl-5- (3-neopentylcyclobutyl) Substituted azole derivatives such as isoxazol-3-yl) -5-oxohexanoic acid (Patent Document 1), N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl Sulfonylbenzene derivatives such as -4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide (Patent Document 2) or 1-acetyl-N- (2-chloro-2'-) Trifluoromethoxy) - [1,1'-biphenyl] -4-yl) piperidine-2-carboxamide biaryl derivatives such as (Patent Document 3) have been reported.
  • JP 2012-236822 A International Publication No. 2012/027965 International Publication No. 2017/131156 WO 2007/003962 International Publication No. 2008/008551
  • this invention aims at providing the novel compound which has ROR (gamma) antagonist activity and exhibits a therapeutic effect or a preventive effect with respect to autoimmune diseases, such as psoriasis.
  • the present invention provides a cyclic amine derivative represented by the following general formula (I), a stereoisomer or a hydrate thereof, or a pharmacologically acceptable salt thereof.
  • R 1 represents a halogen atom
  • n represents 0 to R 2 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or a heteroaryl group
  • 3 represents an alkyl group having 1 to 3 carbon atoms
  • m represents 0 or 1
  • A represents a group represented by the following general formula (II-1) or (II-2).
  • R 4 represents a hydrogen atom, a halogen atom or a methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a halogen atom)
  • p represents Represents an integer of 0 to 2
  • q represents 1 or 2
  • R 5 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or-(CH 2 ) r -OR 7
  • R 6 represents a phenyl group (wherein the optional one hydrogen atom is a halogen atom, and the methyl group (wherein the optional methyl group is a hydrogen atom of one to three substituted by a halogen atom) Or methoxy group (in the methoxy group, one to three arbitrary hydrogen atoms may be substituted with halogen atoms), or ethynyl.
  • R 1 is a fluorine atom or a chlorine atom
  • n is an integer of 0 to 2
  • R 2 is a hydrogen atom, having 1 to 3 carbon atoms
  • R 4 is a hydrogen atom
  • a fluorine atom, a chlorine atom or a methyl group in the methyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom
  • p is 0 or 1
  • R 5 is an alkyl group having 1 to 4 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or-(CH 2 ) r -OR 7
  • R 6 is a phenyl
  • a hydrogen atom may be substituted with a fluorine atom or a chlorine atom)), or an ethynyl group (in the ethynyl group, a hydrogen atom is a methyl group (the methyl group is one) -3 optional hydrogen atoms may be substituted by fluorine atom or chlorine atom)), r is 2 and R 7 is hydrogen atom or methyl It is preferably a group.
  • R 1 is a fluorine atom or a chlorine atom
  • n is 0 or 1
  • R 2 is a hydrogen atom, a methyl group, cyclopropyl
  • R 3 is a methyl group
  • R 4 is a chlorine atom or a trifluoromethyl group
  • p is 1 and q is 2
  • R 5 is a propyl group, a butyl group, an isobutyl group or a cyclopropylmethyl group
  • R 6 is a phenyl group (in this phenyl group, one optional hydrogen atom is a fluorine atom, a chlorine atom, a trifluoromethyl) And trifluoromethoxy, which may be substituted), 1-propynyl or 3,3,3-trifluoropropynyl.
  • ROR ⁇ antagonist activity can be expected, and further, excellent therapeutic effect or preventive effect in autoimmune diseases such as psoriasis can be expected.
  • R 1 is a chlorine atom
  • R 2 is a hydrogen atom, an imidazolyl group or a tetrazolyl group
  • R 4 is a trifluoromethyl group
  • p is 1
  • q is 2
  • R 5 is a propyl group
  • R 6 is a phenyl group (in the phenyl group, one arbitrary hydrogen atom is substituted with a fluorine atom, a chlorine atom, a trifluoromethyl group or a trifluoromethoxy group). Is more preferable).
  • ROR ⁇ antagonist activity can be expected, and further, excellent therapeutic effect or preventive effect in autoimmune diseases such as psoriasis can be expected.
  • the present invention is a medicament comprising, as an active ingredient, the cyclic amine derivative represented by the above general formula (I), a stereoisomer thereof or a hydrate thereof, or a pharmacologically acceptable salt thereof And ROR ⁇ antagonists.
  • the above-mentioned medicine is preferably a therapeutic agent or a preventive agent for an autoimmune disease, and as a therapeutic agent or a preventive agent for the above-mentioned autoimmune disease, a therapeutic agent or a preventive agent for psoriasis is more preferable.
  • the cyclic amine derivative of the present invention since the cyclic amine derivative of the present invention, its stereoisomer or hydrate thereof, or pharmacologically acceptable salts thereof have ROR ⁇ antagonist activity, they can effectively suppress the function of ROR ⁇ , and can self It can be used as a therapeutic agent or prophylactic agent for immune diseases.
  • the cyclic amine derivative of the present invention is characterized by being represented by the following general formula (I).
  • R 1 represents a halogen atom
  • n represents 0 to R 2 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or a heteroaryl group
  • 3 represents an alkyl group having 1 to 3 carbon atoms
  • m represents 0 or 1
  • A represents a group represented by the following general formula (II-1) or (II-2).
  • R 4 represents a hydrogen atom, a halogen atom or a methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a halogen atom)
  • p represents Represents an integer of 0 to 2
  • q represents 1 or 2
  • R 5 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or-(CH 2 ) r -OR 7
  • R 6 represents a phenyl group (wherein the optional one hydrogen atom is a halogen atom, and the methyl group (wherein the optional methyl group is a hydrogen atom of one to three substituted by a halogen atom) Or methoxy group (in the methoxy group, one to three arbitrary hydrogen atoms may be substituted with halogen atoms), or ethynyl.
  • halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
  • C1-C3 alkyl group means a methyl group, an ethyl group, a propyl group or an isopropyl group.
  • C1-C4 alkyl group means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group.
  • the “C1-C5 alkyl group” is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a sec-pentyl group Means a tert-pentyl group, a neopentyl group.
  • the "C1-C6 alkyl group” is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a sec-pentyl group And tert-pentyl, neopentyl, 1-methylpentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl or neohexyl.
  • C3-C5 cycloalkyl group means a cyclopropyl group, a cyclobutyl group or a cyclopentyl group.
  • C 3-6 cycloalkyl group means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
  • C4 or C5 cycloalkylalkyl group means a cyclopropylmethyl group, a cyclopropylethyl group or a cyclobutylmethyl group.
  • C 4 -C 6 cycloalkylalkyl group means a cyclopropylmethyl group, a cyclopropylethyl group, a cyclopropylpropyl group, a cyclobutylmethyl group, a cyclobutylethyl group or a cyclopentylmethyl group.
  • methyl group in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a halogen atom
  • a halogen atom means that one to three arbitrary hydrogen atoms of the methyl group are Each independently represents a group which may be substituted by the above-mentioned halogen atom, and examples thereof include a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group or a trichloromethyl group.
  • methyl group in the methyl group, any one to three optional hydrogen atoms may be substituted with a fluorine atom or a chlorine atom
  • methyl group means any one to three hydrogens of the methyl group.
  • Each of the atoms independently represents a group which may be substituted with a fluorine atom or a chlorine atom, and examples thereof include a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group and a trichloromethyl group.
  • the “methoxy group (in the methoxy group, one to three optional hydrogen atoms may be substituted with a halogen atom)” means that one to three optional hydrogen atoms of the methoxy group are Each independently represents a group which may be substituted by the above-mentioned halogen atom, and examples thereof include a methoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group or a trichloromethoxy group.
  • the “methoxy group (in the methoxy group, one to three arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom)” means any one to three hydrogens of the methoxy group.
  • Each of the atoms independently represents a group which may be substituted with a fluorine atom or a chlorine atom, and examples thereof include a methoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group and a trichloromethoxy group.
  • Heteroaryl group means a heteroaromatic group containing 1 to 4 hetero atoms each independently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, each independently selected from, for example, , Thienyl group, pyrrolyl group, furyl group, thiazolyl group, imidazolyl group, oxazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, thiadiazolyl group, triazolyl group, oxadiazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group Group, triazinyl group, indolyl group, isoindolyl group, benzimidazolyl group, indazolyl group, quinolyl group, isoquinolyl group, quinazolyl group, quinoxalinyl group, phthala
  • a 5-membered heteroaryl group containing 1 to 4 nitrogen atoms is a pyrrolyl group, thiazolyl group, imidazolyl group, oxazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, thiadiazolyl group, triazolyl group, oxadiazolyl group or The tetrazolyl group is meant.
  • the phenyl group in this phenyl group, one arbitrary hydrogen atom may be substituted with a halogen atom, and the methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a halogen atom.
  • the methoxy group means “one of the phenyl groups.
  • Selected hydrogen atoms are the above-mentioned halogen atom, the above-mentioned methyl group (in the methyl group, 1 to 3 arbitrary hydrogen atoms may be substituted by the halogen atom), or the above-mentioned methoxy group
  • the methoxy group means a group which may be substituted with one to three arbitrary hydrogen atoms optionally substituted with a halogen atom), and examples thereof include a phenyl group, a fluorophenyl group, Chlorophenyl group, bromophenyl group, Dophenyl group, tolyl group, (fluoromethyl) phenyl group, (difluoromethyl) phenyl group, (trifluoromethyl) phenyl group, (trichloromethyl) phenyl group, methoxyphenyl group, (fluoromethoxy) phenyl group, (difluoromethoxy) And a phenyl group, a (triflu
  • Phenyl group in the phenyl group, one optional hydrogen atom is substituted with a fluorine atom, a chlorine atom, a methyl group (the methyl group is substituted with one to three optional hydrogen atoms by a fluorine atom or a chlorine atom
  • the methoxy group in the methoxy group, one to three arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom
  • the methoxy group (the methoxy group is a group optionally substituted by 1 to 3 arbitrary hydrogen atoms optionally substituted with a fluorine atom or a chlorine atom), for example, a phenyl group , Fluorophenyl group, Rolophenyl group, tolyl group, (fluoromethyl) phenyl group, (difluoromethyl) phenyl group, (trifluoromethyl) phenyl group, (trichloromethyl) phenyl group, methoxyphenyl group, (fluoromethoxy) phenyl group, (difluoromethoxy) And a phenyl group, a (trifluoromethoxy) phenyl group or a (trichloromethoxy) phenyl group.
  • a phenyl group Fluorophenyl group, Rolophenyl group, tolyl group, (fluoromethyl) phenyl group, (difluoromethyl) phen
  • Phenyl group (the phenyl group may be optionally substituted with one hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group or a trifluoromethoxy group)” is a phenyl group, a fluoro group It means a phenyl group, a chlorophenyl group, a (trifluoromethyl) phenyl group or a (trifluoromethoxy) phenyl group.
  • examples of the substitution position include the 3rd or 4th position of the phenyl group.
  • Ethynyl group (the ethynyl group may be substituted with a hydrogen atom, a methyl group (the methyl group may be substituted with a halogen atom of 1 to 3 arbitrary hydrogen atoms))
  • the above “.)” Means that the hydrogen atom of the ethynyl group is substituted by the above-mentioned methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with halogen atoms).
  • It also means a group which may be, for example, ethynyl group, 1-propynyl group, 3-fluoropropionyl group, 3,3-difluoropropynyl group, 3,3,3-trifluoropropynyl group, 3-chloropropionyl group, 3,3, A 3-dichloropropynyl group or a 3,3,3-trichloropropynyl group may be mentioned.
  • “Ethynyl group (the ethynyl group is substituted with a hydrogen atom, a methyl group (the methyl group may be substituted with a hydrogen atom or a chlorine atom of 1 to 3 arbitrary hydrogen atoms)) And the above methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom).
  • the “cyclic amine derivative represented by the general formula (I), its stereoisomer or hydrate thereof, or the pharmacologically acceptable salt thereof” is a cyclic amine represented by the general formula (I) Derivative, stereoisomer of cyclic amine derivative represented by the general formula (I), hydrate of cyclic amine derivative represented by the general formula (I), stereoisomer of cyclic amine derivative represented by the general formula (I) Hydrate, pharmacologically acceptable salt of cyclic amine derivative represented by the general formula (I), pharmacologically acceptable salt of stereoisomer of cyclic amine derivative represented by the general formula (I), Pharmacologically acceptable salt of the hydrate of the cyclic amine derivative represented by the general formula (I) or pharmacologically acceptable of the hydrate of the stereoisomer of the cyclic amine derivative represented by the general formula (I) Mean salt.
  • R 1 is preferably a fluorine atom or a chlorine atom, and more preferably a chlorine atom.
  • N is preferably an integer of 0 to 2, more preferably 0 or 1, and still more preferably 1.
  • R 2 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or a 5-membered ring containing 1 to 4 nitrogen atoms It is preferably a heteroaryl group, more preferably a hydrogen atom, a methyl group, a cyclopropyl group, an imidazolyl group, a triazolyl group or a tetrazolyl group, and still more preferably a hydrogen atom, an imidazolyl group or a tetrazolyl group.
  • R 3 is preferably a methyl group.
  • R 4 is a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group (in the methyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom) It is preferably a chlorine atom or a trifluoromethyl group, more preferably a trifluoromethyl group.
  • substitution position of R 4 for example, in the case of a tetrahydroisoquinoline derivative in which p is 1 and q is 2 in the following general formula (II-1), the 5 position, 6 position, 7 position or 8 position is mentioned In the case of an indoline derivative in which p is 0 and q is 2 in the following general formula (II-1), the 4-, 5-, 6- or 7-position is mentioned, and the following general formula (II-1) In the case of isoindoline derivatives in which p is 1 and q is 1, the 4- or 5-position is mentioned.
  • P is preferably 0 or 1, and more preferably 1.
  • Q is preferably 2.
  • R 5 is preferably an alkyl group having 1 to 4 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or-(CH 2 ) r -OR 7 , and a propyl group, a butyl group, an isobutyl group or cyclopropyl
  • the methyl group is more preferably a propyl group, a butyl group or an isobutyl group.
  • R 6 is a phenyl group (wherein the optional one hydrogen atom is a fluorine atom, a chlorine atom, a methyl group (the methyl group is an optional hydrogen atom of 1 to 3 is a fluorine atom or chlorine Optionally substituted by an atom) or methoxy group (in the methoxy group, 1 to 3 arbitrary hydrogen atoms may be substituted by a fluorine atom or a chlorine atom), Or ethynyl group (the ethynyl group may be a hydrogen atom, a methyl group (the methyl group may be optionally substituted with 1 to 3 hydrogen atoms, a fluorine atom or a chlorine atom)).
  • R is preferably 2.
  • R 7 is preferably a hydrogen atom or a methyl group.
  • the cyclic amine derivative represented by the above general formula (I) preferably has a configuration represented by the following general formula (Ia). That is, in the cyclic amine derivative represented by the above general formula (I), in the above general formula (I), the configuration of the carbon atom at the 2-position of the piperidinyl group is preferably R configuration.
  • the preferable R 1 , the preferable R 2 , the preferable R 3 , the preferable R 4 , the preferable R 5 , and the preferable R 6 as described above.
  • R 1 is a halogen atom
  • n is an integer of 0 to 3
  • R 2 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms
  • R 4 is a cycloalkyl alkyl group or heteroaryl group having 4 to 6 carbon atoms
  • R 3 is an alkyl group having 1 to 3 carbon atoms
  • m is 0 or 1
  • A is a group represented by the following general formula (II R 4 is a hydrogen atom, a halogen atom or a methyl group (in the methyl group, one to three arbitrary hydrogen atoms are substituted with a halogen atom)
  • p is an integer of 0 to 2;
  • R 2 is a hydrogen atom, an imidazolyl group or a tetrazolyl group;
  • R 4 is a trifluoromethyl group;
  • p is 1;
  • q is 2;
  • 5 is a propyl group, a butyl group or an isobutyl group;
  • R 6 is a phenyl group (in the phenyl group, one optional hydrogen atom is a fluorine atom, a chlorine atom, a trifluoromethyl group or a trifluoromethoxy group)
  • the general formula (I) is more preferably the general formula (Ia) described above.
  • Specific examples of the group represented by the above general formula (II-1) include, for example, indolinyl group, 4-fluoroindolinyl group, 5-fluoroindolinyl group, 6-fluoroindolinyl group, 7-fluoroindolinyl group Group, 4-chloroindolinyl group, 5-chloroindolinyl group, 6-chloroindolinyl group, 7-chloroindolinyl group, 4-methylindolinyl group, 5-methylindolinyl group, 6-methylindolinyl group , 7-methylindolinyl group, 4- (trifluoromethyl) indolinyl group, 5- (trifluoromethyl) indolinyl group, 6- (trifluoromethyl) indolinyl group, 7- (trifluoromethyl) indolinyl group, isoindolinyl group , 4-fluoroisoindolinyl group, 5-fluoroisoindolinyl group, 4-ch
  • the compounds described in Tables 1-1 to 1-3 also include their stereoisomers and their hydrates, and their pharmacologically acceptable salts and their mixtures.
  • the cyclic amine derivatives represented by the above general formula (I) may exist as stereoisomers, but include not only single isomers but also mixtures such as racemates and mixtures of diastereomers.
  • Stepoisomer refers to a compound having the same chemical structure but different arrangement in three-dimensional space, such as, for example, conformer, rotamer, tautomer, optical isomer, diastereomer Etc.
  • the cyclic amine derivative represented by the above general formula (I) may be labeled with one or more isotopes, and the isotopes to be labeled include, for example, 2 H, 3 H, 13 C, 14 C , 15 N, 15 O, 18 O and / or 125 I.
  • Examples of the "pharmaceutically acceptable salt" of the cyclic amine derivative represented by the above general formula (I) include a salt with an inorganic acid or a salt with an organic acid.
  • Examples of salts with inorganic acids include hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides or phosphates, and salts with organic acids include, for example, oxalic acid.
  • “pharmaceutically acceptable salts” of stereoisomers of cyclic amine derivatives represented by the above general formula (I) “hydrates of hydrates of cyclic amine derivatives represented by the above general formula (I) The same applies to “pharmacologically acceptable salts” and “pharmaceutically acceptable salts” of hydrates of stereoisomers of cyclic amine derivatives represented by the above general formula (I).
  • the cyclic amine derivative represented by the above general formula (I) or a stereoisomer thereof, or a pharmacologically acceptable salt thereof may be an anhydride or a solvate such as a hydrate May be formed.
  • a solvate a pharmacologically acceptable solvate is preferable.
  • the pharmacologically acceptable solvate may be either hydrate or non-hydrate, but hydrate is preferred.
  • the solvent constituting the solvate include alcohol solvents such as methanol, ethanol or n-propanol, N, N-dimethylformamide (hereinafter, DMF), dimethyl sulfoxide (hereinafter, DMSO) or water.
  • cyclic amine derivative (I) can be produced by an appropriate method based on the characteristics derived from the basic skeleton and the type of substituent. Starting materials and reagents used for producing these compounds can be generally purchased or can be produced by known methods.
  • the cyclic amine derivative (I) and the intermediates and starting materials used for its preparation can be isolated and purified by known means.
  • Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.
  • each optical isomer or diastereomer can be obtained as a single optically active substance by a known method.
  • Known methods include, for example, crystallization, enzymatic resolution or chiral chromatography.
  • a protective group may be introduced to these groups, and after the reaction, the protective group is optionally deprotected.
  • the target compound can be obtained.
  • an alkylcarbonyl group having 2 to 6 carbon atoms eg, acetyl group
  • benzoyl group an alkyloxycarbonyl group having 2 to 8 carbon atoms (eg, tert-butoxycarbonyl group or benzyloxy) And a carbonyl group
  • an aralkyl group having 7 to 10 carbon atoms eg, benzyl group
  • a phthaloyl group for example, an alkylcarbonyl group having 2 to 6 carbon atoms (eg, acetyl group), benzoyl group, an alkyloxycarbonyl group having 2 to 8 carbon atoms (eg, tert-butoxycarbonyl group or benzyloxy) And a carbonyl group), an aralkyl group having 7 to 10 carbon atoms (eg, benzyl group) or a phthaloyl group.
  • an alkylcarbonyl group having 2 to 6 carbon atoms eg,
  • Examples of the protecting group for the carboxyl group include, for example, an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group or tert-butyl group) or an aralkyl group having 7 to 10 carbon atoms (eg, benzyl group).
  • the deprotection of the protective group varies depending on the type of protective group, but is carried out according to known methods (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method according thereto. be able to.
  • the cyclic amine derivative (I) is, for example, as shown in Scheme 1, a condensation reaction (step 1) of an aniline derivative (III) with a pipecolic acid derivative (IV) in the presence of a condensing agent and a base (step 1), followed by an acid Deprotection reaction of tert-butoxycarbonyl group of N-tert-butoxycarbonylpipecolic acid amide derivative (V) obtained in the first step in the presence (step 2), subsequently, second step in the presence of a base And the condensation reaction of the pipecolic acid amide derivative (VI) obtained in 1. and the organic acid chloride derivative (VII) (step 3).
  • cyclic amine derivative (I) can also be obtained by condensation reaction of pipecolic acid amide derivative (VI) with organic acid anhydride derivative (VIII).
  • the cyclic amine derivative (I) can also be obtained by the condensation reaction of the pipecolic acid amide derivative (VI) and the organic acid derivative (IX) in the presence of a condensing agent and a base.
  • the optically active form of cyclic amine derivative (I) can be obtained, for example, by using the optically active form of pipecolic acid derivative (IV). [Wherein, R 1 , m, A and X are as defined above. ]
  • Step 1 The amount of pipecolic acid derivative (IV) used for the condensation reaction is preferably 0.1 to 10 equivalents, and more preferably 0.5 to 3 equivalents with respect to aniline derivative (III).
  • condensing agent used for the condensation reaction examples include N, N'-dicyclohexylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide hydrochloride (hereinafter referred to as EDC.HCl), N, N'-carbodiimidazole ⁇ [(1-cyano-2-ethoxy-2-oxoethylidene) amino] oxy ⁇ -4-morpholinomethylene ⁇ dimethyl ammonium hexafluorophosphate (hereinafter COMU), O- (7-azabenzotriazole- 1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (hereinafter HATU) or O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyl Although uronium hexafluorophosphate (following, HBTU) is mentioned, HATU or HBTU
  • the amount of the condensing agent used for the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents with respect to the aniline derivative (III).
  • Examples of the base used for the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogencarbonate or potassium carbonate, sodium hydride, hydrogenated metal compounds such as potassium hydride or calcium hydride, methyl lithium Or an alkyllithium such as butyllithium, a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof, but an organic base such as triethylamine or diisopropylethylamine is preferred.
  • organic bases such as triethylamine or diisopropylethylamine
  • inorganic bases such as sodium hydrogencarbonate or potassium carbonate, sodium hydride, hydrogenated metal compounds such as potassium hydride or calcium hydride, methyl lithium Or an alkyllithium such as butyllithium, a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide
  • the amount of the base used for the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents based on the aniline derivative (III).
  • the aniline derivative (III) used for the condensation reaction may be a free form or a salt such as hydrochloride.
  • the reaction solvent used for the condensation reaction is appropriately selected according to the type of reagent used, etc., and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include tetrahydrofuran (hereinafter, THF), 1,4-dioxane, Ether solvents such as ethylene glycol dimethyl ether or dimethoxyethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, or nitrile solvents such as acetonitrile or propionitrile
  • THF tetrahydrofuran
  • Ether solvents such as ethylene glycol dimethyl ether or dimethoxyethane
  • halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane
  • aprotic polar solvents such as DMF or DMSO
  • nitrile solvents such as acetonitrile
  • the reaction temperature of the condensation reaction is preferably 0 to 200 ° C., and more preferably 20 to 100 ° C.
  • the reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the concentration at the start of the reaction of the aniline derivative (III) used for the condensation reaction is preferably 1 mmol / L to 1 mol / L.
  • the aniline derivative (III) and the pipecolic acid derivative (IV) used for the condensation reaction can be purchased or can be produced by a known method or a method analogous thereto.
  • Step 2 Examples of the acid used for the deprotection reaction include acids such as hydrochloric acid, trifluoroacetic acid or hydrofluoric acid, with hydrochloric acid or trifluoroacetic acid being preferred.
  • the amount of the acid used for the deprotection reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents with respect to the N-tert-butoxycarbonylpipecolic acid amide derivative (V).
  • the reaction solvent for the deprotection reaction is appropriately selected depending on the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include diethyl ether, THF, dimethoxyethane or 1,4-dioxane Etc., ester solvents such as ethyl acetate or propyl acetate, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, alcohol solvents such as methanol or ethanol, or mixed solvents thereof. Ester solvents such as ethyl acetate or propyl acetate or chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane are preferred.
  • the reaction temperature of the deprotection reaction is preferably ⁇ 78 ° C. to 200 ° C., and more preferably ⁇ 20 ° C. to 100 ° C.
  • the reaction time of the deprotection reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 50 hours.
  • the concentration of the N-tert-butoxycarbonylpipecolic acid amide derivative (V) used for the deprotection reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
  • the amount of the organic acid chloride derivative (VII), the organic acid anhydride derivative (VIII) or the organic acid derivative (IX) used for the condensation reaction is preferably 0.5 to 10 equivalents relative to the pipecolic acid amide derivative (VI), 1 to 3 equivalents are more preferred.
  • a condensing agent used for a condensation reaction although EDC * HCl, COMU, HATU or HBTU is mentioned, for example, HATU or HBTU is preferable.
  • Examples of the base used for the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogencarbonate or potassium carbonate, sodium hydride, hydrogenated metal compounds such as potassium hydride or calcium hydride, methyl lithium Or an alkyllithium such as butyllithium, a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof, but an organic base such as triethylamine or diisopropylethylamine is preferred.
  • organic bases such as triethylamine or diisopropylethylamine
  • inorganic bases such as sodium hydrogencarbonate or potassium carbonate, sodium hydride, hydrogenated metal compounds such as potassium hydride or calcium hydride, methyl lithium Or an alkyllithium such as butyllithium, a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide
  • the amount of the base used for the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents based on the pipecolic acid amide derivative (VI).
  • the pipecolic acid amide derivative (VI) used for the condensation reaction may be a free form or a salt such as hydrochloride.
  • the reaction solvent used for the condensation reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxymethane Ether solvents such as ethane, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, or nitrile solvents such as acetonitrile or propionitrile Halogenated solvents such as chloroform or 1,2-dichloroethane or aprotic polar solvents such as DMF or DMSO are preferred.
  • the reaction temperature of the condensation reaction is preferably -78 ° C to 200 ° C, and more preferably -20 ° C to 100 ° C.
  • the reaction time of the condensation reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 0.5 to 30 hours.
  • the concentration of the pipecolic acid amide derivative (VI) used for the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
  • the organic acid chloride derivative (VII), the organic acid anhydride derivative (VIII) and the organic acid derivative (IX) used for the condensation reaction can be purchased or can be produced by a known method or a method analogous thereto.
  • an aniline derivative (III-a) in which m is 1 is, for example, a reduction reaction of benzoic acid derivative (X) as shown in Scheme 2 (Step 1)
  • the oxidation reaction (the second step) of the benzyl alcohol derivative (XI) obtained in the first step and subsequently, the benzaldehyde derivative (XII) obtained in the second step, and the amine derivative (XIII) or the amine Reductive amination reaction with derivative (XIV) (step 3), followed by reduction reaction (step 4) of nitrophenyl derivative (XV) obtained in step 3 in the presence of metal and acid Can.
  • R 1 , R 4 , p, q, R 5 , R 6 and A are as defined above.
  • Step 1 Examples of the reducing agent used for the reduction reaction include lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, lithium borohydride, lithium triethylborohydride or borane THF complex, but a borane THF complex is preferable .
  • the amount of reducing agent used for the reduction reaction is preferably 0.25 to 100 equivalents, and more preferably 0.5 to 10 equivalents with respect to benzoic acid derivative (X).
  • the reaction solvent used for the reduction reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxyethane And ethereal solvents such as benzene and toluene; but ether solvents such as THF, 1,4-dioxane, ethylene glycol dimethyl ether and dimethoxyethane are preferable.
  • the reaction temperature of the reduction reaction is preferably -78 ° C to 100 ° C, and more preferably -30 ° C to 50 ° C.
  • the reaction time of the reduction reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 10 minutes to 10 hours.
  • the concentration at the start of the reaction of the benzoic acid derivative (X) used for the reduction reaction is preferably 1 mmol / L to 1 mol / L.
  • the benzoic acid derivative (X) used for the reduction reaction can be purchased or can be produced by a known method or a method analogous thereto.
  • Step 2 Examples of the oxidizing agent used for the oxidation reaction include sulfur trioxide-pyridine, activated dimethyl sulfoxide, desmartine reagent, manganese dioxide or 2,2,6,6-tetramethylpiperidine 1-oxyl (hereinafter TEMPO).
  • TEMPO 2,2,6,6-tetramethylpiperidine 1-oxyl
  • the amount of the oxidizing agent used for the oxidation reaction is preferably 0.5 to 10 equivalents, more preferably 0.8 to 5 equivalents, to the benzyl alcohol derivative (XI).
  • the reaction solvent used for the oxidation reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aromatic amine solvents such as pyridine, dichloromethane, chloroform or Chlorinated solvents such as 2-dichloroethane, ether solvents such as THF or 1,4-dioxane, nitrile solvents such as acetonitrile or propionitrile, or mixed solvents thereof.
  • aromatic amine solvents such as pyridine, dichloromethane, chloroform or Chlorinated solvents such as 2-dichloroethane, ether solvents such as THF or 1,4-dioxane, nitrile solvents such as acetonitrile or propionitrile, or mixed solvents thereof.
  • the reaction temperature of the oxidation reaction is preferably ⁇ 78 ° C. to 100 ° C., and more preferably ⁇ 78 ° C. to 60 ° C.
  • the reaction time of the oxidation reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 5 minutes to 72 hours, and more preferably 0.5 to 48 hours.
  • the concentration at the start of the reaction of the benzyl alcohol acid derivative (XI) used for the oxidation reaction is preferably 1 mmol / L to 1 mol / L.
  • the amount of the amine derivative (XIII) or the amine derivative (XIV) used in the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, to the benzaldehyde derivative (XII).
  • sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride can be mentioned, and sodium triacetoxyborohydride is preferable.
  • the amount of the reducing agent used for the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents based on the benzaldehyde derivative (XII).
  • the reaction solvent used for the reductive amination reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol and ethanol, diethyl ether And ether solvents such as THF, dimethoxyethane or 1,4-dioxane, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane or mixed solvents thereof, but dichloromethane, chloroform or 1,2-dichloroethane Chlorinated solvents such as are preferred.
  • alcohol solvents such as methanol and ethanol
  • diethyl ether And ether solvents such as THF, dimethoxyethane or 1,4-dioxane
  • chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane or mixed solvents thereof, but dichloromethane, chloroform or 1,2-dichloroe
  • the reaction temperature of the reductive amination reaction is preferably ⁇ 78 ° C. to 200 ° C., and more preferably ⁇ 20 ° C. to 100 ° C.
  • the reaction time of the reductive amination reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 0.5 to 30 hours.
  • the concentration of the benzaldehyde derivative (XII) at the start of the reaction used for the reductive amination reaction is preferably 1 mmol / L to 1 mol / L.
  • the amine derivative (XIII) and the amine derivative (XIV) used for the reductive amination reaction can be purchased or can be produced by a known method or a method analogous thereto.
  • Step 4 Examples of the metal used for the reduction reaction include iron powder and tin (II) chloride, with iron powder being preferred.
  • the amount of metal used for the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, to the nitrophenyl derivative (XV).
  • Examples of the acid used for the reduction reaction include acetic acid, hydrochloric acid or an aqueous solution of ammonium chloride, with preference given to acetic acid or an aqueous solution of ammonium chloride.
  • the amount of the acid used for the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, to the nitrophenyl derivative (XV).
  • the reaction solvent used for the reduction reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, for example, alcohol solvents such as methanol or ethanol, diethyl ether, THF And ether solvents such as dimethoxyethane or 1,4-dioxane, water or mixed solvents thereof, alcohol solvents such as methanol or ethanol, diethyl ether, THF, dimethoxyethane or 1,4-dioxane A mixed solvent of an ether solvent and water is preferred.
  • the reaction temperature of the reduction reaction is preferably 0 to 200 ° C., and more preferably 50 to 150 ° C.
  • the reaction time of the reduction reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the concentration of the nitrophenyl derivative (XV) used for the reduction reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
  • aniline derivatives (III) shown in Scheme 1 aniline derivatives (III-b) in which m is 0 are, for example, amine derivatives (XIII) or amine derivatives (XIV) in the presence of a base as shown in Scheme 3.
  • R 1 , R 4 , p, q, R 5 , R 6 and A are as defined above.
  • the amount of the amine derivative (XIII) or the amine derivative (XIV) used for the nucleophilic substitution reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, to the fluorophenyl derivative (XVI).
  • Examples of the base used for the nucleophilic substitution reaction include organic bases such as triethylamine, diisopropylethylamine or N-methylmorpholine, inorganic bases such as sodium carbonate or potassium carbonate, hydrogen such as sodium hydride, potassium hydride or calcium hydride Metal oxides, lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, metal alkoxides such as tert-butyloxy sodium or tert-butyloxy potassium, or mixtures thereof, but triethylamine, diisopropylethylamine or N- Organic bases such as methyl morpholine or sodium hydride, metal hydride compounds such as potassium hydride or calcium hydride are preferred.
  • organic bases such as triethylamine, diisopropylethylamine or N-methylmorpholine
  • inorganic bases such as sodium carbonate or potassium carbonate
  • hydrogen such as sodium hydride, potassium hydride
  • the amount of the base used for the nucleophilic substitution reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, to the fluorophenyl derivative (XVI).
  • the reaction solvent used for the nucleophilic substitution reaction is appropriately selected according to the type of the reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, for example, THF, 1,4-dioxane, ethylene glycol dimethyl ether Or an ether solvent such as dimethoxyethane, a nitrile solvent such as acetonitrile or propionitrile, an aromatic hydrocarbon solvent such as benzene or toluene, an aprotic polar solvent such as DMF or DMSO, water or a mixed solvent thereof Although non-polar polar solvents such as DMF or DMSO are preferred.
  • the reaction temperature of the nucleophilic substitution reaction is preferably ⁇ 78 ° C. to 200 ° C., and more preferably ⁇ 20 ° C. to 160 ° C.
  • the reaction time of the nucleophilic substitution reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the concentration at the start of the reaction of fluorophenyl derivative (XVI) used for the nucleophilic substitution reaction is preferably 1 mmol / L to 1 mol / L.
  • the fluorophenyl derivative (XVI), the amine derivative (XIII) and the amine derivative (XIV) used for the nucleophilic substitution reaction can be purchased or can be produced by a known method or a method analogous thereto.
  • Step 2 Examples of the metal used for the reduction reaction include iron powder and tin (II) chloride, with iron powder being preferred.
  • the amount of metal used for the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, to the nitrophenyl derivative (XVII).
  • Examples of the acid used for the reduction reaction include acetic acid, hydrochloric acid or an aqueous solution of ammonium chloride, with preference given to acetic acid or an aqueous solution of ammonium chloride.
  • the amount of the acid used for the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, to the nitrophenyl derivative (XVII).
  • the reaction solvent used for the reduction reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, for example, alcohol solvents such as methanol or ethanol, diethyl ether, THF And ether solvents such as dimethoxyethane or 1,4-dioxane, water or mixed solvents thereof, alcohol solvents such as methanol or ethanol, diethyl ether, THF, dimethoxyethane or 1,4-dioxane A mixed solvent of an ether solvent and water is preferred.
  • the reaction temperature of the reduction reaction is preferably 0 to 200 ° C., and more preferably 50 to 150 ° C.
  • the reaction time of the reduction reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the concentration at the start of the reaction of the nitrophenyl derivative (XVII) used for the reduction reaction is preferably 1 mmol / L to 1 mol / L.
  • tetrahydroisoquinoline derivatives (XIII-a) in which p is 1 and q is 2 are, for example, trifluoroacetic anhydride as shown in Scheme 4.
  • Step 2 the hydrolysis reaction (third step) of the tetrahydroisoquinoline derivative (XX) obtained in the second step.
  • R 4 is as defined above.
  • the amount of trifluoroacetic anhydride used for the trifluoroacetylation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, with respect to phenethylamine derivative (XVIII).
  • the reaction solvent used for the trifluoroacetylation reaction is appropriately selected according to the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, for example, DMF, N, N-dimethylacetamide, N -Aprotic polar solvents such as methyl-2-pyrrolidone or DMSO, ether solvents such as diethyl ether, THF, dimethoxyethane or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or Chlorinated solvents such as 1,2-dichloroethane or mixed solvents thereof may be mentioned, and chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane are preferable.
  • the reaction temperature of the trifluoroacetylation reaction is preferably -20 ° C to 100 ° C, and more preferably 0 to 50 ° C.
  • the reaction time of the trifluoroacetylation reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the concentration of phenethylamine derivative (XVIII) used for the trifluoroacetylation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
  • the phenethylamine derivative (XVIII) used for the trifluoroacetylation reaction can be purchased or can be produced by a known method or a method analogous thereto.
  • Step 2 The amount of paraformaldehyde used in the cyclization reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the trifluoroacetamide derivative (XIX).
  • Examples of the acid used for the cyclization reaction include hydrochloric acid, acetic acid, trifluoroacetic acid, concentrated sulfuric acid, concentrated nitric acid, and phosphoric acid, but a mixed solution of acetic acid and concentrated sulfuric acid is preferable.
  • the amount of the acid used for the cyclization reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 50 equivalents based on the trifluoroacetamide derivative (XIX).
  • the reaction solvent used for the cyclization reaction is appropriately selected according to the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, and, for example, DMF, N, N-dimethylacetamide, N-methyl- Aprotic polar solvents such as 2-pyrrolidone or DMSO, ether solvents such as diethyl ether, THF, dimethoxyethane or 1,4-dioxane, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane or mixtures thereof A solvent is mentioned.
  • the reaction temperature of the cyclization reaction is preferably -20 ° C to 100 ° C, and more preferably 0 to 50 ° C.
  • the reaction time of the cyclization reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the concentration at the start of reaction of the trifluoroacetamide derivative (XIX) used for the cyclization reaction is preferably 1 mmol / L to 1 mol / L.
  • inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or potassium carbonate, are mentioned, for example.
  • the amount of the base used for the hydrolysis reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 20 equivalents based on the tetrahydroisoquinoline derivative (XX).
  • the reaction solvent used for the hydrolysis reaction is appropriately selected according to the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol and ethanol, acetonitrile or pro Nitrile solvents such as piononitrile, aprotic polar solvents such as DMF, N, N-dimethylacetamide, N-methyl-2-pyrrolidone or DMSO, ethers such as diethyl ether, THF, dimethoxyethane or 1,4-dioxane
  • the solvent include ester solvents such as ethyl acetate or propyl acetate, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, and mixed solvents thereof, and alcohol solvents such as methanol or ethanol, DMF, N , N-dimeth Acetamide, N- methyl-2-pyrrolidone or aprotic polar solvents
  • the reaction temperature of the hydrolysis reaction is preferably -20 ° C to 200 ° C, and more preferably 0 to 150 ° C.
  • the reaction time of the hydrolysis reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the concentration of the tetrahydroisoquinoline derivative (XX) used for the hydrolysis reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
  • the amine derivative (XIV) shown in Schemes 2 and 3 is, for example, as shown in Scheme 5, a reductive amination reaction of aldehyde derivative (XXI) with amine derivative (XXII) or aldehyde derivative (XXIII) with amine derivative It can be obtained by reductive amination reaction with (XXIV).
  • U represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, a cycloalkyl group of 3 to 5 carbon atoms, a cycloalkyl alkyl group of 4 or 5 carbon atoms, or-(CH 2 ) r-1 -OR 7 and R 5 , R 6 , r and R 7 are as defined above.
  • R 5 , R 6 , r and R 7 are as defined above.
  • the amount of amine derivative (XXII) or amine derivative (XXIV) to be used for the reductive amination reaction is preferably 0.5 to 10 equivalents, preferably 1 to 3 with respect to aldehyde derivative (XXI) or aldehyde derivative (XXIII), respectively.
  • the equivalent is more preferred.
  • sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride can be mentioned, and sodium triacetoxyborohydride is preferable.
  • the amount of the reducing agent used for the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents with respect to the aldehyde derivative (XXI) or the aldehyde derivative (XXIII).
  • the reaction solvent used for the reductive amination reaction is appropriately selected according to the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, for example, alcohol solvents such as methanol or ethanol, diethyl
  • the solvent include ether solvents such as ether, THF, dimethoxyethane or 1,4-dioxane, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, and mixed solvents thereof. Chlorinated solvents such as dichloroethane are preferred.
  • the reaction temperature of the reductive amination reaction is preferably ⁇ 78 ° C. to 200 ° C., and more preferably ⁇ 20 ° C. to 100 ° C.
  • the reaction time of the reductive amination reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
  • the concentration at the start of the reaction of the aldehyde derivative (XXI) and the aldehyde derivative (XXIII) used for the reductive amination reaction is preferably 1 mmol / L to 1 mol / L.
  • the amine derivative (XXII), the amine derivative (XXIV), the aldehyde derivative (XXI) and the aldehyde derivative (XXIII) used for the reductive amination reaction can be purchased or can be produced by a known method or a method analogous thereto .
  • the medicament, ROR ⁇ antagonist and therapeutic agent or prophylactic agent for autoimmune diseases of the present invention are cyclic amine derivative (I), stereoisomers thereof or hydrates thereof, or pharmacologically acceptable thereof It is characterized by containing salt as an active ingredient.
  • the above-mentioned autoimmune disease is preferably psoriasis.
  • the “ROR ⁇ antagonist” means a compound having the function of suppressing the function of ROR ⁇ to abolish or attenuate its activity.
  • Autoimmune disease is a general term for diseases in which excessive immune reaction causes symptoms by attacking normal cells and tissues of the patient, and includes, for example, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus Inflammatory bowel disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica, scleroderma, vasculitis, pemphigus, pemphigus or dermatomyositis.
  • the autoimmune diseases of the present invention also include acne, vitiligo or alopecia areata.
  • Allergic disease is a disease derived from the occurrence of excessive immune reaction against a specific antigen, such as allergic dermatitis, contact dermatitis, atopic dermatitis, allergic rhinitis (pollen Disease, allergic conjunctivitis, allergic gastroenteritis, bronchial asthma, childhood asthma or food allergy.
  • Psoriasis is an inflammatory disease of the skin associated with infiltration and activation of immune cells and concomitant epidermal hyperplasia. Typically, white scales adhere thickly on a red rash in various places throughout the body, causing symptoms of scaling that may fall off. Psoriasis includes, for example, psoriasis vulgaris, pustular psoriasis, arthritic psoriasis, psoriatic psoriasis, psoriatic erythroderma.
  • the cyclic amine derivative (I), its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof inhibits the function of ROR ⁇ by inhibiting the binding of ROR ⁇ to a coactivator. It is characterized by suppressing. It is known that ROR ⁇ is involved in various diseases, and that suppression of its function is expected to improve the pathological condition or ameliorate the symptoms, so cyclic amine derivatives (I), their stereoisomers or their hydrates Or a pharmacologically acceptable salt thereof is a medicament for a disease which can be expected to improve the condition or ameliorate the symptoms by suppressing the function of ROR ⁇ , in particular, a therapeutic agent for an autoimmune disease or an allergic disease Or it can be used as a preventive agent.
  • the therapeutic agent or prophylactic agent for the above-mentioned autoimmune diseases is preferably multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica
  • the cyclic amine derivative (I), a stereoisomer thereof or a hydrate of these or a pharmacologically acceptable salt thereof has ROR ⁇ antagonist activity which inhibits the binding of ROR ⁇ to a coactivator, It can be evaluated using in vitro tests.
  • an in vitro test for example, a method of evaluating the binding of ROR ⁇ to an agonist (eg, cholesterol) (WO 2012/158784, WO 2013/018695), a ligand binding domain of ROR ⁇ and a coacti Methods for assessing binding to beta can be mentioned (WO 2012/064744, WO 2013/018695).
  • the transcriptional activity inhibitory action of ROR ⁇ can be evaluated using various reporter gene assays (WO 2012/158784, WO 2012/064744, WO 2013/018695).
  • the cyclic amine derivative (I), its stereoisomer or hydrate thereof, or pharmacologically acceptable salt thereof suppressing the function of ROR ⁇ is derived from various organs such as spleen or peripheral blood Lymphocytes can be used to evaluate IL-17 production or Th17 cell differentiation as an indicator.
  • organs such as spleen or peripheral blood Lymphocytes
  • IL-17 production As a method using IL-17 production as an index, for example, a method of measuring IL-17 production by IL-23 stimulation using mouse splenocytes can be mentioned (The Journal of Biological Chemistry, 2003, 278) , No. 3, p. 1910-1914).
  • Th17 cell differentiation for example, various cytokines (eg, IL-1 ⁇ , IL-6, IL-23 and / or TGF are used, using CD4 positive naive T cells derived from mouse splenocytes or human PBMC). Stimulate with - ⁇ ) and various antibodies (eg, anti-CD3 antibody, anti-CD28 antibody, anti-IL-4 antibody, anti-IFN- ⁇ antibody and / or anti-IL-2 antibody) to differentiate to Th17 and produce IL-17 The method includes measuring the amount or the proportion of IL-17 positive cells etc. (WO 2012/158784, WO 2013/018695).
  • cytokines eg, IL-1 ⁇ , IL-6, IL-23 and / or TGF
  • CD4 positive naive T cells derived from mouse splenocytes or human PBMC.
  • various antibodies eg, anti-CD3 antibody, anti-CD28 antibody, anti-IL-4 antibody, anti-IFN- ⁇ antibody and / or anti-IL-2 antibody
  • the effectiveness of the cyclic amine derivative (I), its stereoisomer or hydrates thereof, or their pharmacologically acceptable salts for the treatment or prevention of autoimmune diseases can be determined using a pathological model It can be evaluated.
  • a pathological model for example, experimental autoimmune encephalomyelitis model (Journal of Neuroscience Research, 2006, 84, pages 1225-1234), imiquimod-induced psoriasis model (Journal of Immunology, 2009, 182) , P. 5836-5845), collagen arthritis model (Annual Review of Immunology, 1984, Volume 2, 199-218), spontaneous lupus erythematosus model (Nature, volume 404, p. 2000).
  • DNFB dinitrofluorobenzene
  • DNFB dinitrofluorobenzene
  • oxazolone-induced atopic dermatitis model Journal of Investigative Dermatology, 2014, vol. 134, p. 2122-2130
  • ovalbumin-induced allergic rhinitis model Journal of Animal Science, 2010, vol. 81, p.
  • the DNFB-induced allergic dermatitis model is common as a model of allergic dermatitis, in particular as a contact dermatitis model.
  • the oxazolone-induced atopic dermatitis model is common as a model of atopic dermatitis.
  • the efficacy of the cyclic amine derivative (I), a stereoisomer thereof or a hydrate of these or a pharmacologically acceptable salt thereof for the treatment or prevention of autoimmune diseases or allergic diseases is for example, a decrease in the amount of binding between the ligand binding domain of ROR ⁇ and the coactivator, or a decrease in the amount of IL-17 production, which is an indicator of the function of ROR ⁇ , can be evaluated using in vitro tests.
  • the efficacy for treatment or prevention of multiple sclerosis can be evaluated using, for example, a decrease in neurological symptom score, which is a characteristic index of multiple sclerosis, using the above-mentioned experimental autoimmune encephalomyelitis model. It can be evaluated.
  • the efficacy for treatment or prevention of psoriasis may be evaluated using, for example, the reduction in thickness of skin such as auricle or the like, which increases with the progression of symptoms of the psoriasis model, using the imiquimod-induced psoriasis model described above as an indicator. it can.
  • the efficacy for treatment or prevention of allergic dermatitis, particularly contact dermatitis is increased using, for example, the above-mentioned DNFB-induced allergic dermatitis model, such as the auricle, etc., along with the progress of skin inflammation.
  • the decrease in skin thickness can be evaluated as an index.
  • the efficacy for the treatment or prevention of atopic dermatitis is, for example, using the above-mentioned oxazolone-induced atopic dermatitis model to decrease the thickness of the skin such as the auricle that increases with the progress of skin inflammation. It can be evaluated on indicators.
  • the cyclic amine derivative (I), its stereoisomer or a hydrate thereof, or a pharmacologically acceptable salt thereof is a mammal (eg, mouse, rat, hamster, rabbit, dog, cat, monkey, etc.)
  • a mammal eg, mouse, rat, hamster, rabbit, dog, cat, monkey, etc.
  • useful medicaments especially, therapeutic or prophylactic agents for autoimmune diseases or allergic diseases
  • the cyclic amine derivative (I), its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof is used clinically as a medicament
  • the cyclic amine derivative (I), its steric structure The isomers or their hydrates, or their pharmacologically acceptable salts can be administered orally or parenterally, as they are or in combination with pharmacologically acceptable carriers. .
  • binders such as an agent, an emulsifying agent, a surfactant, a suspending agent, a diluent or an isotonic agent may be appropriately mixed.
  • Pharmaceutically acceptable carriers include these additives.
  • the above-mentioned medicament can be manufactured by a usual method using appropriately these pharmaceutical carriers.
  • the dosage form of the above-mentioned medicine includes, for example, oral preparations such as tablets, capsules, granules, powders or syrups, parenteral preparations such as inhalants, injections, suppositories or solutions, or topical administration.
  • oral preparations such as tablets, capsules, granules, powders or syrups
  • parenteral preparations such as inhalants, injections, suppositories or solutions, or topical administration.
  • An ointment, a cream or a patch may be mentioned.
  • it may be a known sustained release preparation.
  • Binders include, for example, syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride or tragacanth.
  • Excipients include, for example, sugar, lactose, corn starch, calcium phosphate, sorbitol or glycine.
  • lubricant for example, magnesium stearate, calcium stearate, polyethylene glycol, talc or silica can be mentioned.
  • Disintegrants include, for example, starch or calcium carbonate.
  • Sweetening agents include, for example, glucose, fructose, invert sugar, sorbitol, xylitol, glycerin or simple syrup.
  • the above-mentioned medicament preferably contains 0.00001 to 90% by weight of cyclic amine derivative (I), its stereoisomer or hydrate thereof, or pharmacologically acceptable salt thereof, and 0 More preferably, the content is from 0.1 to 70% by weight.
  • the dose is appropriately selected according to the patient's condition, age and body weight, and administration method, but as an active ingredient amount for adults, 0.1 ⁇ g to 1 g per day for injections and 1 for oral preparations The amount is preferably 1 ⁇ g to 10 g per day, and in the case of a patch, 1 ⁇ g to 10 g per day, each of which can be administered once or several times.
  • the above-mentioned medicines may be used together with other medicines in appropriate amounts or in combination for complementation or enhancement of their therapeutic or preventive effects or reduction of dosage.
  • the compounds used for the synthesis of the compounds of Reference Examples and Examples were commercially available compounds that were not described in the synthesis method.
  • the “room temperature” in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C. % Indicates mol / mol% for yield, volume% for solvents used in column chromatography and high performance liquid chromatography, and weight% unless otherwise specified.
  • the solvent name shown in the NMR data indicates the solvent used for the measurement.
  • the 400 MHz NMR spectrum was measured using a JNM-AL400 nuclear magnetic resonance apparatus (Nippon Denshi Co., Ltd.) or a JNM-ECS400 nuclear magnetic resonance apparatus (Nippon Denshi Co., Ltd.).
  • Silica gel used silica gel 60 (Merck), amine silica gel used amine silica gel DM 1020 (Fuji Silysia Chemical Ltd.), and chromatography used YFLC W-prep 2 XY (Yamazen Co.).
  • Reference Example 2 Synthesis of 2- (2-chloro-4-nitrobenzyl) -1,2,3,4-tetrahydroisoquinoline: The compound of Reference Example 1 (0.150 g, 0.808 mmol) is dissolved in dichloromethane (8.08 mL), and 1,2,3,4-tetrahydroisoquinoline hydrochloride (0.137 g, 0.808 mmol) and hydrogenated tri Sodium acetoxyborohydride (0.393 g, 1.86 mmol) was added at 0 ° C. After stirring at room temperature for 1 hour, distilled water was added to the reaction solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Reference Example 3 (R) -2-((3-Chloro-4-((3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Composition of: The compound of Reference Example 2 (0.146 g, 0.482 mmol) is dissolved in THF (2.41 mL), ethanol (2.41 mL), distilled water (2.41 mL), iron powder (0.108 g, 1.93 mmol) ) And acetic acid (0.276 mL, 4.82 mmol) were added at room temperature. After stirring at 70 ° C.
  • the crude product obtained was used for the subsequent reaction without purification.
  • the above crude product is dissolved in DMF (3.67 mL), HATU (0.209 g, 0.550 mmol), (R) -N-Boc-pipecolic acid (0.109 g, 0.477 mmol) and triethylamine (0) .102 mL, 0.733 mmol) was added at room temperature.
  • Example 1 (R) -N- (3-Chloro-4-((3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) -1- (methylsulfonyl) piperidine-2-carboxamide Hydrochloride Synthesis: The compound of Reference Example 3 (0.100 g, 0.207 mmol) was dissolved in dichloromethane (2.07 mL), and trifluoroacetic acid (0.239 mL, 3.10 mmol) was added at 0 ° C. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
  • Reference Example 5 Synthesis of 2,2,2-trifluoro-1- (7-methyl-3,4-dihydroisoquinolin-2 (1H) -yl) ethan-1-one: The compound of Reference Example 4 (0.525 g, 2.27 mmol) and paraformaldehyde (0.102 g, 3.41 mmol) were added to a mixture of concentrated sulfuric acid (0.454 mL) and acetic acid (2.27 mL) at 0 ° C. The After stirring at room temperature for 36 hours, the reaction solution was added to ice water and extracted with ethyl acetate.
  • Reference Example 6 Synthesis of 7-methyl-1,2,3,4-tetrahydroisoquinoline: The compound of Reference Example 5 (0.335 g, 1.38 mmol) was dissolved in ethanol (4.17 mL), and 2 M aqueous sodium hydroxide solution (3.79 mL) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with ethyl acetate.
  • Reference Example 7 Synthesis of 2- (2-chloro-4-nitrobenzyl) -7-methyl-1,2,3,4-tetrahydroisoquinoline: The compound of Reference Example 6 (0.184 g, 1.25 mmol) is dissolved in dichloromethane (3.75 mL), and the compound of Reference Example 1 (0.230 g, 1.25 mmol) and acetic acid (0.0354 mL) are added at room temperature. The After stirring for 10 minutes at room temperature, sodium triacetoxyborohydride (0.393 g, 1.86 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform.
  • Reference Example 8 Synthesis of 3-chloro-4-((7-methyl-3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline: The compound of Reference Example 7 (0.335 g, 1.06 mmol) is dissolved in THF (1.06 mL), ethanol (1.06 mL), distilled water (1.06 mL), iron powder (0.295 g, 5.29 mmol) ) And acetic acid (0.303 mL, 5.29 mmol) were added at room temperature. After stirring at 50 ° C. for 2 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform.
  • Example 2 (R) -1-Acetyl-N- (3-chloro-4-((7-methyl-3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) piperidine-2- Carboxamide Synthesis: The compound of Reference Example 9 (0.0550 g, 0.110 mmol) was dissolved in dichloromethane (0.552 mL), and trifluoroacetic acid (0.128 mL, 1.66 mmol) was added at 0 ° C. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
  • Reference Example 11 Synthesis of 1- (7-chloro-3,4-dihydroisoquinolin-2 (1H) -yl) -2,2,2-trifluoroethan-1-one: Using the compound of Reference Example 10 in place of the compound of Reference Example 4 and using the same procedure as in Reference Example 5 except the above, the title compound (compound of Reference Example 11 below) (0.311 g, 1.18 mmol, 72 %) As a white solid.
  • Reference Example 12 Synthesis of 7-chloro-1,2,3,4-tetrahydroisoquinoline: Using the compound of Reference Example 11 instead of the compound of Reference Example 5, and according to the same procedure as Reference Example 6 except the above, the title compound (hereinafter, the compound of Reference Example 12) (0.192 g, 1.15 mmol, 97 %) As a colorless oil.
  • Reference Example 13 Synthesis of 7-chloro-2- (2-chloro-4-nitrobenzyl) -1,2,3,4-tetrahydroisoquinoline: Using the compound of Reference Example 12 instead of the compound of Reference Example 6, and using the same procedure as Reference Example 7 except for this, the title compound (hereinafter, the compound of Reference Example 13) (0.342 g, 1.01 mmol, 89 %) As a yellow solid.
  • Reference Example 14 Synthesis of 3-chloro-4-((7-chloro-3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline: Using the compound of Reference Example 13 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 14) (0.270 g, 0.879 mmol, 87) %) As a white solid.
  • Example 3 (R) -1-Acetyl-N- (3-chloro-4-((7-chloro-3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) piperidine-2- Carboxamide Synthesis: Using the compound of Reference Example 15 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 3 below) (0.0390 g, 0.0847 mmol, 83) %) As a white solid.
  • Reference Example 18 Synthesis of 7- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline: The compound of Reference Example 17 (0.400 g, 1.35 mmol) was dissolved in ethanol (4.08 mL), and a 2 M aqueous solution of sodium hydroxide (3.70 mL) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with ethyl acetate.
  • Reference Example 19 Synthesis of 2- (2-chloro-4-nitrobenzyl) -7- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline: The compound of Reference Example 18 (10.0 g, 49.7 mmol) was dissolved in dichloromethane (148 mL), and the compound of Reference Example 1 (9.04 g, 49.7 mmol) and acetic acid (1.40 mL) were added at room temperature. After stirring for 10 minutes at room temperature, sodium triacetoxyborohydride (15.5 g, 73.1 mmol) was added at 0 ° C. After stirring at room temperature for 14 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform.
  • Reference Example 20 Synthesis of 3-chloro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline: The compound of Reference Example 19 (15.6 g, 42.1 mmol) is dissolved in THF (42.1 mL), ethanol (42.1 mL), distilled water (42.1 mL), iron powder (11.8 g, 210 mmol) and Acetic acid (12.0 mL, 210 mmol) was added at room temperature. After stirring at 50 ° C. for 1.5 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform.
  • Reference Example 22 (R) -N- (3-Chloro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) piperidine-2- Carboxamide Synthesis: The compound of Reference Example 21 (14.5 g, 26.3 mmol) was dissolved in dichloromethane (97.0 mL), and trifluoroacetic acid (24.3 mL, 315 mmol) was added at 0 ° C. After stirring at room temperature for 4 hours, the reaction solution was neutralized by adding 4 M aqueous sodium hydroxide solution, and extracted with chloroform.
  • Example 4 (R) -1-Acetyl-N- (3-chloro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) Synthesis of piperidine-2-carboxamide: Using the compound of Reference Example 21 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 4 below) (0.0307 g, 0.0622 mmol, 34) %) As a white amorphous.
  • Example 6 (R) -1- (2- (4H-1,2,4-triazol-4-yl) acetyl) -N- (3-chloro-4-((7- (trifluoromethyl)) Synthesis of -3,4-Dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) piperidine-2-carboxamide: Using the same procedure as in Example 5 except for using 2- (4H-1,2,4-triazol-4-yl) acetic acid instead of 2- (1H-tetrazol-1-yl) acetic acid, The compound (hereinafter, the compound of Example 6) (0.0578 g, 0.103 mmol, 93%) was obtained as a white solid.
  • Example 7 (R) -N- (3-Chloro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) -1- ( Synthesis of methylsulfonyl) piperidine-2-carboxamide hydrochloride: Using the compound of Reference Example 21 instead of the compound of Reference Example 3, and using the same procedure as Example 1 except for the above, the title compound (the compound of Example 7 below) (0.0697 g, 0.0919 mmol, 72) %) As a white amorphous.
  • reaction solution was added to ice water and extracted with ethyl acetate.
  • organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, distilled water and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure.
  • Reference Example 26 Synthesis of 6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline: The compound of Reference Example 24 (0.300 g, 1.01 mmol) was dissolved in ethanol (3.06 mL), and a 2 M aqueous solution of sodium hydroxide (2.78 mL) was added at 0 ° C. After stirring at room temperature for 7 hours, the reaction mixture was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with ethyl acetate.
  • Reference Example 27 Synthesis of 2- (2-chloro-4-nitrobenzyl) -6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline: The compound of Reference Example 26 (7.50 g, 37.3 mmol) was dissolved in dichloromethane (113 mL), and the compound of Reference Example 1 (6.92 g, 37.3 mmol) and acetic acid (1.07 mL) were added at room temperature. After stirring for 15 minutes at room temperature, sodium triacetoxyborohydride (11.9 g, 55.9 mmol) was added at 0 ° C. After stirring at room temperature for 4 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform.
  • Reference Example 28 Synthesis of 3-chloro-4-((6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline:
  • Reference 27 compound (11.5 g, 31.0 mmol) is dissolved in THF (38.8 mL), ethanol (38.8 mL), distilled water (38.8 mL), iron powder (8.66 g, 155 mmol) and acetic acid (8.88 mL, 155 mmol) was added at room temperature. After stirring at 50 ° C. for 2.5 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform.
  • Reference Example 29 (R) -2-((3-Chloro-4-((6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl: Using the compound of Reference Example 28 instead of the compound of Reference Example 8, and according to the same procedure as Reference Example 9 except the above, the title compound (hereinafter, the compound of Reference Example 29) (0.106 g, 0.192 mmol, 94 %) As a colorless oil.
  • Example 8 (R) -1-Acetyl-N- (3-chloro-4-((6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) Synthesis of piperidine-2-carboxamide hydrochloride: The compound of Reference Example 29 (0.0500 g, 0.0906 mmol) was dissolved in dichloromethane (0.906 mL), and trifluoroacetic acid (0.105 mL, 1.36 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
  • Reference Example 30 Synthesis of 8- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline: Using the compound of Reference Example 25 instead of the compound of Reference Example 5, and according to the same procedure as Reference Example 6 except the above, the title compound (hereinafter, the compound of Reference Example 30) (0.190 g, 0.944 mmol, 94 %) As a yellow solid.
  • Reference Example 31 Synthesis of 2- (2-chloro-4-nitrobenzyl) -8- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline: Using the compound of Reference Example 30 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 2 except for the above, the title compound (hereinafter referred to as the compound of Reference Example 31) (0. 1). 296 g (0.798 mmol, 87%) were obtained as a colorless oil.
  • Reference Example 32 Synthesis of 3-chloro-4-((8- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline: Using the compound of Reference Example 31 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 32) (0.192 g, 0.563 mmol, 84 %) As a yellow solid.
  • Reference Example 33 (R) -2-((3-Chloro-4-((8- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl: Using the compound of Reference Example 32 instead of the compound of Reference Example 8, and according to the same procedure as Reference Example 9 except the above, the title compound (hereinafter, the compound of Reference Example 33) (0. 100 g, 0.181 mmol, 88) %) As a colorless oil.
  • Reference Example 35 Synthesis of 2- (2-fluoro-4-nitrobenzyl) -7- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
  • the compound of Reference Example 18 is used in place of the compound of 1,2,3,4-tetrahydroisoquinoline hydrochloride, and the compound of Reference Example 34 is used in place of the compound of Reference Example 1;
  • the title compound (hereinafter, the compound of Reference Example 35) (0.126 g, 0.356 mmol, 79%) was obtained as a pale brown solid.
  • Reference Example 36 Synthesis of 3-fluoro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline: Using the compound of Reference Example 35 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 36) (0.0695 g, 0.214 mmol, 61) %) As a yellow oil.
  • Reference Example 37 (R) -2-((3-fluoro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl: Using the compound of Reference Example 36 instead of the compound of Reference Example 8, and using the same procedure as Reference Example 9 except the above, the title compound (hereinafter, the compound of Reference Example 37) (0.0485 g, 0.0906 mmol, 73 %) As a white amorphous.
  • Example 10 (R) -1-Acetyl-N- (3-fluoro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) Synthesis of piperidine-2-carboxamide: Using the compound of Reference Example 37 instead of the compound of Reference Example 9, and according to the same procedure as Example 2 except the above, the title compound (the compound of Example 10) (0.0140 g, 0.0293 mmol, 79) %) As a white solid.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ : 1.49-1.61 (m, 2 H), 1.72-1.
  • Reference Example 40 Synthesis of tert-butyl (R) -2-((3-chloro-4- (indoline-1-ylmethyl) phenyl) carbamoyl) piperidine-1-carboxylate: The title compound (hereinafter, the compound of Reference Example 40) (0.0887 g, 0.189 mmol, 98) was prepared by using the compound of Reference Example 39 instead of the compound of Reference Example 8 and using the same procedure as in Reference Example 9 except the above. %) As a white amorphous.
  • Example 11 Synthesis of (R) -1-Acetyl-N- (3-chloro-4- (indoline-1-ylmethyl) phenyl) piperidine-2-carboxamide hydrochloride: Using the compound of Reference Example 40 instead of the compound of Reference Example 29, and using the same procedure as Example 8 except for the above, the title compound (the compound of Example 11 below) (0.0313 g, 0.0760 mmol, 89) %) As a white amorphous.
  • Reference Example 42 Synthesis of 3-chloro-4-((5- (trifluoromethyl) indoline-1-yl) methyl) aniline: Using the compound of Reference Example 41 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 42) (0.0304 g, 0.0930 mmol, 58 %) As a light brown solid.
  • Example 12 Synthesis of (R) -1-acetyl-N- (3-chloro-4-((5- (trifluoromethyl) indoline-1-yl) methyl) phenyl) piperidine-2-carboxamide: Using the compound of Reference Example 43 instead of the compound of Reference Example 9, and according to the same procedure as Example 2 except the above, the title compound (the compound of Example 12 below) (0.0106 g, 0.0221 mmol, 60) %) As a white amorphous.
  • Example 13 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4-((5- (trifluoromethyl) indoline-1-yl) Synthesis of methyl) phenyl) piperidine-2-carboxamide:
  • the compound of Reference Example 43 (0.0150 g, 0.0279 mmol) was dissolved in dichloromethane (0.279 mL), and trifluoroacetic acid (0.0322 mL, 0.418 mmol) was added at 0 ° C. After stirring for 5 hours at room temperature, the reaction solution was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
  • Reference Example 45 Synthesis of 3-chloro-4-((5- (trifluoromethyl) isoindolin-2-yl) methyl) aniline: Using the compound of Reference Example 44 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 45) (0.0568 g, 0.174 mmol, 59) %) As a brown oil.
  • Example 14 Synthesis of (R) -1-Acetyl-N- (3-chloro-4-((5- (trifluoromethyl) isoindoline-2-yl) methyl) phenyl) piperidine-2-carboxamide: Using the compound of Reference Example 46 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 14 below) (0.0126 g, 0.0263 mmol, 43) %) was obtained as pale red amorphous.
  • 1 H-NMR 400 MHz, CDCl 3 ) ⁇ : 1.55-1.57 (m, 1 H), 1.72-1.
  • Reference Example 48 Synthesis of 3-chloro-4- (3,4-dihydroisoquinolin-2 (1H) -yl) aniline: Using the compound of Reference Example 47 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 48) (0.872 g, 3.37 mmol, 97 %) As a pale red oil.
  • Reference Example 49 Synthesis of tert-butyl (R) -2-((3-chloro-4- (3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) carbamoyl) piperidine-1-carboxylate:
  • the title compound (hereinafter, the compound of Reference Example 49) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 48 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. .766 g, 1.63 mmol, 84%) were obtained as a white amorphous.
  • the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure.
  • the crude product obtained was used for the subsequent reaction without purification.
  • the above crude product is dissolved in THF (7.01 mL), ethanol (7.01 mL), distilled water (7.01 mL), iron powder (0.313 g, 5.61 mmol) and acetic acid (0.802 mL, 14) .0 mmol) was added at room temperature. After stirring at 70 ° C. for 3 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform.
  • Example 17 (R) -1-Acetyl-N- (3-chloro-4- (7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) piperidine-2 -Synthesis of carboxamide: Using the compound of Reference Example 51 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 17 below) (0.0851 g, 0.177 mmol, 96) %) As a white amorphous.
  • Example 18 (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (3-chloro-4- (7- (trifluoromethyl) -3,4-dihydroisoquinoline Synthesis of -2 (1H) -yl) phenyl) piperidine-2-carboxamide: Using the compound of Reference Example 51 instead of the compound of Reference Example 49, and using the procedure of Example 16 except the above, the title compound (the compound of Example 18 below) (0.123 g, 0.225 mmol, 87) %) As a white amorphous.
  • Reference Example 52 Synthesis of 2- (2-chloro-4-nitrophenyl) -6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline: A procedure similar to Reference Example 47 is used, except that 6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride is used instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride.
  • the title compound (hereinafter, the compound of Reference Example 52) (1.10 g, 3.08 mmol, 85%) was obtained as a yellow-brown oil.
  • Reference Example 53 Synthesis of 3-chloro-4- (6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) aniline: Using the compound of Reference Example 52 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 53) (0.940 g, 2.88 mmol, 99 %) As a tan oil.
  • Example 19 (R) -1-Acetyl-N- (3-chloro-4- (6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) piperidine-2 -Synthesis of carboxamide: Using the compound of Reference Example 54 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 19 below) (0.0576 g, 0.120 mmol, 81) %) As a white amorphous.
  • Example 20 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4- (6- (trifluoromethyl) -3,4-dihydroisoquinoline Synthesis of -2 (1H) -yl) phenyl) piperidine-2-carboxamide: The procedure of Example 16 is repeated using the compound of Reference Example 54 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 20) (0.0987 g, 0.180 mmol, 97%) was obtained as a white amorphous.
  • Reference Example 56 Synthesis of N-benzyl-2-chloro-4-nitro-N-propylaniline: Using the compound of Reference Example 55 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 56) (1. 22 g, 4.00 mmol, 60%) were obtained as a colorless oil.
  • Reference Example 58 Synthesis of tert-butyl (R) -2-((4- (benzyl (propyl) amino) -3-chlorophenyl) carbamoyl) piperidine-1-carboxylate:
  • the title compound (hereinafter, the compound of Reference Example 58) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 57 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylethylamine. .640 g, 1.32 mmol, 80%) were obtained as a white amorphous.
  • Example 21 Synthesis of (R) -1-Acetyl-N- (4- (benzyl (propyl) amino) -3-chlorophenyl) piperidine-2-carboxamide: Using the compound of Reference Example 58 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 21 below) (0.122 g, 0.285 mmol, 36) %) As a white amorphous.
  • Reference Example 60 Synthesis of 2-Chloro-N- (4-fluorobenzyl) -4-nitro-N-propylaniline: Using the compound of Reference Example 59 in place of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 60) (1. 20 g, 3.72 mmol, 31%) were obtained as a tan oil.
  • Reference Example 61 Synthesis of 2-chloro-N 1- (4-fluorobenzyl) -N 1 -propylbenzene-1,4-diamine: Using the compound of Reference Example 60 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 61) (1.02 g, 3.48 mmol, 94 %) As a tan oil.
  • Reference Example 62 Synthesis of tert-butyl (R) -2-((3-chloro-4-((4-fluorobenzyl) (propyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate: Using the compound of Reference Example 61 in place of the compound of Reference Example 8 and triethylamine in place of diisopropylethylamine and following the same procedure as in Reference Example 9 except for the above, the title compound (hereinafter referred to as Compound of Reference Example 62) (0 .481 g, 0.954 mmol, 70%) were obtained as a white amorphous.
  • Example 24 Synthesis of (R) -1-Acetyl-N- (3-chloro-4-((4-fluorobenzyl) (propyl) amino) phenyl) piperidine-2-carboxamide: Using the compound of Reference Example 62 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 24 below) (0.0851 g, 0.191 mmol, 96) %) As a white amorphous.
  • Example 25 (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (3-chloro-4-((4-fluorobenzyl) (propyl) amino) phenyl) piperidine Synthesis of -2-carboxamide: Using the compound of Reference Example 62 instead of the compound of Reference Example 49, and using the same procedure as Example 16 except the above, the title compound (compound of Example 25 below) (0.140 g, 0.273 mmol, 69) %) As a white amorphous.
  • Example 26 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4-((4-fluorobenzyl) (propyl) amino) phenyl) piperidine Synthesis of -2-carboxamide: The procedure of Example 16 is repeated using the compound of Reference Example 62 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 26) (0.100 g, 0.195 mmol, 82%) was obtained as a white amorphous.
  • Reference Example 64 Synthesis of 2-fluoro-N- (4-fluorobenzyl) -N-isobutyl-4-nitroaniline: The compound of Reference Example 63 is used instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride, 3,4-difluoronitrobenzene is used instead of 3-chloro-4-fluoronitrobenzene, and the other conditions are the same as in Reference Example 47.
  • the title compound (hereinafter, the compound of Reference Example 64) (2.03 g, 6.34 mmol, 57%) was obtained as a tan oil.
  • Reference Example 65 Synthesis of 2-fluoro-N 1- (4-fluorobenzyl) -N 1 -isobutylbenzene-1,4-diamine: Using the compound of Reference Example 64 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 65) (1.58 g, 5.44 mmol, 76) %) As a tan oil.
  • Reference Example 66 Synthesis of tert-butyl (R) -2-((3-fluoro-4-((4-fluorobenzyl) (isobutyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
  • the title compound (hereinafter, the compound of Reference Example 66) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 65 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. .675 g, 1.35 mmol, 98%) were obtained as a white amorphous.
  • Example 27 Synthesis of (R) -1-acetyl-N- (3-fluoro-4-((4-fluorobenzyl) (isobutyl) amino) phenyl) piperidine-2-carboxamide: Using the compound of Reference Example 66 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 27 below) (0.0854 g, 0.193 mmol, 97) %) As a white amorphous.
  • Example 28 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-fluoro-4-((4-fluorobenzyl) (isobutyl) amino) phenyl) piperidine Synthesis of -2-carboxamide: The procedure of Example 16 is repeated using the compound of Reference Example 66 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 28) (0.0870 g, 0.170 mmol, 43%) was obtained as a white amorphous.
  • Reference Example 68 Synthesis of 2-chloro-N- (4-chlorobenzyl) -4-nitro-N-propylaniline: Using the compound of Reference Example 67 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 68) (2. 60 g, 7.66 mmol, 70%) were obtained as a tan oil.
  • Reference Example 69 Synthesis of 2-chloro-N 1- (4-chlorobenzyl) -N 1 -propylbenzene-1,4-diamine: Using the compound of Reference Example 68 instead of the compound of Reference Example 7, and using the same procedure as in Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 69) (2.03 g, 6.56 mmol, 86 %) As a tan oil.
  • Reference Example 70 Synthesis of tert-butyl (R) -2-((3-chloro-4-((4-chlorobenzyl) (propyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
  • the title compound (hereinafter, the compound of Reference Example 70) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 69 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. 597 g (1.15 mmol, 89%) were obtained as a white amorphous.
  • Example 29 Synthesis of (R) -1-acetyl-N- (3-chloro-4-((4-chlorobenzyl) (propyl) amino) phenyl) piperidine-2-carboxamide: Using the compound of Reference Example 70 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 29 below) (0.0700 g, 0.151 mmol, 79) %) As a white amorphous.
  • Example 30 (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (3-chloro-4-((4-chlorobenzyl) (propyl) amino) phenyl) piperidine Synthesis of -2-carboxamide: Using the compound of Reference Example 70 instead of the compound of Reference Example 49, and using the same procedure as Example 16 except the above, the title compound (the compound of Example 30 below) (0.185 g, 0.350 mmol, 91) %) As a white amorphous.
  • Example 31 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4-((4-chlorobenzyl) (propyl) amino) phenyl) piperidine Synthesis of -2-carboxamide: The procedure of Example 16 is repeated using the compound of Reference Example 70 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 31) (0.100 g, 0.189 mmol, 82%) was obtained as a white amorphous.
  • Reference Example 72 Synthesis of 2-chloro-4-nitro-N-propyl-N- (4- (trifluoromethyl) benzyl) aniline: Using the compound of Reference Example 71 in place of 1,2,3,4-tetrahydroisoquinoline hydrochloride and using the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 72) (1. 05 g, 2.82 mmol, 24%) were obtained as a tan oil.
  • Reference Example 73 Synthesis of 2-chloro-N 1 -propyl-N 1- (4- (trifluoromethyl) benzyl) benzene-1,4-diamine: The compound of Reference Example 72 (1.00 g, 2.68 mmol) is dissolved in THF (13.4 mL), ethanol (13.4 mL), distilled water (13.4 mL), ammonium chloride (1.44 g, 26.8 mmol) ) And iron (0.599 g, 10.7 mmol) were added at room temperature. After stirring at 70 ° C. for 16 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform.
  • Reference Example 74 Synthesis of tert-butyl (R) -2-((3-chloro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
  • the title compound (hereinafter, the compound of Reference Example 74) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 73 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. .575 g, 1.04 mmol, 89%) were obtained as a white amorphous.
  • Reference Example 75 Synthesis of (R) -N- (3-chloro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) piperidine-2-carboxamide: The compound of Reference Example 74 (0.200 g, 0.361 mmol) was dissolved in dichloromethane (1.81 mL), and trifluoroacetic acid (0.417 mL, 5.41 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, 1 M aqueous sodium hydroxide solution was added for neutralization, and the mixture was extracted with chloroform.
  • Example 34 (R) -N- (3-chloro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) -1- (2-cyclopropylacetyl) piperidine-2-carboxamide Synthesis: The title compound (hereinafter, the compound of Example 34) (0.109 g, 0%) by a procedure similar to Example 33 except for using cyclopropyl acetic acid instead of 1-imidazole acetic acid and dichloromethane instead of DMF 203 mmol, 92%) were obtained as a white amorphous.
  • Example 35 (R) -N- (3-chloro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) -1- (2-cyclobutylacetyl) piperidine-2-carboxamide Synthesis: The title compound (hereinafter, the compound of Example 35) (0.0585 g, 0. 1) was prepared by the same procedure as in Example 33 except for using cyclobutyl acetic acid instead of 1-imidazole acetic acid and dichloromethane instead of DMF. 106 mmol, 97%) were obtained as a white amorphous.
  • Example 37 Synthesis of (R) -N- (3-chloro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) -1- (methylsulfonyl) piperidine-2-carboxamide:
  • the title compound (hereinafter, the compound of Example 37) (0.0470 g, 0.0883 mmol, 98%) was prepared by the same procedure as Example 36 except that methanesulfonyl chloride was used instead of cyclopropyl carbonyl chloride. Obtained as a white amorphous.
  • Reference Example 77 Synthesis of 2-chloro-N-methyl-4-nitro-N- (4- (trifluoromethyl) benzyl) aniline: Using the compound of Reference Example 76 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 77) (0. 1). 557 g (1.62 mmol, 87%) were obtained as a tan oil.
  • Example 38 Synthesis of 1-acetyl-N- (3-chloro-4- (methyl (4- (trifluoromethyl) benzyl) amino) phenyl) piperidine-2-carboxamide: The compound of Reference Example 78 (0.200 g, 0.635 mmol) was dissolved in DMF (6.36 mL), N-acetyl-pipecolic acid (0.141 g, 0.826 mmol), HATU (0.362 g, 0.935 mmol) ) And triethylamine (0.177 mL, 1.27 mmol) were added at room temperature. After stirring at the same temperature for 14 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate.
  • Reference Example 80 Synthesis of 2-chloro-N-isobutyl-4-nitro-N- (4- (trifluoromethyl) benzyl) aniline: Using the compound of Reference Example 79 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 80) (0. 1). 812 g (2.10 mmol, 49%) were obtained as a tan oil.
  • Reference Example 81 Synthesis of 2-chloro-N 1 -isobutyl-N 1- (4- (trifluoromethyl) benzyl) benzene-1,4-diamine: Using the compound of Reference Example 80 instead of the compound of Reference Example 72, and using the same procedure as Reference Example 73 except for this, the title compound (hereinafter, the compound of Reference Example 81) (0.159 g, 0.446 mmol, 21) %) As a tan oil.
  • Reference Example 82 Synthesis of tert-butyl (R) -2-((3-chloro-4- (isobutyl (4- (trifluoromethyl) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate: Using the compound of Reference Example 81 in place of the compound of Reference Example 8 and triethylamine in place of diisopropylamine, and using the same procedure as in Reference Example 9 except for this, the title compound (hereinafter referred to as compound of Reference Example 82) (0) .233 g, 0.410 mmol, 98%) were obtained as a white amorphous.
  • Example 39 Synthesis of (R) -1-Acetyl-N- (3-chloro-4- (isobutyl (4- (trifluoromethyl) benzyl) amino) phenyl) piperidine-2-carboxamide: Using the compound of Reference Example 82 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 39 below) (0.0865 g, 0.170 mmol, 64) %) As a white amorphous.
  • Example 41 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4- (isobutyl (4- (trifluoromethyl) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide: The procedure of Example 16 is repeated using the compound of Reference Example 82 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 41) (0.150 g, 0.260 mmol, 78%) was obtained as a white amorphous.
  • Reference Example 83 Synthesis of N- (4- (trifluoromethyl) benzyl) butane-1-amine: Using 4- (trifluoromethyl) benzaldehyde in place of benzaldehyde and butylamine in place of propylamine, the procedure is the same as in Reference Example 55 except for using the title compound (hereinafter, the compound of Reference Example 83) (1. 15 g, 4.97 mmol, 87%) were obtained as a colorless oil.
  • Reference Example 84 Synthesis of N-butyl-2-chloro-4-nitro-N- (4- (trifluoromethyl) benzyl) aniline: Using the compound of Reference Example 83 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 84) (1. 00 g, 2.56 mmol, 60%) were obtained as a tan oil.
  • Reference Example 85 Synthesis of N 1 -butyl-2-chloro-N 1- (4- (trifluoromethyl) benzyl) benzene-1,4-diamine: The title compound (following, compound of Reference Example 85) (0.565 g, 1.58 mmol, 61) was prepared by using the compound of Reference Example 84 instead of the compound of Reference Example 72 and using the same procedure as in Reference Example 73 except the above. %) As a tan oil.
  • Reference Example 86 Synthesis of tert-butyl (R) -2-((4- (butyl (4- (trifluoromethyl) benzyl) amino) -3-chlorophenyl) carbamoyl) piperidine-1-carboxylate:
  • the title compound (hereinafter, the compound of Reference Example 86) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 85 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. .400 g, 0.704 mmol, 84%) were obtained as a white amorphous.
  • Example 42 Synthesis of (R) -1-Acetyl-N- (4- (butyl (4- (trifluoromethyl) benzyl) amino) -3-chlorophenyl) piperidine-2-carboxamide: Using the compound of Reference Example 86 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 42 below) (0.164 g, 0.322 mmol, 91) %) As a white amorphous.
  • Example 43 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (4- (butyl (4- (trifluoromethyl) benzyl) amino) -3-chlorophenyl) Synthesis of piperidine-2-carboxamide: Using the compound of Reference Example 86 instead of the compound of Reference Example 49, and using the same procedure as Example 16 except the above, the title compound (the compound of Example 43 below) (0.262 g, 0.455 mmol, 65) %) As a white amorphous.
  • Example 44 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (4- (butyl (4- (trifluoromethyl) benzyl) amino) -3-chlorophenyl) Synthesis of piperidine-2-carboxamide: The procedure of Example 16 is repeated using the compound of Reference Example 86 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 44) (0.213 g, 0.368 mmol, quantitative) was obtained as a white amorphous.
  • Reference Example 87 Synthesis of 2-((4- (trifluoromethyl) benzyl) amino) ethan-1-ol: The title compound (hereinafter, the compound of Reference Example 87) was prepared according to the same procedure as in Reference Example 55 except for using 4- (trifluoromethyl) benzaldehyde instead of benzaldehyde and ethanolamine instead of propylamine. .359 g, 1.64 mmol, 57%) were obtained as a colorless oil.
  • Reference Example 88 Synthesis of 2-((2-chloro-4-nitrophenyl) (4- (trifluoromethyl) benzyl) amino) ethan-1-ol: Using the compound of Reference Example 87 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride, and using the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 88) (0. 1). 358 g (0.955 mmol, 60%) were obtained as a tan oil.
  • Reference Example 89 Synthesis of 2-((4-amino-2-chlorophenyl) (4- (trifluoromethyl) benzyl) amino) ethan-1-ol:
  • the title compound (hereinafter, the compound of Reference Example 89) (0.117 g, 0.339 mmol, 64) was prepared by using the compound of Reference Example 88 in place of the compound of Reference Example 72 and using the same procedure as in Reference Example 73 %) As a tan oil.
  • Reference Example 90 Synthesis of 2-methoxy-N- (4- (trifluoromethyl) benzyl) ethan-1-amine: The title compound (hereinafter, the compound of Reference Example 90) was prepared by the same procedure as Reference Example 55 using 4- (trifluoromethyl) benzaldehyde instead of benzaldehyde and methoxyethylamine instead of propylamine. .591 g (2.53 mmol, 88%) were obtained as a colorless oil.
  • Reference Example 91 Synthesis of 2-chloro-N- (2-methoxyethyl) -4-nitro-N- (4- (trifluoromethyl) benzyl) aniline: Using the compound of Reference Example 90 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 91) (0. 1). 453 g (1.17 mmol, 51%) were obtained as a tan oil. 1 H-NMR (400 MHz, CDCl 3 ) ⁇ : 3.27 (s, 2 H), 3.51-3.
  • Example 46 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (3-chloro-4-((2-methoxyethyl) (4- (trifluoromethyl)) Synthesis of benzyl) amino) phenyl) piperidine-2-carboxamide: Using the compound of Reference Example 93 instead of the compound of Reference Example 49, and using the same procedure as Example 16 except the above, the title compound (the compound of Example 46 below) (0.0617 g, 0.107 mmol, 92) %) As a white amorphous.
  • Reference Example 94 Synthesis of 1-Cyclopropyl-N- (4- (trifluoromethyl) benzyl) methanamine: The title compound (the compound of Reference Example 94) was prepared by the same procedure as Reference Example 55 except for using 4- (trifluoromethyl) benzaldehyde instead of benzaldehyde and cyclopropylmethylamine instead of propylamine. (0.660 g, 2.88 mmol, 99%) was obtained as a colorless oil.
  • Reference Example 95 Synthesis of 2-chloro-N- (cyclopropylmethyl) -4-nitro-N- (4- (trifluoromethyl) benzyl) aniline: Using the compound of Reference Example 94 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 95) (0. 1). 350 g, 0.910 mmol, 52%) were obtained as a colorless oil.
  • Reference Example 96 Synthesis of 2-chloro-N 1- (cyclopropylmethyl) -N 1- (4- (trifluoromethyl) benzyl) benzene-1,4-diamine: The title compound (hereinafter, the compound of Reference Example 96) (0.189 g, 0.533 mmol, 59) was prepared by using the compound of Reference Example 95 in place of the compound of Reference Example 72 and using the same procedure as Reference Example 73 except the above. %) As a tan oil.
  • Reference Example 99 Synthesis of 2-fluoro-N 1 -propyl-N 1- (4- (trifluoromethyl) benzyl) benzene-1,4-diamine: The title compound (hereinafter, the compound of Reference Example 99) (1.60 g, 4.90 mmol, 76) was prepared by using the compound of Reference Example 98 in place of the compound of Reference Example 7 and using the same procedure as in Reference Example 8 %) As a tan oil.
  • Reference Example 100 Synthesis of tert-butyl (R) -2-((3-fluoro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
  • the title compound (hereinafter, the compound of Reference Example 100) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 99 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. (5.29 g, 0.984 mmol, 80%) was obtained as a white amorphous.
  • Example 49 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-fluoro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide: The procedure of Example 16 is repeated using the compound of Reference Example 100 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 49) (0.0951 g, 0.173 mmol, 47%) was obtained as a white amorphous.
  • Reference Example 102 Synthesis of 2-chloro-N 1 -propyl-N 1- (3- (trifluoromethyl) benzyl) benzene-1,4-diamine: Using the compound of Reference Example 101 instead of the compound of Reference Example 72, and using the same procedure as Reference Example 73 except for the above, the title compound (hereinafter, the compound of Reference Example 102) (0.207 g, 0.604 mmol, 75% ) was obtained as a tan oil.
  • Reference Example 103 Synthesis of tert-butyl (R) -2-((3-chloro-4- (propyl (3- (trifluoromethyl) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
  • the title compound (hereinafter, the compound of Reference Example 103) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 102 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. 190 g (0.343 mmol, 45%) were obtained as a white amorphous.
  • Example 50 (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (3-chloro-4- (propyl (3- (trifluoromethyl) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide: Using the compound of Reference Example 103 instead of the compound of Reference Example 49, and using the same procedure as Example 16 except the above, the title compound (the compound of Example 50 below) (0.106 g, 0.189 mmol, 55) %) As a white amorphous.
  • Reference Example 104 Synthesis of 2-chloro-4-nitro-N-propyl-N- (4- (trifluoromethoxy) benzyl) aniline: The title compound (hereinafter, the compound of Reference Example 104) (0.478 g) was prepared according to the same procedure as in Reference Example 101 except that 4- (trifluoromethoxy) benzaldehyde was used instead of 3- (trifluoromethyl) benzaldehyde , 1.23 mmol, 47%) were obtained as a tan oil.
  • Reference Example 105 Synthesis of 2-chloro-N 1 -propyl-N 1- (4- (trifluoromethoxy) benzyl) benzene-1,4-diamine: The title compound (hereinafter, the compound of Reference Example 105) (0.244 g, 0.680 mmol, 88%) was prepared by using the compound of Reference Example 104 instead of the compound of Reference Example 72 and using the same procedure as in Reference Example 73 except the above. ) was obtained as a tan oil.
  • Reference Example 106 Synthesis of tert-butyl (R) -2-((3-chloro-4- (propyl (4- (trifluoromethoxy) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
  • the title compound (hereinafter, the compound of Reference Example 106) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 105 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. .381 g, 0.668 mmol, 92%) were obtained as a white amorphous.
  • Example 51 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (3-chloro-4- (propyl (4- (trifluoromethoxy) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide: The title compound (the compound of Example 51 below) (0.0475 g, 0.0822 mmol, 12) was prepared by the same procedure as in Example 16 except for using the compound of Reference Example 106 in place of the compound of Reference Example 49. %) As a white amorphous.
  • Reference Example 108 Synthesis of 2-chloro-4-nitro-N-propyl-N- (3- (trifluoromethoxy) benzyl) aniline: Using the compound of Reference Example 107 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride, and using the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 108) (0. 1). 798 g (2.05 mmol, 24%) were obtained as a colorless oil.
  • Reference Example 109 Synthesis of 2-chloro-N 1 -propyl-N 1- (3- (trifluoromethoxy) benzyl) benzene-1,4-diamine: Using the compound of Reference Example 108 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except the above, the title compound (the compound of Reference Example 109) (0.707 g, 1.97 mmol, 96) %) As a tan oil.
  • Reference Example 110 Synthesis of tert-butyl (R) -2-((3-chloro-4- (propyl (3- (trifluoromethoxy) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
  • the title compound (hereinafter, the compound of Reference Example 110) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 109 was used instead of the compound of Reference Example 8, and triethylamine instead of diisopropylamine. 467 g, 0.819 mmol, 98%) were obtained as a white amorphous.
  • 1 H-NMR 400 MHz, d-DMSO) ⁇ : 0.81-0.88 (m, 3 H), 1.24-1.
  • Example 52 Synthesis of (R) -1-acetyl-N- (3-chloro-4- (propyl (3- (trifluoromethoxy) benzyl) amino) phenyl) piperidine-2-carboxamide: Using the compound of Reference Example 110 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 52 below) (0.122 g, 0.238 mmol, 91) %) As a white amorphous.
  • Example 53 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (3-chloro-4- (propyl (3- (trifluoromethoxy) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide: Using the compound of Reference Example 110 instead of the compound of Reference Example 49, and using the procedure of Example 16 except the above, the title compound (the compound of Example 53 below) (0.0365 g, 0.0631 mmol, 24) %) As a white amorphous.
  • Example 54 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4- (propyl (3- (trifluoromethoxy) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide: The procedure of Example 16 is repeated using the compound of Reference Example 110 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 54) (0.122 g, 0.210 mmol, 80%) was obtained as a white amorphous.
  • Reference Example 111 Synthesis of N- (2-chloro-4-nitrobenzyl) -N- (4- (trifluoromethyl) benzyl) propan-1-amine: Using the compound of Reference Example 71 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 7 except for this, the title compound (hereinafter, the compound of Reference Example 111) (8.54 g, 22.1 mmol, 96 %) As a pale yellow oil.
  • Reference Example 112 Synthesis of 3-chloro-4-((propyl (4- (trifluoromethyl) benzyl) amino) methyl) aniline: Using the compound of Reference Example 111 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 112) (9.57 g, 26.8 mmol, 94 %) As a pale yellow oil.
  • Example 55 Synthesis of (R) -1-acetyl-N- (3-chloro-4-((propyl (4- (trifluoromethyl) benzyl) amino) methyl) phenyl) piperidine-2-carboxamide Using the compound of Reference Example 113 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 55 below) (0.0400 g, 0.0784 mmol, 73) %) As a white amorphous.
  • Example 56 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (3-chloro-4-((propyl (4- (trifluoromethyl) benzyl) amino) Synthesis of methyl) phenyl) piperidine-2-carboxamide: Using the compound of Reference Example 113 instead of the compound of Reference Example 49, and using the procedure of Example 16 except the above, the title compound (the compound of Example 56) (0.0375 g, 0.0650 mmol, 31) %) As a white amorphous.
  • the purified product obtained was dissolved in diethyl ether (1.29 mL) and n-hexane (1.29 mL), and 1 M hydrogen chloride-diethyl ether solution (1.29 mL) was added at room temperature.
  • the reaction solution was filtered, and the collected solid was dried to give the title compound (hereinafter, the compound of Example 57) (0.0439 g, 0.0714 mmol, 33%) as a white solid.
  • Example 58 (R) -N- (3-Chloro-4-((propyl (4- (trifluoromethyl) benzyl) amino) methyl) phenyl) -1- (methylsulfonyl) piperidine-2-carboxamide Synthesis: The compound of Reference Example 113 (8.00 g, 14.1 mmol) was dissolved in dichloromethane (34.1 mL), and trifluoroacetic acid (8.54 mL, 111 mmol) was added at 0 ° C. After stirring at room temperature for 12 hours, the reaction solution was added to a saturated aqueous solution of sodium carbonate and extracted with chloroform.
  • Reference Example 115 Synthesis of 3-chloro-4-((isobutyl (4- (trifluoromethyl) benzyl) amino) methyl) aniline: Using the compound of Reference Example 114 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 115) (0.167 g, 0.450 mmol, 82) %) As a yellow oil.
  • Example 59 (R) -N- (3-chloro-4-((isobutyl (4- (trifluoromethyl) benzyl) amino) methyl) phenyl) -1- (methylsulfonyl) piperidine-2-carboxamide Synthesis: Using the compound of Reference Example 116 instead of the compound of Reference Example 113, and using the same procedure as Example 58 except the above, the title compound (the compound of Example 59 below) (0.172 g, 0.307 mmol, 81) %) As a white amorphous.
  • Reference Example 118 Synthesis of 3-chloro-4-(((cyclopropylmethyl) (4- (trifluoromethyl) benzyl) amino) methyl) aniline: Using the compound of Reference Example 117 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 118) (0.172 g, 0.466 mmol, 73 %) As a yellow oil.
  • Example 60 (R) -N- (3-Chloro-4-(((cyclopropylmethyl) (4- (trifluoromethyl) benzyl) amino) methyl) phenyl) -1- (methylsulfonyl) piperidine- Synthesis of 2-carboxamide: Using the compound of Reference Example 119 instead of the compound of Reference Example 113, and using the same procedure as Example 58 except the above, the title compound (the compound of Example 60 below) (0.137 g, 0.245 mmol, 77) %) As a white amorphous.
  • Reference Example 120 Synthesis of N- (2-chloro-4-nitrobenzyl) -N- (4- (trifluoromethyl) benzyl) butane-1-amine: Using the compound of Reference Example 83 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 7 except the above, the title compound (hereinafter, the compound of Reference Example 120) (0.226 g, 0.564 mmol, 87) %) As a colorless oil.
  • Reference Example 121 Synthesis of 4-((butyl (4- (trifluoromethyl) benzyl) amino) methyl) -3-chloroaniline: Using the compound of Reference Example 120 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 121) (0.160 g, 0.431 mmol, 76) %) As a yellow oil.
  • Example 61 Synthesis of (R) -N- (4-((Butyl (4- (trifluoromethyl) benzyl) amino) methyl) -3-chlorophenyl) -1- (methylsulfonyl) piperidine-2-carboxamide : Using the compound of Reference Example 122 instead of the compound of Reference Example 113, and using the same procedure as Example 58 except the above, the title compound (the compound of Example 61 below) (0.122 g, 0.218 mmol, 80) %) As a white amorphous.
  • the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the crude product obtained was used for the subsequent reaction without purification.
  • the above crude product was dissolved in DMSO (10.0 mL) and 3-chloro-4-fluoronitrobenzene (0.878 g, 5.00 mmol) and diisopropylethylamine (1.75 mL, 10.0 mmol) were added at room temperature . After stirring at 120 ° C. for 23 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure.
  • Reference Example 125 Synthesis of tert-butyl (R) -2-((3-chloro-4- (prop-2-yn-1-yl (propyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate: The title compound (hereinafter, the compound of Reference Example 125) (0.0599 g, 0.138 mmol, 88) was prepared by using the compound of Reference Example 124 instead of the compound of Reference Example 8 and using the same procedure as in Reference Example 9 except the above. %) As a white amorphous.
  • Example 62 Synthesis of (R) -1-acetyl-N- (3-chloro-4- (prop-2-yn-1-yl (propyl) amino) phenyl) piperidine-2-carboxamide: Using the compound of Reference Example 125 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 62 below) (0.0488 g, 0.130 mmol, 94) %) As a white amorphous.
  • Example 63 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (3-chloro-4- (prop-2-yn-1-yl (propyl) amino) Synthesis of Phenyl) piperidine-2-carboxamide: The procedure of Example 13 is repeated using the compound of Reference Example 125 in place of the compound of Reference Example 43 and 1-imidazoleacetic acid instead of 2- (1H-tetrazol-1-yl) acetic acid The title compound (hereinafter, the compound of Example 63) (0.0424 g, 0.0959 mmol, 83%) was obtained as a pale yellow amorphous.
  • Example 64 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4- (prop-2-yn-1-yl (propyl) amino) Synthesis of Phenyl) piperidine-2-carboxamide: Using the compound of Reference Example 125 instead of the compound of Reference Example 43, and using the same procedure as Example 13 except the above, the title compound (the compound of Example 64 below) (0.0500 g 0.113 mmol, 98%) was obtained as a white amorphous.
  • Reference Example 128 Synthesis of tert-butyl (R) -2-((4- (but-2-yn-1-yl (propyl) amino) -3-chlorophenyl) carbamoyl) piperidine-1-carboxylate: Using the compound of Reference Example 127 instead of the compound of Reference Example 8, and according to the same procedure as Reference Example 9 except for this, the title compound (hereinafter, the compound of Reference Example 128) (0.107 g, 0.239 mmol, 97 %) As a white amorphous.
  • Example 65 Synthesis of (R) -1-acetyl-N- (4- (but-2-yn-1-yl (propyl) amino) -3-chlorophenyl) piperidine-2-carboxamide: Using the compound of Reference Example 128 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 65 below) (0.0338 g, 0.0867 mmol, 72) %) As a colorless oil.
  • Example 66 (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (4- (but-2-yn-1-yl (propyl) amino) -3-chlorophenyl ) Synthesis of piperidine-2-carboxamide: The procedure of Example 13 is repeated using the compound of Reference Example 128 in place of the compound of Reference Example 43 and 1-imidazoleacetic acid instead of 2- (1H-tetrazol-1-yl) acetic acid The title compound (hereinafter, the compound of Example 66) (0.0358 g, 0.0785 mmol, 65%) was obtained as a white amorphous.
  • Example 67 (R) -1-Acetyl-N- (3-chloro-4- (propyl (4,4,4-trifluorobut-2-yn-1-yl) amino) phenyl) piperidine-2 -Synthesis of carboxamide: Using the compound of Reference Example 129 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 67 below) (0.0857 g, 0.193 mmol, 92) %) As a white amorphous.
  • Example 68 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (3-chloro-4- (propyl (4,4,4-trifluorobuta-2-) Synthesis of in-1-yl) amino) phenyl) piperidine-2-carboxamide: The procedure of Example 13 is repeated except that the compound of Reference Example 129 is used instead of the compound of Reference Example 43, and 1-imidazoleacetic acid is used instead of 2- (1H-tetrazol-1-yl) acetic acid. The title compound (hereinafter, the compound of Example 68) (0.0772 g, 0.151 mmol, 72%) was obtained as a white amorphous.
  • Reference Example 131 Synthesis of 3-chloro-4-((prop-2-yn-1-yl (propyl) amino) methyl) aniline: Using the compound of Reference Example 130 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 131) (0.0765 g, 0.323 mmol, 73) %) As a colorless oil.
  • ROR ⁇ -coactivator binding inhibitory action Cyclic amine derivative (I), stereoisomer or hydrate thereof, or pharmacologically acceptable thereof for binding of ROR ⁇ ligand binding domain (hereinafter ROR ⁇ -LBD) to coactivator the inhibitory effect of the salt, was assessed using a time-resolved fluorescence energy transfer LanthaScreen TM TR-FRET of (TR-FRET) invitrogen, Inc. using retinoid-Related Orphan Receptor (ROR) gamma Coactivator Assay kit.
  • test compound was dissolved in DMSO and then diluted with a 5 mmol / L DTT-containing TR-FRET Coregulator Buffer D (invitogen) to a final DMSO concentration of 1%.
  • a 5 mmol / L DTT-containing TR-FRET Coregulator Buffer D invitogen
  • To each well of a 384 well black plate (Corning), 4 nmol / L GST-fused ROR ⁇ -LBD (invitogen) diluted with the above buffer and a test compound were added.
  • a test compound-free and GST-fused ROR ⁇ -LBD-free (background), and a test compound-free and GST-fused ROR ⁇ -LBD-added (control) wells were provided.
  • ROR ⁇ -coactivator binding inhibition rate (1 ⁇ ((Fold change upon addition of test compound) ⁇ (Fold change)) / ((Fold change) ⁇ (Fold change) )) ⁇ 100 ...
  • the ROR ⁇ -coactivator binding inhibition rate (%) at 33 ⁇ mol / L of the test compound is shown in Table 2-1 and Table 2-2.
  • IL-17 production inhibitory effect in mouse splenocytes Inhibitory action of cyclic amine derivative (I), its stereoisomer or hydrates thereof, or their pharmacologically acceptable salts on IL-23 production by IL-23 stimulation using mouse splenocytes , The Journal of Biological Chemistry, 2003, 278, No. 3, p. The method described in 1910-1914 was partially modified and evaluated.
  • a single cell suspension was prepared from the spleen of a C57BL / 6J mouse (male, 6 to 31 weeks old) (Nihon Charles River Co., Ltd.), and splenocytes were prepared using Histopaque-1083 (Sigma).
  • the culture medium is RPMI 1640 medium (Gibco), 10% FBS (Gibco), 50 U / mL penicillin, 50 ⁇ g / mL streptomycin (Gibco), 50 ⁇ mol / L 2-mercaptoethanol (Gibco) and 100 U / mL human IL- 2 (Cell Science Research Institute, Inc.) was added and used.
  • the test compound was dissolved in DMSO and then diluted to a final concentration of 0.1% in culture medium.
  • Splenocytes (3 ⁇ 10 5 cells / well) prepared in culture medium are seeded in wells of a 96 well flat bottom plate (Corning Co.), and a test compound and 10 ng / mL of human IL-23 (R & D systems) are added.
  • the cells were cultured at 37 ° C. and 5% CO 2 for 3 days.
  • a human IL-23 non-added and a test compound non-added, and a human IL-23 added and test compound non-added well were provided. After completion of the culture, the culture supernatant was collected, and the amount of IL-17 produced in the supernatant was quantified by ELISA (R & D systems).
  • IL-17 production inhibition rate (%) was calculated from the following formula 2.
  • IL-17 production suppression rate (%) (1- ((IL-23 production amount with addition of IL-23 and test compound))-(IL-17 production amount without IL-23 addition and without test compound) )) / ((The amount of IL-17 produced with addition of IL-23 and no test compound)-(the amount of IL-17 produced without addition of IL-23 and no test compound))) ⁇ 100 ⁇
  • Formula 2 (1- ((IL-23 production amount with addition of IL-23 and test compound))-(IL-17 production amount without IL-23 addition and without test compound) ))) / ((The amount of IL-17 produced with addition of IL-23 and no test compound)-(the amount of IL-17 produced without addition of IL-23 and no test compound))) ⁇ 100 ⁇
  • Formula 2 (1- ((IL-23 production amount with addition of IL-23 and test compound))-(IL-17 production amount without IL-23 addition and without test
  • the inhibition ratio (%) of IL-17 production at 5 ⁇ mol / L of the test compound is shown in Table 3-1 and Table 3-2.
  • Example 72 Suppressive effects on imiquimod-induced mouse psoriasis model: Cyclic amine derivative (I), its stereoisomer or these hydrates, or their pharmacologically acceptable salts thereof in the imiquimod-induced mouse psoriasis model, using an increase in thickness of the auricle as an indicator of symptom deterioration The action was evaluated.
  • the imiquimod-induced mouse psoriasis model was prepared by partially modifying the method of Schaper et al. (The Journal of Dermatological Science, 2013, 71, No. 1, p. 29-36).
  • BALB / c mice male, 7 weeks old (Nihon Charles River Co., Ltd.) were used at 8 weeks of age after preliminary breeding.
  • 5 mg of Becelna cream was applied once a day on the outside of the left and right auricle of the mouse for 8 days from the first day of imiquimod administration (hereinafter, induction day) to 7 days after induction.
  • induction day first day of imiquimod administration
  • the test compound was administered at a dose of 10 mg / kg once a day to the mice for 5 days from the 3rd day to the 7th day after induction.
  • the compound of Example 5 was used as a test compound.
  • the compound of Example 5 was suspended in 0.5 w / v% methylcellulose solution and orally administered.
  • the group to which the compound of Example 5 was administered to mice was taken as the compound administration group of Example 5.
  • the vehicle administration group was similarly administered the solvent (0.5 w / v% methylcellulose solution) of each test compound.
  • the thickness of the left and right auricles before (immune) administration of imiquimod and the thickness of the left and right auricles on day 8 after induction were measured using a digital micrometer (Mitsutoyo).
  • the average thickness of the left and right auricles was taken as the auricle thickness, and the change (the auricular thickness on the 8th day after induction-the auricular thickness before the induction) was used as an index for drug efficacy evaluation.
  • the results are shown in FIG.
  • the “solvent” on the horizontal axis represents a solvent administration group, and the “compound of Example 5” represents a compound administration group of Example 5. * Indicates statistical significance in comparison with vehicle administration group (Aspin-Welch's t-test) (*: P ⁇ 0.05).
  • the auricle thickness at day 8 after induction in the solvent administration group increased by 0.27 mm relative to the auricle thickness before induction. This increase in ear thickness was statistically significantly suppressed by the administration of the compound of Example 5.
  • the cyclic amine derivative (I) of the present invention inhibits the function of ROR ⁇ because they have excellent ROR ⁇ antagonist activity.
  • it can be used as a medicine for a disease that can be expected to improve the pathological condition or ameliorate the symptoms.
  • it can be used as a therapeutic or preventive agent for autoimmune diseases such as psoriasis.

Abstract

The present invention addresses the problem of providing a novel compound which has an antagonistic activity against a retinoid-related orphan receptor γ and can exhibit a therapeutic or prophylactic effect on an autoimmune disease such as psoriasis. The present invention provides a cyclic amine derivative (I) typified below, a stereoisomer or hydrate of the derivative, or a pharmacologically acceptable salt of the derivative or the stereoisomer or hydrate.

Description

環状アミン誘導体及びその医薬用途Cyclic amine derivative and pharmaceutical use thereof
　本発明は、環状アミン誘導体及びその医薬用途に関する。 The present invention relates to cyclic amine derivatives and their pharmaceutical uses.
　自己免疫疾患は、過剰な免疫反応が自己の正常な細胞や組織を攻撃することで症状を来す疾患の総称であり、例えば、多発性硬化症、乾癬、関節リウマチ、全身性エリテマトーデス、炎症性腸疾患、強直性脊椎炎、ぶどう膜炎又はリウマチ性多発性筋痛症が挙げられる。 Autoimmune disease is a general term for diseases in which excessive immune reaction causes symptoms by attacking normal cells and tissues of the patient. For example, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory Intestinal diseases, ankylosing spondylitis, uveitis or polymyalgia rheumatica can be mentioned.
　自己免疫疾患の発症及び進展には様々なメカニズムが提唱されているが、その一つとして、ヘルパーＴ細胞のサブセットの一つであるＴｈ１７細胞及びそれが産生する炎症性サイトカインであるＩＬ－１７が自己免疫疾患の発症及び進展において重要な役割を果たしていることが知られている（非特許文献１及び２）。 Various mechanisms have been proposed for the onset and progression of autoimmune diseases, and one of them is Th17 cells, which is a subset of helper T cells, and IL-17, which is an inflammatory cytokine that it produces. It is known to play an important role in the onset and progression of autoimmune diseases (Non-patent Documents 1 and 2).
　ＩＬ－１７は、線維芽細胞、上皮細胞、血管内皮細胞、マクロファージ等の種々の細胞に作用し、炎症性サイトカイン、ケモカイン、メタロプロテアーゼ及びその他の炎症性メディエーターの誘導や好中球の遊走に関わっている。このため、ＩＬ－１７の産生又は機能を抑制することができれば強い抗炎症作用が発揮されると考えられており、種々の自己免疫疾患を適応症とした抗ＩＬ－１７抗体の臨床試験が実施されている。 IL-17 acts on various cells such as fibroblasts, epithelial cells, vascular endothelial cells and macrophages, and is involved in induction of inflammatory cytokines, chemokines, metalloproteases and other inflammatory mediators and neutrophil migration. ing. Therefore, if it is possible to suppress the production or function of IL-17, a strong anti-inflammatory effect is considered to be exerted, and clinical trials of anti-IL-17 antibodies with indications for various autoimmune diseases are conducted. It is done.
　近年、核内受容体であるレチノイド関連オーファン受容体γ（以下、ＲＯＲγ）が、Ｔｈ１７細胞の分化増殖及びＩＬ－１７の発現に必須な転写因子として機能していることが明らかとなり（非特許文献３）、ＲＯＲγの発現又は機能を抑制することによって、Ｔｈ１７細胞の分化及び活性化並びにＩＬ－１７の産生が抑制されることが示された（非特許文献４）。 In recent years, it has been clarified that the nuclear receptor retinoid-related orphan receptor γ (hereinafter referred to as RORγ) functions as a transcription factor essential for differentiation and proliferation of Th17 cells and expression of IL-17 (non-patent) Reference 3), it was shown that suppressing the expression or function of RORγ suppresses the differentiation and activation of Th17 cells and the production of IL-17 (Non-patent Document 4).
　自己免疫疾患（多発性硬化症、乾癬、全身性エリテマトーデス等）患者では、末梢血単核球におけるＲＯＲγ発現量が健常人と比較して高い値を示すことが報告されている（非特許文献５及び６）。ＲＯＲγのノックアウトマウスでは、多発性硬化症の動物モデルであるマウス実験的自己免疫性脳脊髄炎モデルの病態が抑制されることや、大腸炎等の自己免疫疾患の症状が抑制されることが報告されている（非特許文献３及び７）。 In patients with autoimmune diseases (multiple sclerosis, psoriasis, systemic lupus erythematosus etc.), it has been reported that the expression level of RORγ in peripheral blood mononuclear cells shows a high value as compared with healthy people (Non-patent Document 5) And 6). It is reported that in RORγ knockout mice, the pathological condition of mouse experimental autoimmune encephalomyelitis model, which is an animal model of multiple sclerosis, is suppressed, and symptoms of autoimmune diseases such as colitis are suppressed. (Non-Patent Documents 3 and 7).
　さらに、ＲＯＲγが転写因子として機能するためには、ＲＯＲγとコアクチベーターとの結合が必要であることが示唆されている（非特許文献８）。このため、ＲＯＲγとコアクチベーターとの結合を阻害する化合物であるＲＯＲγアンタゴニストは、自己免疫疾患の治療剤又は予防剤として有用であると期待されている。 Furthermore, it has been suggested that in order for RORγ to function as a transcription factor, binding between RORγ and a coactivator is necessary (Non-patent Document 8). Therefore, RORγ antagonists, which are compounds that inhibit the binding of RORγ to coactivators, are expected to be useful as therapeutic or prophylactic agents for autoimmune diseases.
　一方、ＲＯＲγアンタゴニストとしては、これまでにＮ－（５－（Ｎ－（４－（１，１，１，３，３，３－ヘキサフルオロ－２－ヒドロキシプロパン－２－イル）フェニル）スルファモイル）－４－メチルチアゾール－２－イル）アセトアミド（非特許文献９）や、６－（２－クロロ－４－メチルフェニル）－３－（４－シクロプロピル－５－（３－ネオペンチルシクロブチル）イソオキサゾール－３－イル）－５－オキソヘキサン酸をはじめとする置換アゾール誘導体（特許文献１）や、Ｎ－（２－クロロ－２’－（トリフルオロメトキシ）－［１，１’－ビフェニル］－４－イル）－２－（４－（メチルスルホニル）フェニル）アセトアミド等のスルホニルベンゼン誘導体（特許文献２）や、１－アセチル－Ｎ－（２－クロロ－２’－（トリフルオロメトキシ）－［１，１’－ビフェニル］－４－イル）ピペリジン－２－カルボキサミド等のビアリール誘導体（特許文献３）が報告されている。 On the other hand, as RORγ antagonists, N- (5- (N- (4- (1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl) phenyl) sulfamoyl) has hitherto been described. -4-methylthiazol-2-yl) acetamide (Non-patent Document 9), 6- (2-chloro-4-methylphenyl) -3- (4-cyclopropyl-5- (3-neopentylcyclobutyl) Substituted azole derivatives such as isoxazol-3-yl) -5-oxohexanoic acid (Patent Document 1), N- (2-chloro-2 '-(trifluoromethoxy)-[1,1'-biphenyl Sulfonylbenzene derivatives such as -4-yl) -2- (4- (methylsulfonyl) phenyl) acetamide (Patent Document 2) or 1-acetyl-N- (2-chloro-2'-) Trifluoromethoxy) - [1,1'-biphenyl] -4-yl) piperidine-2-carboxamide biaryl derivatives such as (Patent Document 3) have been reported.
　また、１位置換ピペリジン－２－カルボキサミド等の環状アミン構造を有する化合物としては、ＧＰＲアゴニストとして、４－［（Ｅ）－４－（４－メトキシカルボニルフェニル）ブタ－３－エニル］ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチル　エステル等（特許文献４）や、オレキシン受容体アンタゴニストとして、Ｎ－ビフェニル－２－イル－２－メチル－１－［３－（１－メチル－１Ｈ－ベンゾイミダゾール－２－イル）プロパノイル］－Ｌ－プロリンアミド等が報告されているが（特許文献５）、これらの化合物のＲＯＲγに対する作用については開示も示唆もされていない。 In addition, as a compound having a cyclic amine structure such as 1-substituted piperidine-2-carboxamide, 4-[(E) -4- (4-methoxycarbonylphenyl) but-3-enyl] piperidine-1 as a GPR agonist N-biphenyl-2-yl-2-methyl-1- [3- (1-methyl-1H-benzimidazole-2- (2-hydroxy-1-hydroxy)] as an orexin receptor antagonist Although (yl) propanoyl] -L-prolinamide and the like have been reported (Patent Document 5), the action of these compounds on RORγ is neither disclosed nor suggested.
特開２０１２－２３６８２２号公報JP 2012-236822 A 国際公開第２０１２／０２７９６５号International Publication No. 2012/027965 国際公開第２０１７／１３１１５６号International Publication No. 2017/131156 国際公開第２００７／００３９６２号WO 2007/003962 国際公開第２００８／００８５５１号International Publication No. 2008/008551
　しかしながら、自己免疫疾患の実際の治療には、免疫系全体に対して作用するステロイド剤又は免疫抑制剤が内服薬として用いられており、感染症等の重篤な副作用の懸念から十分な薬効が認められる前に投与を中止せざるを得ないケースが臨床的に多数存在しているのが現状である。このため、自己免疫疾患の発症及び進展メカニズムにおいて重要な役割を果たしている分子を標的とした新たな医薬の開発が切望されている。 However, in the actual treatment of autoimmune diseases, steroids or immunosuppressants that act on the entire immune system are used as internal medicines, and sufficient efficacy has been recognized due to concerns about serious side effects such as infections. At present, there are a large number of cases where the administration must be discontinued before being taken. For this reason, development of new medicines targeting molecules that play an important role in the onset and progression mechanism of autoimmune diseases is desired.
　そこで本発明は、ＲＯＲγアンタゴニスト活性を有し、乾癬等の自己免疫疾患に対して治療効果又は予防効果を発揮する新規な化合物を提供することを目的とする。 Then, this invention aims at providing the novel compound which has ROR (gamma) antagonist activity and exhibits a therapeutic effect or a preventive effect with respect to autoimmune diseases, such as psoriasis.
　本発明者らは上記課題を解決するために鋭意研究を重ねた結果、ＲＯＲγアンタゴニスト活性を有する新規な環状アミン誘導体を見出し、本発明を完成するに至った。 As a result of intensive studies to solve the above problems, the present inventors have found novel cyclic amine derivatives having RORγ antagonist activity, and have completed the present invention.
　すなわち、本発明は、下記の一般式（Ｉ）で示される環状アミン誘導体、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩を提供する。
Figure JPOXMLDOC01-appb-C000003
 ［式中、Ｒ１は、ハロゲン原子を表し、Ｘは、－Ｃ（＝Ｏ）－（ＣＨ２）ｎ－Ｒ２又は－Ｓ（＝Ｏ）２－Ｒ３を表し、ｎは、０～３の整数を表し、Ｒ２は、水素原子、炭素数１～３のアルキル基、炭素数３～６のシクロアルキル基、炭素数４～６のシクロアルキルアルキル基又はヘテロアリール基を表し、Ｒ３は、炭素数１～３のアルキル基を表し、ｍは、０又は１を表し、Ａは、下記の一般式（ＩＩ－１）又は（ＩＩ－２）で示される基を表す。
Figure JPOXMLDOC01-appb-C000004
 （式中、Ｒ４は、水素原子、ハロゲン原子又はメチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）を表し、ｐは、０～２の整数を表し、ｑは、１又は２を表し、Ｒ５は、炭素数１～６のアルキル基、炭素数４～６のシクロアルキルアルキル基又は－（ＣＨ２）ｒ－ＯＲ７を表し、Ｒ６は、フェニル基（該フェニル基は、１個の任意の水素原子が、ハロゲン原子、メチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）若しくはメトキシ基（該メトキシ基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）、で置換されていてもよい。）又はエチニル基（該エチニル基は、水素原子が、メチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）で置換されていてもよい。）を表し、ｒは、２～４の整数を表し、Ｒ７は、水素原子又は炭素数１～３のアルキル基を表す。）］ That is, the present invention provides a cyclic amine derivative represented by the following general formula (I), a stereoisomer or a hydrate thereof, or a pharmacologically acceptable salt thereof.
Figure JPOXMLDOC01-appb-C000003
 [Wherein, R 1 represents a halogen atom, X represents -C (= O)-(CH 2 ) n -R 2 or -S (= O) 2 -R 3 , n represents 0 to R 2 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or a heteroaryl group, 3 represents an alkyl group having 1 to 3 carbon atoms, m represents 0 or 1, and A represents a group represented by the following general formula (II-1) or (II-2).
Figure JPOXMLDOC01-appb-C000004
 (Wherein R 4 represents a hydrogen atom, a halogen atom or a methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a halogen atom), and p represents Represents an integer of 0 to 2, q represents 1 or 2, and R 5 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or-(CH 2 ) r -OR 7 R 6 represents a phenyl group (wherein the optional one hydrogen atom is a halogen atom, and the methyl group (wherein the optional methyl group is a hydrogen atom of one to three substituted by a halogen atom) Or methoxy group (in the methoxy group, one to three arbitrary hydrogen atoms may be substituted with halogen atoms), or ethynyl. Group (the ethynyl group is a hydrogen atom, a methyl group (the methyl group is one) Three arbitrary hydrogen atom may be substituted with a halogen atom.) May be substituted with.) Represent, r is an integer of 2 ~ 4, R 7 is hydrogen or C Represents an alkyl group of 1 to 3).
　上記の一般式（Ｉ）で示される環状アミン誘導体において、Ｒ１は、フッ素原子又は塩素原子であり、ｎは、０～２の整数であり、Ｒ２は、水素原子、炭素数１～３のアルキル基、炭素数３～６のシクロアルキル基、炭素数４～６のシクロアルキルアルキル基又は１個～４個の窒素原子を含む５員環ヘテロアリール基であり、Ｒ４は、水素原子、フッ素原子、塩素原子又はメチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）であり、ｐは、０又は１であり、Ｒ５は、炭素数１～４のアルキル基、炭素数４～６のシクロアルキルアルキル基又は－（ＣＨ２）ｒ－ＯＲ７であり、Ｒ６は、フェニル基（該フェニル基は、１個の任意の水素原子が、フッ素原子、塩素原子、メチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）若しくはメトキシ基（該メトキシ基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）、で置換されていてもよい。）又はエチニル基（該エチニル基は、水素原子が、メチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）で置換されていてもよい。）であり、ｒは、２であり、Ｒ７は、水素原子又はメチル基であることが好ましい。 In the cyclic amine derivative represented by the above general formula (I), R 1 is a fluorine atom or a chlorine atom, n is an integer of 0 to 2, and R 2 is a hydrogen atom, having 1 to 3 carbon atoms A cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or a 5-membered heteroaryl group containing 1 to 4 nitrogen atoms, and R 4 is a hydrogen atom , A fluorine atom, a chlorine atom or a methyl group (in the methyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom), p is 0 or 1 R 5 is an alkyl group having 1 to 4 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or-(CH 2 ) r -OR 7 , and R 6 is a phenyl group (the phenyl group is 1 arbitrary hydrogen atom is fluorine atom, chlorine atom, methyl Group (in the methyl group, any one to three hydrogen atoms may be substituted with a fluorine atom or a chlorine atom) or a methoxy group (in the methoxy group, any one to 3 groups). A hydrogen atom may be substituted with a fluorine atom or a chlorine atom)), or an ethynyl group (in the ethynyl group, a hydrogen atom is a methyl group (the methyl group is one) -3 optional hydrogen atoms may be substituted by fluorine atom or chlorine atom)), r is 2 and R 7 is hydrogen atom or methyl It is preferably a group.
　この場合には、より高いＲＯＲγアンタゴニスト活性が期待できる。 In this case, higher RORγ antagonist activity can be expected.
　また、上記の一般式（Ｉ）で示される環状アミン誘導体において、Ｒ１は、フッ素原子又は塩素原子であり、ｎは、０又は１であり、Ｒ２は、水素原子、メチル基、シクロプロピル基、イミダゾリル基、トリアゾリル基又はテトラゾリル基であり、Ｒ３は、メチル基であり、Ｒ４は、塩素原子又はトリフルオロメチル基であり、ｐは、１であり、ｑは、２であり、Ｒ５は、プロピル基、ブチル基、イソブチル基又はシクロプロピルメチル基であり、Ｒ６は、フェニル基（該フェニル基は、１個の任意の水素原子が、フッ素原子、塩素原子、トリフルオロメチル基若しくはトリフルオロメトキシ基、で置換されていてもよい。）、１－プロピニル基又は３，３，３－トリフルオロプロピニル基であることがより好ましい。 In the cyclic amine derivative represented by the above general formula (I), R 1 is a fluorine atom or a chlorine atom, n is 0 or 1, and R 2 is a hydrogen atom, a methyl group, cyclopropyl A imidazolyl group, a triazolyl group or a tetrazolyl group, R 3 is a methyl group, R 4 is a chlorine atom or a trifluoromethyl group, p is 1 and q is 2; R 5 is a propyl group, a butyl group, an isobutyl group or a cyclopropylmethyl group, R 6 is a phenyl group (in this phenyl group, one optional hydrogen atom is a fluorine atom, a chlorine atom, a trifluoromethyl) And trifluoromethoxy, which may be substituted), 1-propynyl or 3,3,3-trifluoropropynyl.
　この場合には、より高いＲＯＲγアンタゴニスト活性が期待でき、さらに乾癬等の自己免疫疾患における優れた治療効果又は予防効果が期待できる。 In this case, higher RORγ antagonist activity can be expected, and further, excellent therapeutic effect or preventive effect in autoimmune diseases such as psoriasis can be expected.
　また、上記の一般式（Ｉ）で示される環状アミン誘導体において、Ｒ１は、塩素原子であり、Ｘは、－Ｃ（＝Ｏ）－（ＣＨ２）ｎ－Ｒ２であり、ｎは、１であり、Ｒ２は、水素原子、イミダゾリル基又はテトラゾリル基であり、Ｒ４は、トリフルオロメチル基であり、ｐは、１であり、ｑは、２であり、Ｒ５は、プロピル基、ブチル基又はイソブチル基であり、Ｒ６は、フェニル基（該フェニル基は、１個の任意の水素原子が、フッ素原子、塩素原子、トリフルオロメチル基又はトリフルオロメトキシ基、で置換されていてもよい。）であることがさらに好ましい。 Further, in the cyclic amine derivative represented by the above general formula (I), R 1 is a chlorine atom, X is —C (= O) — (CH 2 ) n —R 2 and n is 1, R 2 is a hydrogen atom, an imidazolyl group or a tetrazolyl group, R 4 is a trifluoromethyl group, p is 1, q is 2 and R 5 is a propyl group And R 6 is a phenyl group (in the phenyl group, one arbitrary hydrogen atom is substituted with a fluorine atom, a chlorine atom, a trifluoromethyl group or a trifluoromethoxy group). Is more preferable).
　この場合には、より高いＲＯＲγアンタゴニスト活性が期待でき、さらに乾癬等の自己免疫疾患における優れた治療効果又は予防効果が期待できる。 In this case, higher RORγ antagonist activity can be expected, and further, excellent therapeutic effect or preventive effect in autoimmune diseases such as psoriasis can be expected.
　また本発明は、上記の一般式（Ｉ）で示される環状アミン誘導体、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩を有効成分として含有する、医薬及びＲＯＲγアンタゴニストを提供する。 Also, the present invention is a medicament comprising, as an active ingredient, the cyclic amine derivative represented by the above general formula (I), a stereoisomer thereof or a hydrate thereof, or a pharmacologically acceptable salt thereof And RORγ antagonists.
　上記の医薬は、自己免疫疾患の治療剤又は予防剤であることが好ましく、上記の自己免疫疾患の治療剤又は予防剤としては、乾癬の治療剤又は予防剤であることがより好ましい。 The above-mentioned medicine is preferably a therapeutic agent or a preventive agent for an autoimmune disease, and as a therapeutic agent or a preventive agent for the above-mentioned autoimmune disease, a therapeutic agent or a preventive agent for psoriasis is more preferable.
　本発明の環状アミン誘導体、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩は、ＲＯＲγアンタゴニスト活性を有するため、ＲＯＲγの機能を効果的に抑制でき、自己免疫疾患の治療剤又は予防剤として利用できる。 Since the cyclic amine derivative of the present invention, its stereoisomer or hydrate thereof, or pharmacologically acceptable salts thereof have RORγ antagonist activity, they can effectively suppress the function of RORγ, and can self It can be used as a therapeutic agent or prophylactic agent for immune diseases.
イミキモド誘発マウス乾癬モデルにおける耳介厚の増加に対する実施例５の化合物の抑制効果を示す図である。It is a figure which shows the inhibitory effect of the compound of Example 5 with respect to the increase in ear thickness in a imiquimod induced mouse psoriasis model.
　本発明の環状アミン誘導体は、下記の一般式（Ｉ）で示されることを特徴としている。
Figure JPOXMLDOC01-appb-C000005
 ［式中、Ｒ１は、ハロゲン原子を表し、Ｘは、－Ｃ（＝Ｏ）－（ＣＨ２）ｎ－Ｒ２又は－Ｓ（＝Ｏ）２－Ｒ３を表し、ｎは、０～３の整数を表し、Ｒ２は、水素原子、炭素数１～３のアルキル基、炭素数３～６のシクロアルキル基、炭素数４～６のシクロアルキルアルキル基又はヘテロアリール基を表し、Ｒ３は、炭素数１～３のアルキル基を表し、ｍは、０又は１を表し、Ａは、下記の一般式（ＩＩ－１）又は（ＩＩ－２）で示される基を表す。
Figure JPOXMLDOC01-appb-C000006
 （式中、Ｒ４は、水素原子、ハロゲン原子又はメチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）を表し、ｐは、０～２の整数を表し、ｑは、１又は２を表し、Ｒ５は、炭素数１～６のアルキル基、炭素数４～６のシクロアルキルアルキル基又は－（ＣＨ２）ｒ－ＯＲ７を表し、Ｒ６は、フェニル基（該フェニル基は、１個の任意の水素原子が、ハロゲン原子、メチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）若しくはメトキシ基（該メトキシ基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）、で置換されていてもよい。）又はエチニル基（該エチニル基は、水素原子が、メチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）で置換されていてもよい。）を表し、ｒは、２～４の整数を表し、Ｒ７は、水素原子又は炭素数１～３のアルキル基を表す。）］ The cyclic amine derivative of the present invention is characterized by being represented by the following general formula (I).
Figure JPOXMLDOC01-appb-C000005
 [Wherein, R 1 represents a halogen atom, X represents -C (= O)-(CH 2 ) n -R 2 or -S (= O) 2 -R 3 , n represents 0 to R 2 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or a heteroaryl group, 3 represents an alkyl group having 1 to 3 carbon atoms, m represents 0 or 1, and A represents a group represented by the following general formula (II-1) or (II-2).
Figure JPOXMLDOC01-appb-C000006
 (Wherein R 4 represents a hydrogen atom, a halogen atom or a methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a halogen atom), and p represents Represents an integer of 0 to 2, q represents 1 or 2, and R 5 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or-(CH 2 ) r -OR 7 R 6 represents a phenyl group (wherein the optional one hydrogen atom is a halogen atom, and the methyl group (wherein the optional methyl group is a hydrogen atom of one to three substituted by a halogen atom) Or methoxy group (in the methoxy group, one to three arbitrary hydrogen atoms may be substituted with halogen atoms), or ethynyl. Group (the ethynyl group is a hydrogen atom, a methyl group (the methyl group is one) Three arbitrary hydrogen atom may be substituted with a halogen atom.) May be substituted with.) Represent, r is an integer of 2 ~ 4, R 7 is hydrogen or C Represents an alkyl group of 1 to 3).
　本明細書で使用する次の用語は、特に断りがない限り、下記の定義のとおりである。 The following terms used herein are as defined below unless otherwise indicated.
　「ハロゲン原子」は、フッ素原子、塩素原子、臭素原子又はヨウ素原子を意味する。 The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
　「炭素数１～３のアルキル基」は、メチル基、エチル基、プロピル基又はイソプロピル基を意味する。 The "C1-C3 alkyl group" means a methyl group, an ethyl group, a propyl group or an isopropyl group.
　「炭素数１～４のアルキル基」は、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基又はｔｅｒｔ－ブチル基を意味する。 The "C1-C4 alkyl group" means a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group.
　「炭素数１～５のアルキル基」は、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ペンチル基、イソペンチル基、ｓｅｃ－ペンチル基、ｔｅｒｔ－ペンチル基、ネオペンチル基を意味する。 The “C1-C5 alkyl group” is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a sec-pentyl group Means a tert-pentyl group, a neopentyl group.
　「炭素数１～６のアルキル基」は、メチル基、エチル基、プロピル基、イソプロピル基、ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ペンチル基、イソペンチル基、ｓｅｃ－ペンチル基、ｔｅｒｔ－ペンチル基、ネオペンチル基、１－メチルペンチル基、ヘキシル基、イソヘキシル基、ｓｅｃ－ヘキシル基、ｔｅｒｔ－ヘキシル基又はネオヘキシル基を意味する。 The "C1-C6 alkyl group" is a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a sec-pentyl group And tert-pentyl, neopentyl, 1-methylpentyl, hexyl, isohexyl, sec-hexyl, tert-hexyl or neohexyl.
　「炭素数３～５のシクロアルキル基」は、シクロプロピル基、シクロブチル基又はシクロペンチル基を意味する。 The "C3-C5 cycloalkyl group" means a cyclopropyl group, a cyclobutyl group or a cyclopentyl group.
　「炭素数３～６のシクロアルキル基」は、シクロプロピル基、シクロブチル基、シクロペンチル基又はシクロヘキシル基を意味する。 The “C 3-6 cycloalkyl group” means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
　「炭素数４若しくは５のシクロアルキルアルキル基」は、シクロプロピルメチル基、シクロプロピルエチル基又はシクロブチルメチル基を意味する。 The "C4 or C5 cycloalkylalkyl group" means a cyclopropylmethyl group, a cyclopropylethyl group or a cyclobutylmethyl group.
　「炭素数４～６のシクロアルキルアルキル基」は、シクロプロピルメチル基、シクロプロピルエチル基、シクロプロピルプロピル基、シクロブチルメチル基、シクロブチルエチル基又はシクロペンチルメチル基を意味する。 The “C 4 -C 6 cycloalkylalkyl group” means a cyclopropylmethyl group, a cyclopropylethyl group, a cyclopropylpropyl group, a cyclobutylmethyl group, a cyclobutylethyl group or a cyclopentylmethyl group.
　「メチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）」とは、メチル基の１個～３個の任意の水素原子が、それぞれ独立して、上記のハロゲン原子で置換されていてもよい基を意味し、例えば、メチル基、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基又はトリクロロメチル基が挙げられる。 The “methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a halogen atom)” means that one to three arbitrary hydrogen atoms of the methyl group are Each independently represents a group which may be substituted by the above-mentioned halogen atom, and examples thereof include a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group or a trichloromethyl group.
　「メチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）」とは、メチル基の１個～３個の任意の水素原子が、それぞれ独立して、フッ素原子又は塩素原子で置換されていてもよい基を意味し、例えば、メチル基、フルオロメチル基、ジフルオロメチル基、トリフルオロメチル基又はトリクロロメチル基が挙げられる。 The “methyl group (in the methyl group, any one to three optional hydrogen atoms may be substituted with a fluorine atom or a chlorine atom)” means any one to three hydrogens of the methyl group. Each of the atoms independently represents a group which may be substituted with a fluorine atom or a chlorine atom, and examples thereof include a methyl group, a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group and a trichloromethyl group.
　「メトキシ基（該メトキシ基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）」とは、メトキシ基の１個～３個の任意の水素原子が、それぞれ独立して、上記のハロゲン原子で置換されていてもよい基を意味し、例えば、メトキシ基、フルオロメトキシ基、ジフルオロメトキシ基、トリフルオロメトキシ基又はトリクロロメトキシ基が挙げられる。 The “methoxy group (in the methoxy group, one to three optional hydrogen atoms may be substituted with a halogen atom)” means that one to three optional hydrogen atoms of the methoxy group are Each independently represents a group which may be substituted by the above-mentioned halogen atom, and examples thereof include a methoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group or a trichloromethoxy group.
　「メトキシ基（該メトキシ基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）」とは、メトキシ基の１個～３個の任意の水素原子が、それぞれ独立して、フッ素原子又は塩素原子で置換されていてもよい基を意味し、例えば、メトキシ基、フルオロメトキシ基、ジフルオロメトキシ基、トリフルオロメトキシ基又はトリクロロメトキシ基が挙げられる。 The “methoxy group (in the methoxy group, one to three arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom)” means any one to three hydrogens of the methoxy group. Each of the atoms independently represents a group which may be substituted with a fluorine atom or a chlorine atom, and examples thereof include a methoxy group, a fluoromethoxy group, a difluoromethoxy group, a trifluoromethoxy group and a trichloromethoxy group.
　「ヘテロアリール基」とは、窒素原子、酸素原子及び硫黄原子からなる群から任意に選択されるヘテロ原子を、それぞれ独立して１個～４個含む複素環式芳香族基を意味し、例えば、チエニル基、ピロリル基、フリル基、チアゾリル基、イミダゾリル基、オキサゾリル基、ピラゾリル基、イソチアゾリル基、イソオキサゾリル基、チアジアゾリル基、トリアゾリル基、オキサジアゾリル基、テトラゾリル基、ピリジル基、ピリダジニル基、ピリミジニル基、ピラジニル基、トリアジニル基、インドリル基、イソインドリル基、ベンゾイミダゾリル基、インダゾリル基、キノリル基、イソキノリル基、キナゾリル基、キノキサリニル基、フタラジニル基、ベンゾチアゾリル基、ベンゾイソチアゾリル基、ベンゾチアジアゾリル基、ベンゾオキサゾリル基、ベンゾイソオキサゾリル基、ベンゾフラニル基又はベンゾチエニル基が挙げられる。 “Heteroaryl group” means a heteroaromatic group containing 1 to 4 hetero atoms each independently selected from the group consisting of nitrogen atom, oxygen atom and sulfur atom, each independently selected from, for example, , Thienyl group, pyrrolyl group, furyl group, thiazolyl group, imidazolyl group, oxazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, thiadiazolyl group, triazolyl group, oxadiazolyl group, tetrazolyl group, pyridyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group Group, triazinyl group, indolyl group, isoindolyl group, benzimidazolyl group, indazolyl group, quinolyl group, isoquinolyl group, quinazolyl group, quinoxalinyl group, phthalazinyl group, benzothiazolyl group, benzisothiazolyl group, benzothiadiazolyl group, benzookiokiki Zoriru group, benzisoxazolyl group include a benzofuranyl group or a benzothienyl group.
　「１個～４個の窒素原子を含む５員環ヘテロアリール基」は、ピロリル基、チアゾリル基、イミダゾリル基、オキサゾリル基、ピラゾリル基、イソチアゾリル基、イソオキサゾリル基、チアジアゾリル基、トリアゾリル基、オキサジアゾリル基又はテトラゾリル基を意味する。 “A 5-membered heteroaryl group containing 1 to 4 nitrogen atoms” is a pyrrolyl group, thiazolyl group, imidazolyl group, oxazolyl group, pyrazolyl group, isothiazolyl group, isoxazolyl group, thiadiazolyl group, triazolyl group, oxadiazolyl group or The tetrazolyl group is meant.
　「フェニル基（該フェニル基は、１個の任意の水素原子が、ハロゲン原子、メチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）若しくはメトキシ基（該メトキシ基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）、で置換されていてもよい。）」とは、フェニル基の１個の任意の水素原子が、上記のハロゲン原子、上記のメチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）又は上記のメトキシ基（該メトキシ基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）、で置換されていてもよい基を意味し、例えば、フェニル基、フルオロフェニル基、クロロフェニル基、ブロモフェニル基、ヨードフェニル基、トリル基、（フルオロメチル）フェニル基、（ジフルオロメチル）フェニル基、（トリフルオロメチル）フェニル基、（トリクロロメチル）フェニル基、メトキシフェニル基、（フルオロメトキシ）フェニル基、（ジフルオロメトキシ）フェニル基、（トリフルオロメトキシ）フェニル基又は（トリクロロメトキシ）フェニル基が挙げられる。 “The phenyl group (in this phenyl group, one arbitrary hydrogen atom may be substituted with a halogen atom, and the methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a halogen atom. And the methoxy group (the methoxy group may be substituted with any of 1 to 3 optional hydrogen atoms which may be substituted with a halogen atom)) means “one of the phenyl groups. Selected hydrogen atoms are the above-mentioned halogen atom, the above-mentioned methyl group (in the methyl group, 1 to 3 arbitrary hydrogen atoms may be substituted by the halogen atom), or the above-mentioned methoxy group (The methoxy group means a group which may be substituted with one to three arbitrary hydrogen atoms optionally substituted with a halogen atom), and examples thereof include a phenyl group, a fluorophenyl group, Chlorophenyl group, bromophenyl group, Dophenyl group, tolyl group, (fluoromethyl) phenyl group, (difluoromethyl) phenyl group, (trifluoromethyl) phenyl group, (trichloromethyl) phenyl group, methoxyphenyl group, (fluoromethoxy) phenyl group, (difluoromethoxy) And a phenyl group, a (trifluoromethoxy) phenyl group or a (trichloromethoxy) phenyl group.
　「フェニル基（該フェニル基は、１個の任意の水素原子が、フッ素原子、塩素原子、メチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）若しくはメトキシ基（該メトキシ基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）」とは、フェニル基の１個の任意の水素原子が、フッ素原子、塩素原子、上記のメチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）又は上記のメトキシ基（該メトキシ基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）で置換されていてもよい基を意味し、例えば、フェニル基、フルオロフェニル基、クロロフェニル基、トリル基、（フルオロメチル）フェニル基、（ジフルオロメチル）フェニル基、（トリフルオロメチル）フェニル基、（トリクロロメチル）フェニル基、メトキシフェニル基、（フルオロメトキシ）フェニル基、（ジフルオロメトキシ）フェニル基、（トリフルオロメトキシ）フェニル基又は（トリクロロメトキシ）フェニル基が挙げられる。 “Phenyl group (in the phenyl group, one optional hydrogen atom is substituted with a fluorine atom, a chlorine atom, a methyl group (the methyl group is substituted with one to three optional hydrogen atoms by a fluorine atom or a chlorine atom And the methoxy group (in the methoxy group, one to three arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom) ”means one of the phenyl groups. Is a fluorine atom, a chlorine atom, the above methyl group (in the methyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom), or the above. The methoxy group (the methoxy group is a group optionally substituted by 1 to 3 arbitrary hydrogen atoms optionally substituted with a fluorine atom or a chlorine atom), for example, a phenyl group , Fluorophenyl group, Rolophenyl group, tolyl group, (fluoromethyl) phenyl group, (difluoromethyl) phenyl group, (trifluoromethyl) phenyl group, (trichloromethyl) phenyl group, methoxyphenyl group, (fluoromethoxy) phenyl group, (difluoromethoxy) And a phenyl group, a (trifluoromethoxy) phenyl group or a (trichloromethoxy) phenyl group.
　「フェニル基（該フェニル基は、１個の任意の水素原子が、フッ素原子、塩素原子、トリフルオロメチル基若しくはトリフルオロメトキシ基、で置換されていてもよい。）」は、フェニル基、フルオロフェニル基、クロロフェニル基、（トリフルオロメチル）フェニル基又は（トリフルオロメトキシ）フェニル基を意味する。上記フェニル基が置換基を有する場合、その置換位置としては、例えば、該フェニル基の３位又は４位が挙げられる。 “Phenyl group (the phenyl group may be optionally substituted with one hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group or a trifluoromethoxy group)” is a phenyl group, a fluoro group It means a phenyl group, a chlorophenyl group, a (trifluoromethyl) phenyl group or a (trifluoromethoxy) phenyl group. When the phenyl group has a substituent, examples of the substitution position include the 3rd or 4th position of the phenyl group.
　「エチニル基（該エチニル基は、水素原子が、メチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）で置換されていてもよい。）」とは、エチニル基の水素原子が、上記のメチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）で置換されていてもよい基を意味し、例えば、エチニル基、１－プロピニル基、３－フルオロプロピオニル基、３，３－ジフルオロプロピニル基、３，３，３－トリフルオロプロピニル基、３－クロロプロピオニル基、３，３－ジクロロプロピニル基又は３，３，３－トリクロロプロピニル基が挙げられる。 “Ethynyl group (the ethynyl group may be substituted with a hydrogen atom, a methyl group (the methyl group may be substituted with a halogen atom of 1 to 3 arbitrary hydrogen atoms)) The above “.)” Means that the hydrogen atom of the ethynyl group is substituted by the above-mentioned methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with halogen atoms). It also means a group which may be, for example, ethynyl group, 1-propynyl group, 3-fluoropropionyl group, 3,3-difluoropropynyl group, 3,3,3-trifluoropropynyl group, 3-chloropropionyl group, 3,3, A 3-dichloropropynyl group or a 3,3,3-trichloropropynyl group may be mentioned.
　「エチニル基（該エチニル基は、水素原子が、メチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）で置換されていてもよい。）」とは、エチニル基の水素原子が、上記のメチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）で置換されていてもよい基を意味し、例えば、エチニル基、１－プロピニル基、３－フルオロプロピオニル基、３，３－ジフルオロプロピニル基、３，３，３－トリフルオロプロピニル基、３－クロロプロピオニル基、３，３－ジクロロプロピニル基又は３，３，３－トリクロロプロピニル基が挙げられる。 “Ethynyl group (the ethynyl group is substituted with a hydrogen atom, a methyl group (the methyl group may be substituted with a hydrogen atom or a chlorine atom of 1 to 3 arbitrary hydrogen atoms)) And the above methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom). For example, ethynyl group, 1-propynyl group, 3-fluoropropionyl group, 3,3-difluoropropynyl group, 3,3,3-trifluoropropynyl group, 3- Examples include chloropropionyl group, 3,3-dichloropropynyl group or 3,3,3-trichloropropynyl group.
　「一般式（Ｉ）で示される環状アミン誘導体、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩」とは、一般式（Ｉ）で示される環状アミン誘導体、一般式（Ｉ）で示される環状アミン誘導体の立体異性体、一般式（Ｉ）で示される環状アミン誘導体の水和物、一般式（Ｉ）で示される環状アミン誘導体の立体異性体の水和物、一般式（Ｉ）で示される環状アミン誘導体の薬理学的に許容される塩、一般式（Ｉ）で示される環状アミン誘導体の立体異性体の薬理学的に許容される塩、一般式（Ｉ）で示される環状アミン誘導体の水和物の薬理学的に許容される塩又は一般式（Ｉ）で示される環状アミン誘導体の立体異性体の水和物の薬理学的に許容される塩を意味する。 The “cyclic amine derivative represented by the general formula (I), its stereoisomer or hydrate thereof, or the pharmacologically acceptable salt thereof” is a cyclic amine represented by the general formula (I) Derivative, stereoisomer of cyclic amine derivative represented by the general formula (I), hydrate of cyclic amine derivative represented by the general formula (I), stereoisomer of cyclic amine derivative represented by the general formula (I) Hydrate, pharmacologically acceptable salt of cyclic amine derivative represented by the general formula (I), pharmacologically acceptable salt of stereoisomer of cyclic amine derivative represented by the general formula (I), Pharmacologically acceptable salt of the hydrate of the cyclic amine derivative represented by the general formula (I) or pharmacologically acceptable of the hydrate of the stereoisomer of the cyclic amine derivative represented by the general formula (I) Mean salt.
　上記の環状アミン誘導体は、一般式（Ｉ）において、Ｒ１は、フッ素原子又は塩素原子であることが好ましく、塩素原子であることがより好ましい。 In the above-mentioned cyclic amine derivative, in the general formula (I), R 1 is preferably a fluorine atom or a chlorine atom, and more preferably a chlorine atom.
　Ｘは、－Ｃ（＝Ｏ）－（ＣＨ２）ｎ－Ｒ２であることが好ましい。 X is preferably -C (= O)-(CH 2 ) n -R 2 .
　ｎは、０～２の整数であることが好ましく、０又は１であることがより好ましく、１であることがさらに好ましい。 N is preferably an integer of 0 to 2, more preferably 0 or 1, and still more preferably 1.
　Ｒ２は、水素原子、炭素数１～３のアルキル基、炭素数３～６のシクロアルキル基、炭素数４～６のシクロアルキルアルキル基又は１個～４個の窒素原子を含む５員環ヘテロアリール基であることが好ましく、水素原子、メチル基、シクロプロピル基、イミダゾリル基、トリアゾリル基又はテトラゾリル基であることがより好ましく、水素原子、イミダゾリル基又はテトラゾリル基であることがさらに好ましい。 R 2 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or a 5-membered ring containing 1 to 4 nitrogen atoms It is preferably a heteroaryl group, more preferably a hydrogen atom, a methyl group, a cyclopropyl group, an imidazolyl group, a triazolyl group or a tetrazolyl group, and still more preferably a hydrogen atom, an imidazolyl group or a tetrazolyl group.
　Ｒ３は、メチル基であることが好ましい。 R 3 is preferably a methyl group.
　Ｒ４は、水素原子、フッ素原子、塩素原子又はメチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）であることが好ましく、塩素原子又はトリフルオロメチル基であることがより好ましく、トリフルオロメチル基であることがさらに好ましい。Ｒ４の置換位置としては、例えば、下記の一般式（ＩＩ－１）においてｐが１で、ｑが２であるテトラヒドロイソキノリン誘導体の場合、５位、６位、７位又は８位が挙げられ、下記の一般式（ＩＩ－１）においてｐが０で、ｑが２であるインドリン誘導体の場合、４位、５位、６位又は７位が挙げられ、下記の一般式（ＩＩ－１）においてｐが１で、ｑが１であるイソインドリン誘導体の場合、４位又は５位が挙げられる。 R 4 is a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group (in the methyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom) It is preferably a chlorine atom or a trifluoromethyl group, more preferably a trifluoromethyl group. As the substitution position of R 4 , for example, in the case of a tetrahydroisoquinoline derivative in which p is 1 and q is 2 in the following general formula (II-1), the 5 position, 6 position, 7 position or 8 position is mentioned In the case of an indoline derivative in which p is 0 and q is 2 in the following general formula (II-1), the 4-, 5-, 6- or 7-position is mentioned, and the following general formula (II-1) In the case of isoindoline derivatives in which p is 1 and q is 1, the 4- or 5-position is mentioned.
　ｐは、０又は１であることが好ましく、１であることがより好ましい。 P is preferably 0 or 1, and more preferably 1.
　ｑは、２であることが好ましい。 Q is preferably 2.
　Ｒ５は、炭素数１～４のアルキル基、炭素数４～６のシクロアルキルアルキル基又は－（ＣＨ２）ｒ－ＯＲ７であることが好ましく、プロピル基、ブチル基、イソブチル基又はシクロプロピルメチル基であることがより好ましく、プロピル基、ブチル基又はイソブチル基であることがさらに好ましい。 R 5 is preferably an alkyl group having 1 to 4 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or-(CH 2 ) r -OR 7 , and a propyl group, a butyl group, an isobutyl group or cyclopropyl The methyl group is more preferably a propyl group, a butyl group or an isobutyl group.
　Ｒ６は、フェニル基（該フェニル基は、１個の任意の水素原子が、フッ素原子、塩素原子、メチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）若しくはメトキシ基（該メトキシ基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）、で置換されていてもよい。）又はエチニル基（該エチニル基は、水素原子が、メチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）で置換されていてもよい。）であることが好ましく、フェニル基（該フェニル基は、１個の任意の水素原子が、フッ素原子、塩素原子、トリフルオロメチル基若しくはトリフルオロメトキシ基、で置換されていてもよい。）、１－プロピニル基又は３，３，３－トリフルオロプロピニル基であることがより好ましく、フェニル基（該フェニル基は、１個の任意の水素原子が、フッ素原子、塩素原子、トリフルオロメチル基又はトリフルオロメトキシ基、で置換されていてもよい。）であることがさらに好ましい。 R 6 is a phenyl group (wherein the optional one hydrogen atom is a fluorine atom, a chlorine atom, a methyl group (the methyl group is an optional hydrogen atom of 1 to 3 is a fluorine atom or chlorine Optionally substituted by an atom) or methoxy group (in the methoxy group, 1 to 3 arbitrary hydrogen atoms may be substituted by a fluorine atom or a chlorine atom), Or ethynyl group (the ethynyl group may be a hydrogen atom, a methyl group (the methyl group may be optionally substituted with 1 to 3 hydrogen atoms, a fluorine atom or a chlorine atom)). And the phenyl group (in the phenyl group, one arbitrary hydrogen atom is substituted with a fluorine atom, a chlorine atom, a trifluoromethyl group or a trifluoromethoxy group). Being done More preferably 1-propynyl group or 3,3,3-trifluoropropynyl group, and the phenyl group (in the phenyl group, one optional hydrogen atom is a fluorine atom or a chlorine atom Trifluoromethyl group or trifluoromethoxy group may be substituted.
　ｒは、２であることが好ましい。 R is preferably 2.
　Ｒ７は、水素原子又はメチル基であることが好ましい。 R 7 is preferably a hydrogen atom or a methyl group.
　上記の一般式（Ｉ）で表される環状アミン誘導体は、下記の一般式（Ｉ－ａ）で表される立体配置を有することが好ましい。すなわち、上記の一般式（Ｉ）で表される環状アミン誘導体は、上記の一般式（Ｉ）中、ピペリジニル基の２位の炭素原子の立体配置がＲ配置であることが好ましい。
Figure JPOXMLDOC01-appb-C000007
 The cyclic amine derivative represented by the above general formula (I) preferably has a configuration represented by the following general formula (Ia). That is, in the cyclic amine derivative represented by the above general formula (I), in the above general formula (I), the configuration of the carbon atom at the 2-position of the piperidinyl group is preferably R configuration.
Figure JPOXMLDOC01-appb-C000007
　上記の一般式（Ｉ）で示される環状アミン誘導体において、上記の好ましいＲ１、上記の好ましいＲ２、上記の好ましいＲ３、上記の好ましいＲ４、上記の好ましいＲ５、上記の好ましいＲ６、上記の好ましいＲ７、上記の好ましいＸ、上記の好ましいｎ、上記の好ましいｐ、上記の好ましいｑ、上記の好ましいｒ、上記の好ましい一般式（Ｉ）について任意の態様を選択し、それらを組み合わせることができる。例えば、以下の組み合わせが挙げられるが、これらに限定されるものではない。 In the cyclic amine derivative represented by the above general formula (I), the preferable R 1 , the preferable R 2 , the preferable R 3 , the preferable R 4 , the preferable R 5 , and the preferable R 6 as described above. , Any of the above preferred R 7 , preferred X, preferred X, preferred n, preferred p, preferred q, preferred r, preferred general formula (I), and any aspect selected. It can be combined. For example, the following combinations may be mentioned, but are not limited thereto.
　実施態様の一つとして、上記の一般式（Ｉ）で示される環状アミン誘導体において、Ｒ１は、ハロゲン原子であり、Ｘは、－Ｃ（＝Ｏ）－（ＣＨ２）ｎ－Ｒ２又は－Ｓ（＝Ｏ）２－Ｒ３であり、ｎは、０～３の整数であり、Ｒ２は、水素原子、炭素数１～３のアルキル基、炭素数３～６のシクロアルキル基、炭素数４～６のシクロアルキルアルキル基又はヘテロアリール基であり、Ｒ３は、炭素数１～３のアルキル基であり、ｍは、０又は１であり、Ａは、下記の一般式（ＩＩ－１）又は（ＩＩ－２）で示される基であり、Ｒ４は、水素原子、ハロゲン原子又はメチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）であり、ｐは、０～２の整数であり、ｑは、１又は２であり、Ｒ５は、炭素数１～６のアルキル基、炭素数４～６のシクロアルキルアルキル基又は－（ＣＨ２）ｒ－ＯＲ７であり、Ｒ６は、フェニル基（該フェニル基は、１個の任意の水素原子が、ハロゲン原子、メチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）若しくはメトキシ基（該メトキシ基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）、で置換されていてもよい。）又はエチニル基（該エチニル基は、水素原子が、メチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）で置換されていてもよい。）であり、ｒは、２～４の整数であり、Ｒ７は、水素原子又は炭素数１～３のアルキル基であり、一般式（Ｉ）は、下記の一般式（Ｉ－ａ）であることが好ましい。
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000009
 As one of the embodiments, in the cyclic amine derivative represented by the above general formula (I), R 1 is a halogen atom, and X is —C (= O) — (CH 2 ) n —R 2 or -S (= O) 2 -R 3 , n is an integer of 0 to 3, R 2 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, R 4 is a cycloalkyl alkyl group or heteroaryl group having 4 to 6 carbon atoms, R 3 is an alkyl group having 1 to 3 carbon atoms, m is 0 or 1, and A is a group represented by the following general formula (II R 4 is a hydrogen atom, a halogen atom or a methyl group (in the methyl group, one to three arbitrary hydrogen atoms are substituted with a halogen atom) And p is an integer of 0 to 2; q is 1 or 2; and R 5 is An alkyl group having 1 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or-(CH 2 ) r -OR 7 , and R 6 is a phenyl group (wherein the phenyl group is any one hydrogen atom The atom is a halogen atom, a methyl group (in the methyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a halogen atom), or a methoxy group (the methoxy group is 1 to 3) (Optionally substituted hydrogen atom may be substituted with a halogen atom)), or ethynyl group (in the ethynyl group, the hydrogen atom is a methyl group (the methyl group is one) To 3 optional hydrogen atoms may be substituted with halogen atoms)), r is an integer of 2 to 4 and R 7 is a hydrogen atom or It is an alkyl group having 1 to 3 carbon atoms, and formula (I) is It is preferable that it is a general formula (Ia).
Figure JPOXMLDOC01-appb-C000008
Figure JPOXMLDOC01-appb-C000009
　別の実施態様としては、上記の一般式（Ｉ）で示される環状アミン誘導体において、Ｒ１は、塩素原子であり、Ｘは、－Ｃ（＝Ｏ）－（ＣＨ２）ｎ－Ｒ２であり、ｎは、１であり、Ｒ２は、水素原子、イミダゾリル基又はテトラゾリル基であり、Ｒ４は、トリフルオロメチル基であり、ｐは、１であり、ｑは、２であり、Ｒ５は、プロピル基、ブチル基又はイソブチル基であり、Ｒ６は、フェニル基（該フェニル基は、１個の任意の水素原子が、フッ素原子、塩素原子、トリフルオロメチル基又はトリフルオロメトキシ基、で置換されていてもよい。）であり、一般式（Ｉ）は、上記の一般式（Ｉ－ａ）であることがより好ましい。 As another embodiment, in the cyclic amine derivative represented by the above general formula (I), R 1 is a chlorine atom, and X is —C (= O) — (CH 2 ) n —R 2 And n is 1; R 2 is a hydrogen atom, an imidazolyl group or a tetrazolyl group; R 4 is a trifluoromethyl group; p is 1; q is 2; 5 is a propyl group, a butyl group or an isobutyl group; R 6 is a phenyl group (in the phenyl group, one optional hydrogen atom is a fluorine atom, a chlorine atom, a trifluoromethyl group or a trifluoromethoxy group) And the general formula (I) is more preferably the general formula (Ia) described above.
　上記の一般式（ＩＩ－１）で示される基の具体例としては、例えば、インドリニル基、４－フルオロインドリニル基、５－フルオロインドリニル基、６－フルオロインドリニル基、７－フルオロインドリニル基、４－クロロインドリニル基、５－クロロインドリニル基、６－クロロインドリニル基、７－クロロインドリニル基、４－メチルインドリニル基、５－メチルインドリニル基、６－メチルインドリニル基、７－メチルインドリニル基、４－（トリフルオロメチル）インドリニル基、５－（トリフルオロメチル）インドリニル基、６－（トリフルオロメチル）インドリニル基、７－（トリフルオロメチル）インドリニル基、イソインドリニル基、４－フルオロイソインドリニル基、５－フルオロイソインドリニル基、４－クロロイソインドリニル基、５－クロロイソインドリニル基、４－メチルイソインドリニル基、５－メチルイソインドリニル基、４－（トリフルオロメチル）イソインドリニル基、５－（トリフルオロメチル）イソインドリニル基、１，２，３，４－テトラヒドロイソキノリル基、５－フルオロ－１，２，３，４－テトラヒドロイソキノリル基、６－フルオロ－１，２，３，４－テトラヒドロイソキノリル基、７－フルオロ－１，２，３，４－テトラヒドロイソキノリル基、８－フルオロ－１，２，３，４－テトラヒドロイソキノリル基、５－クロロ－１，２，３，４－テトラヒドロイソキノリル基、６－クロロ－１，２，３，４－テトラヒドロイソキノリル基、７－クロロ－１，２，３，４－テトラヒドロイソキノリル基、８－クロロ－１，２，３，４－テトラヒドロイソキノリル基、５－メチル－１，２，３，４－テトラヒドロイソキノリル基、６－メチル－１，２，３，４－テトラヒドロイソキノリル基、７－メチル－１，２，３，４－テトラヒドロイソキノリル基、８－メチル－１，２，３，４－テトラヒドロイソキノリル基、５－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリル基、６－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリル基、７－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリル基、８－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリル基、２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｄ］アゼピル基、６－フルオロ－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｄ］アゼピル基、７－フルオロ－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｄ］アゼピル基、６－クロロ－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｄ］アゼピル基、７－クロロ－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｄ］アゼピル基、６－メチル－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｄ］アゼピル基、７－メチル－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｄ］アゼピル基、６－（トリフルオロメチル）－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｄ］アゼピル基、７－（トリフルオロメチル）－２，３，４，５－テトラヒドロ－１Ｈ－ベンゾ［ｄ］アゼピル基が挙げられる。 Specific examples of the group represented by the above general formula (II-1) include, for example, indolinyl group, 4-fluoroindolinyl group, 5-fluoroindolinyl group, 6-fluoroindolinyl group, 7-fluoroindolinyl group Group, 4-chloroindolinyl group, 5-chloroindolinyl group, 6-chloroindolinyl group, 7-chloroindolinyl group, 4-methylindolinyl group, 5-methylindolinyl group, 6-methylindolinyl group , 7-methylindolinyl group, 4- (trifluoromethyl) indolinyl group, 5- (trifluoromethyl) indolinyl group, 6- (trifluoromethyl) indolinyl group, 7- (trifluoromethyl) indolinyl group, isoindolinyl group , 4-fluoroisoindolinyl group, 5-fluoroisoindolinyl group, 4-chloroiso Anddolinyl group, 5-chloroisoindolinyl group, 4-methylisoindolinyl group, 5-methylisoindolinyl group, 4- (trifluoromethyl) isoindolinyl group, 5- (trifluoromethyl) isoindolinyl group, 1,2 , 3,4-tetrahydroisoquinolyl group, 5-fluoro-1,2,3,4-tetrahydroisoquinolyl group, 6-fluoro-1,2,3,4-tetrahydroisoquinolyl group, 7-fluoro -1,2,3,4-tetrahydroisoquinolyl group, 8-fluoro-1,2,3,4-tetrahydroisoquinolyl group, 5-chloro-1,2,3,4-tetrahydroisoquinolyl group 6-chloro-1,2,3,4-tetrahydroisoquinolyl, 7-chloro-1,2,3,4-tetrahydroisoquinolyl, 8-chloro-1,2,3, -Tetrahydroisoquinolyl group, 5-methyl-1,2,3,4-tetrahydroisoquinolyl group, 6-methyl-1,2,3,4-tetrahydroisoquinolyl group, 7-methyl-1,2 , 3,4-tetrahydroisoquinolyl group, 8-methyl-1,2,3,4-tetrahydroisoquinolyl group, 5- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinolyl group , 6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinolyl group, 7- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinolyl group, 8- (trifluoro) Methyl) -1,2,3,4-tetrahydroisoquinolyl group, 2,3,4,5-tetrahydro-1H-benzo [d] azepyr group, 6-fluoro-2,3,4,5-tetrahydro- 1H-benzo [d] Zepyr group, 7-fluoro-2,3,4,5-tetrahydro-1H-benzo [d] azepyr group, 6-chloro-2,3,4,5-tetrahydro-1H-benzo [d] azepyr group, 7 -Chloro-2,3,4,5-tetrahydro-1H-benzo [d] azepyr group, 6-methyl-2,3,4,5-tetrahydro-1H-benzo [d] azepyr group, 7-methyl-2 , 3,4,5-Tetrahydro-1H-benzo [d] azepyr group, 6- (trifluoromethyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepyr group, 7- (trifluoro) And methyl) -2,3,4,5-tetrahydro-1H-benzo [d] azepyr group.
　上記の一般式（Ｉ）で示される環状アミン誘導体の好ましい化合物の具体例を表１－１～表１－３に示すが、本発明はこれらに限定されるものではない。 Specific examples of preferable compounds of the cyclic amine derivative represented by the above general formula (I) are shown in Tables 1-1 to 1-3, but the present invention is not limited thereto.
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
　表１－１～表１－３に記載される化合物は、その立体異性体及びこれらの水和物、及び、それらの薬理学的に許容される塩並びにそれらの混合物も包含する。 The compounds described in Tables 1-1 to 1-3 also include their stereoisomers and their hydrates, and their pharmacologically acceptable salts and their mixtures.
　上記の一般式（Ｉ）で示される環状アミン誘導体は、立体異性体が存在する場合があるが、単一異性体のみならず、ラセミ体及びジアステレオマー混合物等の混合物も包含する。 The cyclic amine derivatives represented by the above general formula (I) may exist as stereoisomers, but include not only single isomers but also mixtures such as racemates and mixtures of diastereomers.
　「立体異性体」とは、同じ化学構造を有するが、３次元空間での配置が異なる化合物をいい、例えば、配座異性体、回転異性体、互変異性体、光学異性体、ジアステレオマー等が挙げられる。 "Stereoisomer" refers to a compound having the same chemical structure but different arrangement in three-dimensional space, such as, for example, conformer, rotamer, tautomer, optical isomer, diastereomer Etc.
　上記の一般式（Ｉ）で示される環状アミン誘導体は、一つ以上の同位元素で標識されていてもよく、標識される同位元素としては、例えば、２Ｈ、３Ｈ、１３Ｃ、１４Ｃ、１５Ｎ、１５Ｏ、１８Ｏ及び／又は１２５Ｉが挙げられる。 The cyclic amine derivative represented by the above general formula (I) may be labeled with one or more isotopes, and the isotopes to be labeled include, for example, 2 H, 3 H, 13 C, 14 C , 15 N, 15 O, 18 O and / or 125 I.
　上記の一般式（Ｉ）で示される環状アミン誘導体の「薬理学的に許容される塩」としては、例えば、無機酸との塩又は有機酸との塩が挙げられる。無機酸との塩としては、例えば、塩酸塩、硫酸塩、硝酸塩、臭化水素酸塩、ヨウ化水素酸塩又はリン酸塩等が挙げられ、有機酸との塩としては、例えば、シュウ酸塩、マロン酸塩、クエン酸塩、フマル酸塩、乳酸塩、リンゴ酸塩、コハク酸塩、酒石酸塩、酢酸塩、トリフルオロ酢酸塩、マレイン酸塩、グルコン酸塩、安息香酸塩、アスコルビン酸塩、グルタル酸塩、マンデル酸塩、フタル酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、カンファースルホン酸塩、アスパラギン酸塩、グルタミン酸塩又はケイ皮酸塩等が挙げられる。また、上記の一般式（Ｉ）で示される環状アミン誘導体の立体異性体の「薬理学的に許容される塩」、上記の一般式（Ｉ）で示される環状アミン誘導体の水和物の「薬理学的に許容される塩」、上記の一般式（Ｉ）で示される環状アミン誘導体の立体異性体の水和物の「薬理学的に許容される塩」についても同様である。 Examples of the "pharmaceutically acceptable salt" of the cyclic amine derivative represented by the above general formula (I) include a salt with an inorganic acid or a salt with an organic acid. Examples of salts with inorganic acids include hydrochlorides, sulfates, nitrates, hydrobromides, hydroiodides or phosphates, and salts with organic acids include, for example, oxalic acid. Salt, malonate, citrate, fumarate, lactate, malate, succinate, tartrate, acetate, trifluoroacetate, maleate, gluconate, benzoate, ascorbic acid Salt, glutarate, mandelate, phthalate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, aspartate, glutamate or cinnamate An acid salt etc. are mentioned. In addition, “pharmaceutically acceptable salts” of stereoisomers of cyclic amine derivatives represented by the above general formula (I), “hydrates of hydrates of cyclic amine derivatives represented by the above general formula (I) The same applies to "pharmacologically acceptable salts" and "pharmaceutically acceptable salts" of hydrates of stereoisomers of cyclic amine derivatives represented by the above general formula (I).
　上記の一般式（Ｉ）で示される環状アミン誘導体若しくはその立体異性体、又は、それらの薬理学的に許容される塩は、無水物であってもよいし、水和物等の溶媒和物を形成していても構わない。ここで溶媒和物としては、薬理学的に許容される溶媒和物が好ましい。薬理学的に許容される溶媒和物は、水和物又は非水和物のいずれであっても構わないが、水和物が好ましい。溶媒和物を構成する溶媒としては、例えば、メタノール、エタノール若しくはｎ－プロパノール等のアルコール系溶媒、Ｎ，Ｎ－ジメチルホルムアミド（以下、ＤＭＦ）、ジメチルスルホキシド（以下、ＤＭＳＯ）又は水が挙げられる。 The cyclic amine derivative represented by the above general formula (I) or a stereoisomer thereof, or a pharmacologically acceptable salt thereof may be an anhydride or a solvate such as a hydrate May be formed. Here, as a solvate, a pharmacologically acceptable solvate is preferable. The pharmacologically acceptable solvate may be either hydrate or non-hydrate, but hydrate is preferred. Examples of the solvent constituting the solvate include alcohol solvents such as methanol, ethanol or n-propanol, N, N-dimethylformamide (hereinafter, DMF), dimethyl sulfoxide (hereinafter, DMSO) or water.
　上記の一般式（Ｉ）で示される環状アミン誘導体（以下、環状アミン誘導体（Ｉ））は、その基本骨格や置換基の種類に由来する特徴に基づいた適切な方法で製造することができる。なお、これらの化合物の製造に使用する出発物質と試薬は、一般に購入することができるか又は公知の方法で製造できる。 The cyclic amine derivative represented by the above general formula (I) (hereinafter, cyclic amine derivative (I)) can be produced by an appropriate method based on the characteristics derived from the basic skeleton and the type of substituent. Starting materials and reagents used for producing these compounds can be generally purchased or can be produced by known methods.
　環状アミン誘導体（Ｉ）並びにその製造に使用する中間体及び出発物質は、公知の手段によって単離精製することができる。単離精製のための公知の手段としては、例えば、溶媒抽出、再結晶又はクロマトグラフィーが挙げられる。 The cyclic amine derivative (I) and the intermediates and starting materials used for its preparation can be isolated and purified by known means. Known means for isolation and purification include, for example, solvent extraction, recrystallization or chromatography.
　環状アミン誘導体（Ｉ）が、立体異性体を含有する場合には、公知の方法により、それぞれの光学異性体やジアステレオマーを単一の光学活性体として得ることができる。公知の方法としては、例えば、結晶化、酵素分割又はキラルクロマトグラフィーが挙げられる。 When the cyclic amine derivative (I) contains a stereoisomer, each optical isomer or diastereomer can be obtained as a single optically active substance by a known method. Known methods include, for example, crystallization, enzymatic resolution or chiral chromatography.
　以下に記載する製造方法の各反応において、原料化合物がアミノ基又はカルボキシル基を有する場合、これらの基に保護基が導入されていてもよく、反応後に必要に応じて保護基を脱保護することにより目的化合物を得ることができる。 In each reaction of the production method described below, when the raw material compound has an amino group or a carboxyl group, a protective group may be introduced to these groups, and after the reaction, the protective group is optionally deprotected. Thus, the target compound can be obtained.
　アミノ基の保護基としては、例えば、炭素数２～６のアルキルカルボニル基（例えば、アセチル基）、ベンゾイル基、炭素数２～８のアルキルオキシカルボニル基（例えば、ｔｅｒｔ－ブトキシカルボニル基又はベンジルオキシカルボニル基）、炭素数７～１０のアラルキル基（例えば、ベンジル基）又はフタロイル基が挙げられる。 As a protecting group of an amino group, for example, an alkylcarbonyl group having 2 to 6 carbon atoms (eg, acetyl group), benzoyl group, an alkyloxycarbonyl group having 2 to 8 carbon atoms (eg, tert-butoxycarbonyl group or benzyloxy) And a carbonyl group), an aralkyl group having 7 to 10 carbon atoms (eg, benzyl group) or a phthaloyl group.
　カルボキシル基の保護基としては、例えば、炭素数１～６のアルキル基（例えば、メチル基、エチル基又はｔｅｒｔ－ブチル基）又は炭素数７～１０アラルキル基（例えば、ベンジル基）が挙げられる。 Examples of the protecting group for the carboxyl group include, for example, an alkyl group having 1 to 6 carbon atoms (eg, methyl group, ethyl group or tert-butyl group) or an aralkyl group having 7 to 10 carbon atoms (eg, benzyl group).
　保護基の脱保護は、保護基の種類によって異なるが、公知の方法（例えば、Ｇｒｅｅｎｅ，　Ｔ．Ｗ．、「Ｇｒｅｅｎｅ’ｓ　Ｐｒｏｔｅｃｔｉｖｅ　Ｇｒｏｕｐｓ　ｉｎ　Ｏｒｇａｎｉｃ　Ｓｙｎｔｈｅｓｉｓ」、Ｗｉｌｅｙ－Ｉｎｔｅｒｓｃｉｅｎｃｅ社）又はそれに準ずる方法に従って行うことができる。 The deprotection of the protective group varies depending on the type of protective group, but is carried out according to known methods (for example, Greene, TW, "Greene's Protective Groups in Organic Synthesis", Wiley-Interscience) or a method according thereto. be able to.
　環状アミン誘導体（Ｉ）は、例えば、スキーム１に示すように、縮合剤及び塩基存在下、アニリン誘導体（ＩＩＩ）とピペコリン酸誘導体（ＩＶ）との縮合反応（第１工程）、続いて、酸存在下、第１工程で得られたＮ－ｔｅｒｔ－ブトキシカルボニルピペコリン酸アミド誘導体（Ｖ）のｔｅｒｔ－ブトキシカルボニル基の脱保護反応（第２工程）、続いて、塩基存在下、第２工程で得られたピペコリン酸アミド誘導体（ＶＩ）と有機酸クロリド誘導体（ＶＩＩ）との縮合反応、により得ることができる（第３工程）。また、ピペコリン酸アミド誘導体（ＶＩ）と有機酸無水物誘導体（ＶＩＩＩ）との縮合反応により、環状アミン誘導体（Ｉ）を得ることもできる。また、縮合剤及び塩基存在下、ピペコリン酸アミド誘導体（ＶＩ）と有機酸誘導体（ＩＸ）との縮合反応により、環状アミン誘導体（Ｉ）を得ることもできる。なお、環状アミン誘導体（Ｉ）の光学活性体については、例えば、ピペコリン酸誘導体（ＩＶ）の光学活性体を用いることで得ることができる。
Figure JPOXMLDOC01-appb-C000013
 ［式中、Ｒ１、ｍ、Ａ及びＸは、上記定義に同じである。］ The cyclic amine derivative (I) is, for example, as shown in Scheme 1, a condensation reaction (step 1) of an aniline derivative (III) with a pipecolic acid derivative (IV) in the presence of a condensing agent and a base (step 1), followed by an acid Deprotection reaction of tert-butoxycarbonyl group of N-tert-butoxycarbonylpipecolic acid amide derivative (V) obtained in the first step in the presence (step 2), subsequently, second step in the presence of a base And the condensation reaction of the pipecolic acid amide derivative (VI) obtained in 1. and the organic acid chloride derivative (VII) (step 3). In addition, cyclic amine derivative (I) can also be obtained by condensation reaction of pipecolic acid amide derivative (VI) with organic acid anhydride derivative (VIII). The cyclic amine derivative (I) can also be obtained by the condensation reaction of the pipecolic acid amide derivative (VI) and the organic acid derivative (IX) in the presence of a condensing agent and a base. The optically active form of cyclic amine derivative (I) can be obtained, for example, by using the optically active form of pipecolic acid derivative (IV).
Figure JPOXMLDOC01-appb-C000013
 [Wherein, R 1 , m, A and X are as defined above. ]
（第１工程）
　縮合反応に用いるピペコリン酸誘導体（ＩＶ）の量は、アニリン誘導体（ＩＩＩ）に対して０．１～１０当量が好ましく、０．５～３当量がより好ましい。 (Step 1)
The amount of pipecolic acid derivative (IV) used for the condensation reaction is preferably 0.1 to 10 equivalents, and more preferably 0.5 to 3 equivalents with respect to aniline derivative (III).
　縮合反応に用いる縮合剤としては、例えば、Ｎ，Ｎ’－ジシクロヘキシルカルボジイミド、Ｎ－エチル－Ｎ’－３－ジメチルアミノプロピルカルボジイミド塩酸塩（以下、ＥＤＣ・ＨＣｌ）、Ｎ，Ｎ’－カルボジイミダゾール、｛｛[（１－シアノ－２－エトキシ－２－オキソエチリデン）アミノ]オキシ｝－４－モルホリノメチレン｝ジメチルアンモニウムヘキサフルオロリン酸塩（以下、ＣＯＭＵ）、Ｏ－（７－アザベンゾトリアゾール－１－イル）－１，１，３，３－テトラメチルウロニウムヘキサフルオロホスファート（以下、ＨＡＴＵ）又はＯ－（ベンゾトリアゾール－１－イル）－Ｎ，Ｎ，Ｎ’，Ｎ’－テトラメチルウロニウムヘキサフルオロホスファート（以下、ＨＢＴＵ）が挙げられるが、ＨＡＴＵ又はＨＢＴＵが好ましい。 Examples of the condensing agent used for the condensation reaction include N, N'-dicyclohexylcarbodiimide, N-ethyl-N'-3-dimethylaminopropylcarbodiimide hydrochloride (hereinafter referred to as EDC.HCl), N, N'-carbodiimidazole {{[(1-cyano-2-ethoxy-2-oxoethylidene) amino] oxy} -4-morpholinomethylene} dimethyl ammonium hexafluorophosphate (hereinafter COMU), O- (7-azabenzotriazole- 1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate (hereinafter HATU) or O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyl Although uronium hexafluorophosphate (following, HBTU) is mentioned, HATU or HBTU is preferred
　縮合反応に用いる縮合剤の量は、アニリン誘導体（ＩＩＩ）に対して０．５～１０当量が好ましく、１～３当量がより好ましい。 The amount of the condensing agent used for the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents with respect to the aniline derivative (III).
　縮合反応に用いる塩基としては、例えば、トリエチルアミン若しくはジイソプロピルエチルアミン等の有機塩基、炭酸水素ナトリウム若しくは炭酸カリウム等の無機塩基、水素化ナトリウム、水素化カリウム若しくは水素化カルシウム等の水素化金属化合物、メチルリチウム若しくはブチルリチウム等のアルキルリチウム、リチウムヘキサメチルジシラジド若しくはリチウムジイソプロピルアミド等のリチウムアミド又はそれらの混合物が挙げられるが、トリエチルアミン又はジイソプロピルエチルアミン等の有機塩基が好ましい。 Examples of the base used for the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogencarbonate or potassium carbonate, sodium hydride, hydrogenated metal compounds such as potassium hydride or calcium hydride, methyl lithium Or an alkyllithium such as butyllithium, a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof, but an organic base such as triethylamine or diisopropylethylamine is preferred.
　縮合反応に用いる塩基の量は、アニリン誘導体（ＩＩＩ）に対して０．５～１０当量が好ましく、１～５当量がより好ましい。 The amount of the base used for the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents based on the aniline derivative (III).
　縮合反応に用いるアニリン誘導体（ＩＩＩ）は、フリー体であってもよいし、塩酸塩等の塩であっても構わない。 The aniline derivative (III) used for the condensation reaction may be a free form or a salt such as hydrochloride.
　縮合反応に用いる反応溶媒は、用いる試薬の種類等に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、テトラヒドロフラン（以下、ＴＨＦ）、１，４－ジオキサン、エチレングリコールジメチルエーテル若しくはジメトキシエタン等のエーテル系溶媒、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等のハロゲン系溶媒、ＤＭＦ若しくはＤＭＳＯ等の非プロトン性極性溶媒又はアセトニトリル若しくはプロピオニトリル等のニトリル系溶媒が挙げられるが、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等のハロゲン系溶媒又はＤＭＦ若しくはＤＭＳＯ等の非プロトン性極性溶媒が好ましい。 The reaction solvent used for the condensation reaction is appropriately selected according to the type of reagent used, etc., and is not particularly limited as long as it does not inhibit the reaction, and examples thereof include tetrahydrofuran (hereinafter, THF), 1,4-dioxane, Ether solvents such as ethylene glycol dimethyl ether or dimethoxyethane, halogen solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, or nitrile solvents such as acetonitrile or propionitrile However, preferred are halogen-based solvents such as dichloromethane, chloroform or 1,2-dichloroethane or aprotic polar solvents such as DMF or DMSO.
　縮合反応の反応温度は、０～２００℃が好ましく、２０～１００℃がより好ましい。 The reaction temperature of the condensation reaction is preferably 0 to 200 ° C., and more preferably 20 to 100 ° C.
　縮合反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、１～３０時間が好ましい。 The reaction time of the condensation reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
　縮合反応に用いるアニリン誘導体（ＩＩＩ）の反応開始時の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration at the start of the reaction of the aniline derivative (III) used for the condensation reaction is preferably 1 mmol / L to 1 mol / L.
　縮合反応に用いるアニリン誘導体（ＩＩＩ）及びピペコリン酸誘導体（ＩＶ）は、購入することができるか又は公知の方法若しくはそれに準じた方法で製造できる。 The aniline derivative (III) and the pipecolic acid derivative (IV) used for the condensation reaction can be purchased or can be produced by a known method or a method analogous thereto.
（第２工程）
　脱保護反応に用いる酸としては、例えば、塩酸、トリフルオロ酢酸又はフッ化水素酸等の酸が挙げられるが、塩酸又はトリフルオロ酢酸が好ましい。 (Step 2)
Examples of the acid used for the deprotection reaction include acids such as hydrochloric acid, trifluoroacetic acid or hydrofluoric acid, with hydrochloric acid or trifluoroacetic acid being preferred.
　脱保護反応に用いる酸の量は、Ｎ－ｔｅｒｔ－ブトキシカルボニルピペコリン酸アミド誘導体（Ｖ）に対して０．５～１００当量が好ましく、１～３０当量がより好ましい。 The amount of the acid used for the deprotection reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 30 equivalents with respect to the N-tert-butoxycarbonylpipecolic acid amide derivative (V).
　脱保護反応の反応溶媒は、用いる試薬の種類等に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、ジエチルエーテル、ＴＨＦ、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、酢酸エチル若しくは酢酸プロピル等のエステル系溶媒、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒、メタノール若しくはエタノール等のアルコール系溶媒又はそれらの混合溶媒が挙げられるが、酢酸エチル若しくは酢酸プロピル等のエステル系溶媒又はジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒が好ましい。 The reaction solvent for the deprotection reaction is appropriately selected depending on the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include diethyl ether, THF, dimethoxyethane or 1,4-dioxane Etc., ester solvents such as ethyl acetate or propyl acetate, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, alcohol solvents such as methanol or ethanol, or mixed solvents thereof. Ester solvents such as ethyl acetate or propyl acetate or chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane are preferred.
　脱保護反応の反応温度は、－７８℃～２００℃が好ましく、－２０℃～１００℃がより好ましい。 The reaction temperature of the deprotection reaction is preferably −78 ° C. to 200 ° C., and more preferably −20 ° C. to 100 ° C.
　脱保護反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、１～５０時間が好ましい。 The reaction time of the deprotection reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 50 hours.
　脱保護反応に用いるＮ－ｔｅｒｔ－ブトキシカルボニルピペコリン酸アミド誘導体（Ｖ）の反応開始時の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration of the N-tert-butoxycarbonylpipecolic acid amide derivative (V) used for the deprotection reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
（第３工程）
　縮合反応に用いる有機酸クロリド誘導体（ＶＩＩ）、有機酸無水物誘導体（ＶＩＩＩ）又は有機酸誘導体（ＩＸ）の量は、ピペコリン酸アミド誘導体（ＶＩ）に対して０．５～１０当量が好ましく、１～３当量がより好ましい。 (Third step)
The amount of the organic acid chloride derivative (VII), the organic acid anhydride derivative (VIII) or the organic acid derivative (IX) used for the condensation reaction is preferably 0.5 to 10 equivalents relative to the pipecolic acid amide derivative (VI), 1 to 3 equivalents are more preferred.
　縮合反応に用いる縮合剤としては、例えば、ＥＤＣ・ＨＣｌ、ＣＯＭＵ、ＨＡＴＵ又はＨＢＴＵが挙げられるが、ＨＡＴＵ又はＨＢＴＵが好ましい。 As a condensing agent used for a condensation reaction, although EDC * HCl, COMU, HATU or HBTU is mentioned, for example, HATU or HBTU is preferable.
　縮合反応に用いる塩基としては、例えば、トリエチルアミン若しくはジイソプロピルエチルアミン等の有機塩基、炭酸水素ナトリウム若しくは炭酸カリウム等の無機塩基、水素化ナトリウム、水素化カリウム若しくは水素化カルシウム等の水素化金属化合物、メチルリチウム若しくはブチルリチウム等のアルキルリチウム、リチウムヘキサメチルジシラジド若しくはリチウムジイソプロピルアミド等のリチウムアミド又はそれらの混合物が挙げられるが、トリエチルアミン又はジイソプロピルエチルアミン等の有機塩基が好ましい。 Examples of the base used for the condensation reaction include organic bases such as triethylamine or diisopropylethylamine, inorganic bases such as sodium hydrogencarbonate or potassium carbonate, sodium hydride, hydrogenated metal compounds such as potassium hydride or calcium hydride, methyl lithium Or an alkyllithium such as butyllithium, a lithium amide such as lithium hexamethyldisilazide or lithium diisopropylamide, or a mixture thereof, but an organic base such as triethylamine or diisopropylethylamine is preferred.
　縮合反応に用いる塩基の量は、ピペコリン酸アミド誘導体（ＶＩ）に対して０．５～１０当量が好ましく、１～５当量がより好ましい。 The amount of the base used for the condensation reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 5 equivalents based on the pipecolic acid amide derivative (VI).
　縮合反応に用いるピペコリン酸アミド誘導体（ＶＩ）は、フリー体であってもよいし、塩酸塩等の塩であっても構わない。 The pipecolic acid amide derivative (VI) used for the condensation reaction may be a free form or a salt such as hydrochloride.
　縮合反応に用いる反応溶媒は、用いる試薬の種類等に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、ＴＨＦ、１，４－ジオキサン、エチレングリコールジメチルエーテル若しくはジメトキシエタン等のエーテル系溶媒、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒、ＤＭＦ若しくはＤＭＳＯ等の非プロトン性極性溶媒又はアセトニトリル若しくはプロピオニトリル等のニトリル系溶媒が挙げられるが、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等のハロゲン系溶媒又はＤＭＦ若しくはＤＭＳＯ等の非プロトン性極性溶媒が好ましい。 The reaction solvent used for the condensation reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxymethane Ether solvents such as ethane, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, aprotic polar solvents such as DMF or DMSO, or nitrile solvents such as acetonitrile or propionitrile Halogenated solvents such as chloroform or 1,2-dichloroethane or aprotic polar solvents such as DMF or DMSO are preferred.
　縮合反応の反応温度は、－７８℃～２００℃が好ましく、－２０℃～１００℃がより好ましい。 The reaction temperature of the condensation reaction is preferably -78 ° C to 200 ° C, and more preferably -20 ° C to 100 ° C.
　縮合反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、０．５～３０時間が好ましい。 The reaction time of the condensation reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 0.5 to 30 hours.
　縮合反応に用いるピペコリン酸アミド誘導体（ＶＩ）の反応開始時の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration of the pipecolic acid amide derivative (VI) used for the condensation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
　縮合反応に用いる有機酸クロリド誘導体（ＶＩＩ）、有機酸無水物誘導体（ＶＩＩＩ）及び有機酸誘導体（ＩＸ）は、購入することができるか又は公知の方法若しくはそれに準じた方法で製造できる。 The organic acid chloride derivative (VII), the organic acid anhydride derivative (VIII) and the organic acid derivative (IX) used for the condensation reaction can be purchased or can be produced by a known method or a method analogous thereto.
　スキーム１に示したアニリン誘導体（ＩＩＩ）のうち、ｍが１であるアニリン誘導体（ＩＩＩ－ａ）は、例えば、スキーム２に示すように、安息香酸誘導体（Ｘ）の還元反応（第１工程）、続いて、第１工程で得られたベンジルアルコール誘導体（ＸＩ）の酸化反応（第２工程）、続いて、第２工程で得られたベンズアルデヒド誘導体（ＸＩＩ）と、アミン誘導体（ＸＩＩＩ）又はアミン誘導体（ＸＩＶ）との還元的アミノ化反応（第３工程）、続いて、金属及び酸存在下、第３工程で得られたニトロフェニル誘導体（ＸＶ）の還元反応（第４工程）により得ることができる。
Figure JPOXMLDOC01-appb-C000014
 ［式中、Ｒ１、Ｒ４、ｐ、ｑ、Ｒ５、Ｒ６及びＡは、上記定義に同じである。］ Among the aniline derivatives (III) shown in Scheme 1, an aniline derivative (III-a) in which m is 1 is, for example, a reduction reaction of benzoic acid derivative (X) as shown in Scheme 2 (Step 1) Then, the oxidation reaction (the second step) of the benzyl alcohol derivative (XI) obtained in the first step, and subsequently, the benzaldehyde derivative (XII) obtained in the second step, and the amine derivative (XIII) or the amine Reductive amination reaction with derivative (XIV) (step 3), followed by reduction reaction (step 4) of nitrophenyl derivative (XV) obtained in step 3 in the presence of metal and acid Can.
Figure JPOXMLDOC01-appb-C000014
 [Wherein, R 1 , R 4 , p, q, R 5 , R 6 and A are as defined above. ]
（第１工程）
　還元反応に用いる還元剤としては、例えば、水素化アルミニウムリチウム、水素化ジイソブチルアルミニウム、水素化ホウ素ナトリウム、水素化ホウ素リチウム、水素化トリエチルホウ素リチウム又はボランＴＨＦ錯体が挙げられるが、ボランＴＨＦ錯体が好ましい。 (Step 1)
Examples of the reducing agent used for the reduction reaction include lithium aluminum hydride, diisobutylaluminum hydride, sodium borohydride, lithium borohydride, lithium triethylborohydride or borane THF complex, but a borane THF complex is preferable .
　還元反応に用いる還元剤の量は、安息香酸誘導体（Ｘ）に対して０．２５～１００当量が好ましく、０．５～１０当量がより好ましい。 The amount of reducing agent used for the reduction reaction is preferably 0.25 to 100 equivalents, and more preferably 0.5 to 10 equivalents with respect to benzoic acid derivative (X).
　還元反応に用いる反応溶媒は、用いる試薬の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、ＴＨＦ、１，４－ジオキサン、エチレングリコールジメチルエーテル若しくはジメトキシエタン等のエーテル系溶媒、ベンゼン若しくはトルエン等の芳香族炭化水素系溶媒が挙げられるが、ＴＨＦ、１，４－ジオキサン、エチレングリコールジメチルエーテル若しくはジメトキシエタン等のエーテル系溶媒が好ましい。 The reaction solvent used for the reduction reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include THF, 1,4-dioxane, ethylene glycol dimethyl ether or dimethoxyethane And ethereal solvents such as benzene and toluene; but ether solvents such as THF, 1,4-dioxane, ethylene glycol dimethyl ether and dimethoxyethane are preferable.
　還元反応の反応温度は、－７８℃～１００℃が好ましく、－３０℃～５０℃がより好ましい。 The reaction temperature of the reduction reaction is preferably -78 ° C to 100 ° C, and more preferably -30 ° C to 50 ° C.
　還元反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、１０分間～１０時間が好ましい。 The reaction time of the reduction reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 10 minutes to 10 hours.
　還元反応に用いる安息香酸誘導体（Ｘ）の反応開始時の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration at the start of the reaction of the benzoic acid derivative (X) used for the reduction reaction is preferably 1 mmol / L to 1 mol / L.
　還元反応に用いる安息香酸誘導体（Ｘ）は、購入することができるか又は公知の方法若しくはそれに準じた方法で製造できる。 The benzoic acid derivative (X) used for the reduction reaction can be purchased or can be produced by a known method or a method analogous thereto.
（第２工程）
　酸化反応に用いる酸化剤としては、例えば、三酸化硫黄－ピリジン、活性化ジメチルスルホキシド、デスマーチン試薬、二酸化マンガン又は２，２，６，６－テトラメチルピペリジン１－オキシル（以下、ＴＥＭＰＯ）が挙げられる。 (Step 2)
Examples of the oxidizing agent used for the oxidation reaction include sulfur trioxide-pyridine, activated dimethyl sulfoxide, desmartine reagent, manganese dioxide or 2,2,6,6-tetramethylpiperidine 1-oxyl (hereinafter TEMPO). Be
　酸化反応に用いる酸化剤の量は、ベンジルアルコール誘導体（ＸＩ）に対して０．５～１０当量が好ましく、０．８～５当量がより好ましい。 The amount of the oxidizing agent used for the oxidation reaction is preferably 0.5 to 10 equivalents, more preferably 0.8 to 5 equivalents, to the benzyl alcohol derivative (XI).
　酸化反応に用いる反応溶媒は、用いる試薬の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、ピリジン等の芳香族アミン系溶媒、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒、ＴＨＦ若しくは１，４－ジオキサン等のエーテル系溶媒、アセトニトリル若しくはプロピオニトリル等のニトリル系溶媒又はそれらの混合溶媒が挙げられる。 The reaction solvent used for the oxidation reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include aromatic amine solvents such as pyridine, dichloromethane, chloroform or Chlorinated solvents such as 2-dichloroethane, ether solvents such as THF or 1,4-dioxane, nitrile solvents such as acetonitrile or propionitrile, or mixed solvents thereof.
　酸化反応の反応温度は、－７８℃～１００℃が好ましく、－７８℃～６０℃がより好ましい。 The reaction temperature of the oxidation reaction is preferably −78 ° C. to 100 ° C., and more preferably −78 ° C. to 60 ° C.
　酸化反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、５分間～７２時間が好ましく、０．５～４８時間がより好ましい。 The reaction time of the oxidation reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 5 minutes to 72 hours, and more preferably 0.5 to 48 hours.
　酸化反応に用いるベンジルアルコール酸誘導体（ＸＩ）の反応開始時の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration at the start of the reaction of the benzyl alcohol acid derivative (XI) used for the oxidation reaction is preferably 1 mmol / L to 1 mol / L.
（第３工程）
　還元的アミノ化反応に用いるアミン誘導体（ＸＩＩＩ）又はアミン誘導体（ＸＩＶ）の量は、ベンズアルデヒド誘導体（ＸＩＩ）に対して０．５～１０当量が好ましく、１～３当量がより好ましい。 (Third step)
The amount of the amine derivative (XIII) or the amine derivative (XIV) used in the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, to the benzaldehyde derivative (XII).
　還元的アミノ化反応に用いる還元剤としては、例えば、水素化ホウ素ナトリウム、水素化シアノホウ素ナトリウム又は水素化トリアセトキシホウ素ナトリウムが挙げられるが、水素化トリアセトキシホウ素ナトリウムが好ましい。 As the reducing agent used for the reductive amination reaction, for example, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride can be mentioned, and sodium triacetoxyborohydride is preferable.
　還元的アミノ化反応に用いる還元剤の量は、ベンズアルデヒド誘導体（ＸＩＩ）に対して０．５～１０当量が好ましく、１～３当量がより好ましい。 The amount of the reducing agent used for the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents based on the benzaldehyde derivative (XII).
　還元的アミノ化反応に用いる反応溶媒は、用いる試薬の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、メタノール若しくはエタノール等のアルコール系溶媒、ジエチルエーテル、ＴＨＦ、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒又はそれらの混合溶媒が挙げられるが、ジクロロメタン、クロロホルム又は１，２－ジクロロエタン等の塩素系溶媒が好ましい。 The reaction solvent used for the reductive amination reaction is appropriately selected according to the type of reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol and ethanol, diethyl ether And ether solvents such as THF, dimethoxyethane or 1,4-dioxane, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane or mixed solvents thereof, but dichloromethane, chloroform or 1,2-dichloroethane Chlorinated solvents such as are preferred.
　還元的アミノ化反応の反応温度は、－７８℃～２００℃が好ましく、－２０℃～１００℃がより好ましい。 The reaction temperature of the reductive amination reaction is preferably −78 ° C. to 200 ° C., and more preferably −20 ° C. to 100 ° C.
　還元的アミノ化反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、０．５～３０時間が好ましい。 The reaction time of the reductive amination reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 0.5 to 30 hours.
　還元的アミノ化反応に用いるベンズアルデヒド誘導体（ＸＩＩ）の反応開始時の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration of the benzaldehyde derivative (XII) at the start of the reaction used for the reductive amination reaction is preferably 1 mmol / L to 1 mol / L.
　還元的アミノ化反応に用いるアミン誘導体（ＸＩＩＩ）及びアミン誘導体（ＸＩＶ）は、購入することができるか又は公知の方法若しくはそれに準じた方法で製造できる。 The amine derivative (XIII) and the amine derivative (XIV) used for the reductive amination reaction can be purchased or can be produced by a known method or a method analogous thereto.
（第４工程）
　還元反応に用いる金属としては、例えば、鉄粉又は塩化スズ（ＩＩ）が挙げられるが、鉄粉が好ましい。 (Step 4)
Examples of the metal used for the reduction reaction include iron powder and tin (II) chloride, with iron powder being preferred.
　還元反応に用いる金属の量は、ニトロフェニル誘導体（ＸＶ）に対して０．５～５０当量が好ましく、１～１０当量がより好ましい。 The amount of metal used for the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, to the nitrophenyl derivative (XV).
　還元反応に用いる酸としては、例えば、酢酸、塩酸又は塩化アンモニウム水溶液が挙げられるが、酢酸又は塩化アンモニウム水溶液が好ましい。 Examples of the acid used for the reduction reaction include acetic acid, hydrochloric acid or an aqueous solution of ammonium chloride, with preference given to acetic acid or an aqueous solution of ammonium chloride.
　還元反応に用いる酸の量は、ニトロフェニル誘導体（ＸＶ）に対して０．５～５０当量が好ましく、１～１０当量がより好ましい。 The amount of the acid used for the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, to the nitrophenyl derivative (XV).
　還元反応に用いる反応溶媒は、用いる試薬の種類等に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、メタノール若しくはエタノール等のアルコール系溶媒、ジエチルエーテル、ＴＨＦ、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、水又はそれらの混合溶媒が挙げられるが、メタノール又はエタノール等のアルコール系溶媒、ジエチルエーテル、ＴＨＦ、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒と水との混合溶媒が好ましい。 The reaction solvent used for the reduction reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, for example, alcohol solvents such as methanol or ethanol, diethyl ether, THF And ether solvents such as dimethoxyethane or 1,4-dioxane, water or mixed solvents thereof, alcohol solvents such as methanol or ethanol, diethyl ether, THF, dimethoxyethane or 1,4-dioxane A mixed solvent of an ether solvent and water is preferred.
　還元反応の反応温度は、０～２００℃が好ましく、５０～１５０℃がより好ましい。 The reaction temperature of the reduction reaction is preferably 0 to 200 ° C., and more preferably 50 to 150 ° C.
　還元反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、１～３０時間が好ましい。 The reaction time of the reduction reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
　還元反応に用いるニトロフェニル誘導体（ＸＶ）の反応開始時の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration of the nitrophenyl derivative (XV) used for the reduction reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
　スキーム１に示したアニリン誘導体（ＩＩＩ）のうち、ｍが０であるアニリン誘導体（ＩＩＩ－ｂ）は、例えば、スキーム３に示すように、塩基存在下、アミン誘導体（ＸＩＩＩ）又はアミン誘導体（ＸＩＶ）のフルオロフェニル誘導体（ＸＶＩ）に対する求核置換反応（第１工程）、続いて、金属及び酸存在下、第１工程で得られたニトロフェニル誘導体（ＸＶＩＩ）の還元反応（第２工程）により得ることができる。
Figure JPOXMLDOC01-appb-C000015
 ［式中、Ｒ１、Ｒ４、ｐ、ｑ、Ｒ５、Ｒ６及びＡは、上記定義に同じである。］ Among aniline derivatives (III) shown in Scheme 1, aniline derivatives (III-b) in which m is 0 are, for example, amine derivatives (XIII) or amine derivatives (XIV) in the presence of a base as shown in Scheme 3. Nucleophilic substitution reaction (step 1) on fluorophenyl derivative (XVI) of (1), followed by reduction reaction (step 2) of nitrophenyl derivative (XVII) obtained in step 1 in the presence of metal and acid You can get it.
Figure JPOXMLDOC01-appb-C000015
 [Wherein, R 1 , R 4 , p, q, R 5 , R 6 and A are as defined above. ]
（第１工程）
　求核置換反応に用いるアミン誘導体（ＸＩＩＩ）又はアミン誘導体（ＸＩＶ）の量は、フルオロフェニル誘導体（ＸＶＩ）に対して０．５～１０当量が好ましく、１～３当量がより好ましい。 (Step 1)
The amount of the amine derivative (XIII) or the amine derivative (XIV) used for the nucleophilic substitution reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, to the fluorophenyl derivative (XVI).
　求核置換反応に用いる塩基としては、例えば、トリエチルアミン、ジイソプロピルエチルアミン若しくはＮ－メチルモルホリン等の有機塩基、炭酸ナトリウム若しくは炭酸カリウム等の無機塩基、水素化ナトリウム、水素化カリウム若しくは水素化カルシウム等の水素化金属化合物、リチウムヘキサメチルジシラジド若しくはリチウムジイソプロピルアミド等のリチウムアミド、ｔｅｒｔ－ブチルオキシナトリウム若しくはｔｅｒｔ－ブチルオキシカリウム等の金属アルコキシド又はそれらの混合物が挙げられるが、トリエチルアミン、ジイソプロピルエチルアミン若しくはＮ－メチルモルホリン等の有機塩基又は水素化ナトリウム、水素化カリウム若しくは水素化カルシウム等の水素化金属化合物が好ましい。 Examples of the base used for the nucleophilic substitution reaction include organic bases such as triethylamine, diisopropylethylamine or N-methylmorpholine, inorganic bases such as sodium carbonate or potassium carbonate, hydrogen such as sodium hydride, potassium hydride or calcium hydride Metal oxides, lithium amides such as lithium hexamethyldisilazide or lithium diisopropylamide, metal alkoxides such as tert-butyloxy sodium or tert-butyloxy potassium, or mixtures thereof, but triethylamine, diisopropylethylamine or N- Organic bases such as methyl morpholine or sodium hydride, metal hydride compounds such as potassium hydride or calcium hydride are preferred.
　求核置換反応に用いる塩基の量は、フルオロフェニル誘導体（ＸＶＩ）に対して０．５～１０当量が好ましく、１～３当量がより好ましい。 The amount of the base used for the nucleophilic substitution reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents, to the fluorophenyl derivative (XVI).
　求核置換反応に用いる反応溶媒は、用いる試薬の種類等に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、ＴＨＦ、１，４－ジオキサン、エチレングリコールジメチルエーテル若しくはジメトキシエタン等のエーテル系溶媒、アセトニトリル若しくはプロピオニトリル等のニトリル系溶媒、ベンゼン若しくはトルエン等の芳香族炭化水素系溶媒、ＤＭＦ若しくはＤＭＳＯ等の非プロトン性極性溶媒、水又はそれらの混合溶媒が挙げられるが、ＤＭＦ又はＤＭＳＯ等の非プロトン性極性溶媒が好ましい。 The reaction solvent used for the nucleophilic substitution reaction is appropriately selected according to the type of the reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, for example, THF, 1,4-dioxane, ethylene glycol dimethyl ether Or an ether solvent such as dimethoxyethane, a nitrile solvent such as acetonitrile or propionitrile, an aromatic hydrocarbon solvent such as benzene or toluene, an aprotic polar solvent such as DMF or DMSO, water or a mixed solvent thereof Although non-polar polar solvents such as DMF or DMSO are preferred.
　求核置換反応の反応温度は、－７８℃～２００℃が好ましく、－２０℃～１６０℃がより好ましい。 The reaction temperature of the nucleophilic substitution reaction is preferably −78 ° C. to 200 ° C., and more preferably −20 ° C. to 160 ° C.
　求核置換反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、１～３０時間が好ましい。 The reaction time of the nucleophilic substitution reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
　求核置換反応に用いるフルオロフェニル誘導体（ＸＶＩ）の反応開始時の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration at the start of the reaction of fluorophenyl derivative (XVI) used for the nucleophilic substitution reaction is preferably 1 mmol / L to 1 mol / L.
　求核置換反応に用いるフルオロフェニル誘導体（ＸＶＩ）、アミン誘導体（ＸＩＩＩ）及びアミン誘導体（ＸＩＶ）は、購入することができるか又は公知の方法若しくはそれに準じた方法で製造できる。 The fluorophenyl derivative (XVI), the amine derivative (XIII) and the amine derivative (XIV) used for the nucleophilic substitution reaction can be purchased or can be produced by a known method or a method analogous thereto.
（第２工程）
　還元反応に用いる金属としては、例えば、鉄粉又は塩化スズ（ＩＩ）が挙げられるが、鉄粉が好ましい。 (Step 2)
Examples of the metal used for the reduction reaction include iron powder and tin (II) chloride, with iron powder being preferred.
　還元反応に用いる金属の量は、ニトロフェニル誘導体（ＸＶＩＩ）に対して０．５～５０当量が好ましく、１～１０当量がより好ましい。 The amount of metal used for the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, to the nitrophenyl derivative (XVII).
　還元反応に用いる酸としては、例えば、酢酸、塩酸又は塩化アンモニウム水溶液が挙げられるが、酢酸又は塩化アンモニウム水溶液が好ましい。 Examples of the acid used for the reduction reaction include acetic acid, hydrochloric acid or an aqueous solution of ammonium chloride, with preference given to acetic acid or an aqueous solution of ammonium chloride.
　還元反応に用いる酸の量は、ニトロフェニル誘導体（ＸＶＩＩ）に対して０．５～５０当量が好ましく、１～１０当量がより好ましい。 The amount of the acid used for the reduction reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 10 equivalents, to the nitrophenyl derivative (XVII).
　還元反応に用いる反応溶媒は、用いる試薬の種類等に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、メタノール若しくはエタノール等のアルコール系溶媒、ジエチルエーテル、ＴＨＦ、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、水又はそれらの混合溶媒が挙げられるが、メタノール又はエタノール等のアルコール系溶媒、ジエチルエーテル、ＴＨＦ、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒と水との混合溶媒が好ましい。 The reaction solvent used for the reduction reaction is appropriately selected according to the type of reagent used, etc., but is not particularly limited as long as it does not inhibit the reaction, for example, alcohol solvents such as methanol or ethanol, diethyl ether, THF And ether solvents such as dimethoxyethane or 1,4-dioxane, water or mixed solvents thereof, alcohol solvents such as methanol or ethanol, diethyl ether, THF, dimethoxyethane or 1,4-dioxane A mixed solvent of an ether solvent and water is preferred.
　還元反応の反応温度は、０～２００℃が好ましく、５０～１５０℃がより好ましい。 The reaction temperature of the reduction reaction is preferably 0 to 200 ° C., and more preferably 50 to 150 ° C.
　還元反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、１～３０時間が好ましい。 The reaction time of the reduction reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
　還元反応に用いるニトロフェニル誘導体（ＸＶＩＩ）の反応開始時の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration at the start of the reaction of the nitrophenyl derivative (XVII) used for the reduction reaction is preferably 1 mmol / L to 1 mol / L.
　スキーム２及び３に示したアミン誘導体（ＸＩＩＩ）のうち、ｐが１であり、ｑが２であるテトラヒドロイソキノリン誘導体（ＸＩＩＩ－ａ）は、例えば、スキーム４に示すように、トリフルオロ酢酸無水物によるフェネチルアミン誘導体（ＸＶＩＩＩ）のトリフルオロアセチル化反応（第１工程）、続いて、パラホルムアルデヒド及び酸存在下、第１工程で得られたトリフルオロアセトアミド誘導体（ＸＩＸ）の環化反応（第２工程）、続いて、第２工程で得られたテトラヒドロイソキノリン誘導体（ＸＸ）の加水分解反応（第３工程）により得ることができる。
Figure JPOXMLDOC01-appb-C000016
 ［式中、Ｒ４は、上記定義に同じである。］ Among the amine derivatives (XIII) shown in Schemes 2 and 3, tetrahydroisoquinoline derivatives (XIII-a) in which p is 1 and q is 2 are, for example, trifluoroacetic anhydride as shown in Scheme 4. Trifluoroacetylation reaction of phenethylamine derivative (XVIII) according to (Step 1), followed by cyclization reaction (Step 2) of trifluoroacetamide derivative (XIX) obtained in Step 1 in the presence of paraformaldehyde and an acid And the hydrolysis reaction (third step) of the tetrahydroisoquinoline derivative (XX) obtained in the second step.
Figure JPOXMLDOC01-appb-C000016
 [Wherein, R 4 is as defined above. ]
（第１工程）
　トリフルオロアセチル化反応に用いるトリフルオロ酢酸無水物の量は、フェネチルアミン誘導体（ＸＶＩＩＩ）に対して０．５～２０当量が好ましく、１～５当量がより好ましい。 (Step 1)
The amount of trifluoroacetic anhydride used for the trifluoroacetylation reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, with respect to phenethylamine derivative (XVIII).
　トリフルオロアセチル化反応に用いる反応溶媒としては、用いる試薬の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、ＤＭＦ、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン若しくはＤＭＳＯ等の非プロトン性極性溶媒、ジエチルエーテル、ＴＨＦ、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、酢酸エチル若しくは酢酸プロピル等のエステル系溶媒、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒又はそれらの混合溶媒が挙げられるが、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒が好ましい。 The reaction solvent used for the trifluoroacetylation reaction is appropriately selected according to the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, for example, DMF, N, N-dimethylacetamide, N -Aprotic polar solvents such as methyl-2-pyrrolidone or DMSO, ether solvents such as diethyl ether, THF, dimethoxyethane or 1,4-dioxane, ester solvents such as ethyl acetate or propyl acetate, dichloromethane, chloroform or Chlorinated solvents such as 1,2-dichloroethane or mixed solvents thereof may be mentioned, and chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane are preferable.
　トリフルオロアセチル化反応の反応温度は、－２０℃～１００℃が好ましく、０～５０℃がより好ましい。 The reaction temperature of the trifluoroacetylation reaction is preferably -20 ° C to 100 ° C, and more preferably 0 to 50 ° C.
　トリフルオロアセチル化反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、１～３０時間が好ましい。 The reaction time of the trifluoroacetylation reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
　トリフルオロアセチル化反応に用いるフェネチルアミン誘導体（ＸＶＩＩＩ）の反応開始時の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration of phenethylamine derivative (XVIII) used for the trifluoroacetylation reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
　トリフルオロアセチル化反応に用いるフェネチルアミン誘導体（ＸＶＩＩＩ）は、購入することができるか又は公知の方法若しくはそれに準じた方法で製造できる。 The phenethylamine derivative (XVIII) used for the trifluoroacetylation reaction can be purchased or can be produced by a known method or a method analogous thereto.
（第２工程）
　環化反応に用いるパラホルムアルデヒドの量は、トリフルオロアセトアミド誘導体（ＸＩＸ）に対して０．５～２０当量が好ましく、１～５当量がより好ましい。 (Step 2)
The amount of paraformaldehyde used in the cyclization reaction is preferably 0.5 to 20 equivalents, more preferably 1 to 5 equivalents, relative to the trifluoroacetamide derivative (XIX).
　環化反応に用いる酸としては、例えば、塩酸、酢酸、トリフルオロ酢酸、濃硫酸、濃硝酸又はリン酸等が挙げられるが、酢酸及び濃硫酸の混合液が好ましい。 Examples of the acid used for the cyclization reaction include hydrochloric acid, acetic acid, trifluoroacetic acid, concentrated sulfuric acid, concentrated nitric acid, and phosphoric acid, but a mixed solution of acetic acid and concentrated sulfuric acid is preferable.
　環化反応に用いる酸の量は、トリフルオロアセトアミド誘導体（ＸＩＸ）に対して０．５～１００当量が好ましく、１～５０当量がより好ましい。 The amount of the acid used for the cyclization reaction is preferably 0.5 to 100 equivalents, more preferably 1 to 50 equivalents based on the trifluoroacetamide derivative (XIX).
　環化反応に用いる反応溶媒は、用いる試薬の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、ＤＭＦ、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン若しくはＤＭＳＯ等の非プロトン性極性溶媒、ジエチルエーテル、ＴＨＦ、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒又はそれらの混合溶媒が挙げられる。 The reaction solvent used for the cyclization reaction is appropriately selected according to the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, and, for example, DMF, N, N-dimethylacetamide, N-methyl- Aprotic polar solvents such as 2-pyrrolidone or DMSO, ether solvents such as diethyl ether, THF, dimethoxyethane or 1,4-dioxane, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane or mixtures thereof A solvent is mentioned.
　環化反応の反応温度は、－２０℃～１００℃が好ましく、０～５０℃がより好ましい。 The reaction temperature of the cyclization reaction is preferably -20 ° C to 100 ° C, and more preferably 0 to 50 ° C.
　環化反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、１～３０時間が好ましい。 The reaction time of the cyclization reaction is appropriately selected according to the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
　環化反応に用いるトリフルオロアセトアミド誘導体（ＸＩＸ）の反応開始時の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration at the start of reaction of the trifluoroacetamide derivative (XIX) used for the cyclization reaction is preferably 1 mmol / L to 1 mol / L.
（第３工程）
　加水分解反応に用いる塩基としては、例えば、水酸化リチウム、水酸化ナトリウム、水酸化カリウム、水酸化バリウム又は炭酸カリウム等の無機塩基が挙げられる。 (Third step)
As a base used for a hydrolysis reaction, inorganic bases, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide or potassium carbonate, are mentioned, for example.
　加水分解反応に用いる塩基の量は、テトラヒドロイソキノリン誘導体（ＸＸ）に対して０．５～５０当量が好ましく、１～２０当量がより好ましい。 The amount of the base used for the hydrolysis reaction is preferably 0.5 to 50 equivalents, more preferably 1 to 20 equivalents based on the tetrahydroisoquinoline derivative (XX).
　加水分解反応に用いる反応溶媒としては、用いる試薬の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、メタノール若しくはエタノール等のアルコール系溶媒、アセトニトリル若しくはプロピオニトリル等のニトリル系溶媒、ＤＭＦ、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン若しくはＤＭＳＯ等の非プロトン性極性溶媒、ジエチルエーテル、ＴＨＦ、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、酢酸エチル若しくは酢酸プロピル等のエステル系溶媒、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒又はそれらの混合溶媒が挙げられるが、メタノール若しくはエタノール等のアルコール系溶媒、ＤＭＦ、Ｎ，Ｎ－ジメチルアセトアミド、Ｎ－メチル－２－ピロリドン若しくはＤＭＳＯ等の非プロトン性極性溶媒又はジエチルエーテル、ＴＨＦ、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒が好ましい。 The reaction solvent used for the hydrolysis reaction is appropriately selected according to the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol and ethanol, acetonitrile or pro Nitrile solvents such as piononitrile, aprotic polar solvents such as DMF, N, N-dimethylacetamide, N-methyl-2-pyrrolidone or DMSO, ethers such as diethyl ether, THF, dimethoxyethane or 1,4-dioxane Examples of the solvent include ester solvents such as ethyl acetate or propyl acetate, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, and mixed solvents thereof, and alcohol solvents such as methanol or ethanol, DMF, N , N-dimeth Acetamide, N- methyl-2-pyrrolidone or aprotic polar solvents or diethyl ether such as DMSO, THF, ether solvents such as dimethoxyethane or 1,4-dioxane are preferred.
　加水分解反応の反応温度は、－２０℃～２００℃が好ましく、０～１５０℃がより好ましい。 The reaction temperature of the hydrolysis reaction is preferably -20 ° C to 200 ° C, and more preferably 0 to 150 ° C.
　加水分解反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、１～３０時間が好ましい。 The reaction time of the hydrolysis reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
　加水分解反応に用いるテトラヒドロイソキノリン誘導体（ＸＸ）の反応開始時の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration of the tetrahydroisoquinoline derivative (XX) used for the hydrolysis reaction at the start of the reaction is preferably 1 mmol / L to 1 mol / L.
　スキーム２及び３に示したアミン誘導体（ＸＩＶ）は、例えば、スキーム５に示すように、アルデヒド誘導体（ＸＸＩ）とアミン誘導体（ＸＸＩＩ）との還元的アミノ化反応又はアルデヒド誘導体（ＸＸＩＩＩ）とアミン誘導体（ＸＸＩＶ）との還元的アミノ化反応により得ることができる。
Figure JPOXMLDOC01-appb-C000017
 ［式中、Ｕは、水素原子、炭素数１～５のアルキル基、炭素数３～５のシクロアルキル基、炭素数４若しくは５のシクロアルキルアルキル基又は－（ＣＨ２）ｒ－１－ＯＲ７を表し、Ｒ５、Ｒ６、ｒ及びＲ７は、上記定義に同じである。］ The amine derivative (XIV) shown in Schemes 2 and 3 is, for example, as shown in Scheme 5, a reductive amination reaction of aldehyde derivative (XXI) with amine derivative (XXII) or aldehyde derivative (XXIII) with amine derivative It can be obtained by reductive amination reaction with (XXIV).
Figure JPOXMLDOC01-appb-C000017
 [Wherein, U represents a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, a cycloalkyl group of 3 to 5 carbon atoms, a cycloalkyl alkyl group of 4 or 5 carbon atoms, or-(CH 2 ) r-1 -OR 7 and R 5 , R 6 , r and R 7 are as defined above. ]
　還元的アミノ化反応に用いるアミン誘導体（ＸＸＩＩ）又はアミン誘導体（ＸＸＩＶ）の量は、それぞれ、アルデヒド誘導体（ＸＸＩ）又はアルデヒド誘導体（ＸＸＩＩＩ）に対して０．５～１０当量が好ましく、１～３当量がより好ましい。 The amount of amine derivative (XXII) or amine derivative (XXIV) to be used for the reductive amination reaction is preferably 0.5 to 10 equivalents, preferably 1 to 3 with respect to aldehyde derivative (XXI) or aldehyde derivative (XXIII), respectively. The equivalent is more preferred.
　還元的アミノ化反応に用いる還元剤としては、例えば、水素化ホウ素ナトリウム、水素化シアノホウ素ナトリウム又は水素化トリアセトキシホウ素ナトリウムが挙げられるが、水素化トリアセトキシホウ素ナトリウムが好ましい。 As the reducing agent used for the reductive amination reaction, for example, sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride can be mentioned, and sodium triacetoxyborohydride is preferable.
　還元的アミノ化反応に用いる還元剤の量は、アルデヒド誘導体（ＸＸＩ）又はアルデヒド誘導体（ＸＸＩＩＩ）に対して０．５～１０当量が好ましく、１～３当量がより好ましい。 The amount of the reducing agent used for the reductive amination reaction is preferably 0.5 to 10 equivalents, more preferably 1 to 3 equivalents with respect to the aldehyde derivative (XXI) or the aldehyde derivative (XXIII).
　還元的アミノ化反応に用いる反応溶媒としては、用いる試薬の種類に応じて適宜選択されるが、反応を阻害しないものであれば特に限定されず、例えば、メタノール若しくはエタノール等のアルコール系溶媒、ジエチルエーテル、ＴＨＦ、ジメトキシエタン若しくは１，４－ジオキサン等のエーテル系溶媒、ジクロロメタン、クロロホルム若しくは１，２－ジクロロエタン等の塩素系溶媒又はそれらの混合溶媒が挙げられるが、ジクロロメタン、クロロホルム又は１，２－ジクロロエタン等の塩素系溶媒が好ましい。 The reaction solvent used for the reductive amination reaction is appropriately selected according to the type of the reagent used, but is not particularly limited as long as it does not inhibit the reaction, for example, alcohol solvents such as methanol or ethanol, diethyl Examples of the solvent include ether solvents such as ether, THF, dimethoxyethane or 1,4-dioxane, chlorinated solvents such as dichloromethane, chloroform or 1,2-dichloroethane, and mixed solvents thereof. Chlorinated solvents such as dichloroethane are preferred.
　還元的アミノ化反応の反応温度は、－７８℃～２００℃が好ましく、－２０℃～１００℃がより好ましい。 The reaction temperature of the reductive amination reaction is preferably −78 ° C. to 200 ° C., and more preferably −20 ° C. to 100 ° C.
　還元的アミノ化反応の反応時間は、反応温度等の条件に応じて適宜選択されるが、１～３０時間が好ましい。 The reaction time of the reductive amination reaction is appropriately selected depending on the conditions such as the reaction temperature, but is preferably 1 to 30 hours.
　還元的アミノ化反応に用いるアルデヒド誘導体（ＸＸＩ）及びアルデヒド誘導体（ＸＸＩＩＩ）の反応開始時の濃度は、１ｍｍｏｌ／Ｌ～１ｍｏｌ／Ｌが好ましい。 The concentration at the start of the reaction of the aldehyde derivative (XXI) and the aldehyde derivative (XXIII) used for the reductive amination reaction is preferably 1 mmol / L to 1 mol / L.
　還元的アミノ化反応に用いるアミン誘導体（ＸＸＩＩ）、アミン誘導体（ＸＸＩＶ）、アルデヒド誘導体（ＸＸＩ）及びアルデヒド誘導体（ＸＸＩＩＩ）は、購入することができるか又は公知の方法若しくはそれに準じた方法で製造できる。 The amine derivative (XXII), the amine derivative (XXIV), the aldehyde derivative (XXI) and the aldehyde derivative (XXIII) used for the reductive amination reaction can be purchased or can be produced by a known method or a method analogous thereto .
　本発明の医薬、ＲＯＲγアンタゴニスト、及び、自己免疫疾患の治療剤又は予防剤は、環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩を有効成分として含有することを特徴としている。上記の自己免疫疾患は、好ましくは、乾癬である。 The medicament, RORγ antagonist and therapeutic agent or prophylactic agent for autoimmune diseases of the present invention are cyclic amine derivative (I), stereoisomers thereof or hydrates thereof, or pharmacologically acceptable thereof It is characterized by containing salt as an active ingredient. The above-mentioned autoimmune disease is preferably psoriasis.
　「ＲＯＲγアンタゴニスト」とは、ＲＯＲγの機能を抑制して、その活性を消失又は減弱する作用を有する化合物を意味する。 The “RORγ antagonist” means a compound having the function of suppressing the function of RORγ to abolish or attenuate its activity.
　「自己免疫疾患」とは、過剰な免疫反応が自己の正常な細胞や組織を攻撃することで症状を来す疾患の総称であり、例えば、多発性硬化症、乾癬、関節リウマチ、全身性エリテマトーデス、炎症性腸疾患、強直性脊椎炎、ぶどう膜炎、リウマチ性多発性筋痛症、強皮症、血管炎、天疱瘡、類天疱瘡又は皮膚筋炎が挙げられる。また、本発明の自己免疫疾患には、ざ瘡、白斑又は円形脱毛症が含まれる。 "Autoimmune disease" is a general term for diseases in which excessive immune reaction causes symptoms by attacking normal cells and tissues of the patient, and includes, for example, multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus Inflammatory bowel disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica, scleroderma, vasculitis, pemphigus, pemphigus or dermatomyositis. The autoimmune diseases of the present invention also include acne, vitiligo or alopecia areata.
　「アレルギー性疾患」とは、免疫反応が特定の抗原に対して過剰に起こることに由来する疾患であり、例えば、アレルギー性皮膚炎、接触性皮膚炎、アトピー性皮膚炎、アレルギー性鼻炎（花粉症）、アレルギー性結膜炎、アレルギー性胃腸炎、気管支喘息、小児喘息又は食物アレルギーが挙げられる。 "Allergic disease" is a disease derived from the occurrence of excessive immune reaction against a specific antigen, such as allergic dermatitis, contact dermatitis, atopic dermatitis, allergic rhinitis (pollen Disease, allergic conjunctivitis, allergic gastroenteritis, bronchial asthma, childhood asthma or food allergy.
　「乾癬」とは、免疫細胞の浸潤及び活性化とそれに伴う表皮肥厚を伴う皮膚の炎症性疾患である。典型的には、全身の色々な場所で赤い発疹の上に白色の鱗屑が厚く付着し、それがはがれ落ちる落屑という症状が起こる。乾癬としては、例えば、尋常性乾癬、膿庖性乾癬、関節症性乾癬、滴状乾癬、乾癬性紅皮症が挙げられる。 "Psoriasis" is an inflammatory disease of the skin associated with infiltration and activation of immune cells and concomitant epidermal hyperplasia. Typically, white scales adhere thickly on a red rash in various places throughout the body, causing symptoms of scaling that may fall off. Psoriasis includes, for example, psoriasis vulgaris, pustular psoriasis, arthritic psoriasis, psoriatic psoriasis, psoriatic erythroderma.
　環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩は、ＲＯＲγとコアクチベーターとの結合を阻害することにより、ＲＯＲγの機能を抑制することを特徴としている。ＲＯＲγは様々な疾患に関与し、また、その機能の抑制によって病態の改善又は症状の寛解が期待できることが知られていることから、環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩は、ＲＯＲγの機能を抑制することによって病態の改善又は症状の寛解が期待できる疾患に対する医薬、特に、自己免疫疾患又はアレルギー性疾患の治療剤又は予防剤として用いることができる。上記の自己免疫疾患の治療剤又は予防剤は、好ましくは、多発性硬化症、乾癬、関節リウマチ、全身性エリテマトーデス、炎症性腸疾患、強直性脊椎炎、ぶどう膜炎、リウマチ性多発性筋痛症、強皮症、血管炎、天疱瘡、類天疱瘡、皮膚筋炎、ざ瘡、白斑又は円形脱毛症の治療剤又は予防剤として用いることができ、より好ましくは、乾癬の治療剤又は予防剤として用いることができる。 The cyclic amine derivative (I), its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof inhibits the function of RORγ by inhibiting the binding of RORγ to a coactivator. It is characterized by suppressing. It is known that RORγ is involved in various diseases, and that suppression of its function is expected to improve the pathological condition or ameliorate the symptoms, so cyclic amine derivatives (I), their stereoisomers or their hydrates Or a pharmacologically acceptable salt thereof is a medicament for a disease which can be expected to improve the condition or ameliorate the symptoms by suppressing the function of RORγ, in particular, a therapeutic agent for an autoimmune disease or an allergic disease Or it can be used as a preventive agent. The therapeutic agent or prophylactic agent for the above-mentioned autoimmune diseases is preferably multiple sclerosis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, inflammatory bowel disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica Can be used as a therapeutic or preventive agent for atrophy, scleroderma, vasculitis, pemphigus, pemphigus, dermatomyositis, acne, vitiligo or alopecia areata, more preferably a therapeutic or preventive agent for psoriasis It can be used as
　環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩がＲＯＲγとコアクチベーターとの結合を阻害するＲＯＲγアンタゴニスト活性を有することは、ｉｎ　ｖｉｔｒｏ試験を用いて評価できる。ｉｎ　ｖｉｔｒｏ試験としては、例えば、ＲＯＲγとアゴニスト（例えば、コレステロール）との結合を評価する方法（国際公開第２０１２／１５８７８４号、国際公開第２０１３／０１８６９５号）や、ＲＯＲγのリガンド結合ドメインとコアクチベーターとの結合を評価する方法が挙げられる（国際公開第２０１２／０６４７４４号、国際公開第２０１３／０１８６９５号）。また、ＲＯＲγの転写活性阻害作用は、各種レポータージーンアッセイを用いて評価することができる（国際公開第２０１２／１５８７８４号、国際公開第２０１２／０６４７４４号、国際公開第２０１３／０１８６９５号）。 The cyclic amine derivative (I), a stereoisomer thereof or a hydrate of these or a pharmacologically acceptable salt thereof has RORγ antagonist activity which inhibits the binding of RORγ to a coactivator, It can be evaluated using in vitro tests. As an in vitro test, for example, a method of evaluating the binding of RORγ to an agonist (eg, cholesterol) (WO 2012/158784, WO 2013/018695), a ligand binding domain of RORγ and a coacti Methods for assessing binding to beta can be mentioned (WO 2012/064744, WO 2013/018695). In addition, the transcriptional activity inhibitory action of RORγ can be evaluated using various reporter gene assays (WO 2012/158784, WO 2012/064744, WO 2013/018695).
　環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩がＲＯＲγの機能を抑制することは、脾臓又は末梢血等の各種臓器由来のリンパ球細胞を用いて、ＩＬ－１７の産生又はＴｈ１７細胞分化を指標に評価することができる。ＩＬ－１７産生を指標にした方法としては、例えば、マウス脾細胞を用いて、ＩＬ－２３刺激によるＩＬ－１７産生を測定する方法が挙げられる（Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｂｉｏｌｏｇｉｃａｌ　Ｃｈｅｍｉｓｔｒｙ、２００３年、第２７８巻、第３号、ｐ．１９１０－１９１４）。Ｔｈ１７細胞分化を指標にした方法としては、例えば、マウス脾細胞又はヒトＰＢＭＣ由来のＣＤ４陽性ｎａｉｖｅ　Ｔ細胞を用いて、各種サイトカイン（例えば、ＩＬ－１β、ＩＬ－６、ＩＬ－２３及び／又はＴＧＦ－β）と各種抗体（例えば、抗ＣＤ３抗体、抗ＣＤ２８抗体、抗ＩＬ－４抗体、抗ＩＦＮ－γ抗体及び／又は抗ＩＬ－２抗体）で刺激してＴｈ１７に分化させ、ＩＬ－１７産生量又はＩＬ－１７陽性細胞割合等を測定する方法が挙げられる（国際公開第２０１２／１５８７８４号、国際公開第２０１３／０１８６９５号）。 The cyclic amine derivative (I), its stereoisomer or hydrate thereof, or pharmacologically acceptable salt thereof suppressing the function of RORγ is derived from various organs such as spleen or peripheral blood Lymphocytes can be used to evaluate IL-17 production or Th17 cell differentiation as an indicator. As a method using IL-17 production as an index, for example, a method of measuring IL-17 production by IL-23 stimulation using mouse splenocytes can be mentioned (The Journal of Biological Chemistry, 2003, 278) , No. 3, p. 1910-1914). As a method using Th17 cell differentiation as an index, for example, various cytokines (eg, IL-1β, IL-6, IL-23 and / or TGF are used, using CD4 positive naive T cells derived from mouse splenocytes or human PBMC). Stimulate with -β) and various antibodies (eg, anti-CD3 antibody, anti-CD28 antibody, anti-IL-4 antibody, anti-IFN-γ antibody and / or anti-IL-2 antibody) to differentiate to Th17 and produce IL-17 The method includes measuring the amount or the proportion of IL-17 positive cells etc. (WO 2012/158784, WO 2013/018695).
　環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩が自己免疫疾患の治療又は予防に有効であることは、病態モデルを用いて評価できる。病態モデルとしては、例えば、実験的自己免疫性脳脊髄炎モデル（Ｊｏｕｒｎａｌ　ｏｆ　Ｎｅｕｒｏｓｃｉｅｎｃｅ　Ｒｅｓｅａｒｃｈ、２００６年、第８４巻、ｐ．１２２５－１２３４）、イミキモド誘発乾癬モデル（Ｊｏｕｒｎａｌ　ｏｆ　Ｉｍｍｕｎｏｌｏｇｙ、２００９年、第１８２巻、ｐ．５８３６－５８４５）、コラーゲン関節炎モデル（Ａｎｎｕａｌ　Ｒｅｖｉｅｗ　ｏｆ　Ｉｍｍｕｎｏｌｏｇｙ、１９８４年、第２巻、ｐ．１９９－２１８）、全身性エリテマトーデスの自然発症モデル（Ｎａｔｕｒｅ、２０００年、第４０４巻、ｐ．９９５－９９９）、ＴＮＢＳ誘発大腸炎モデル（Ｅｕｒｏｐｅａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐｈａｒｍａｃｏｌｏｇｙ、２００１年、第４３１巻、ｐ．１０３－１１０）、強直性脊椎炎モデル（Ａｒｔｈｒｉｔｉｓ　Ｒｅｓｅａｒｃｈ　＆　Ｔｈｅｒａｐｙ、２０１２年、第１４巻、ｐ．２５３－２６５）、実験的自己免疫性ぶどう膜炎モデル（Ｊｏｕｒｎａｌ　ｏｆ　Ｉｍｍｕｎｏｌｏｇｙ、２００６年、第３６巻、ｐ．３０７１－３０８１）、強皮症モデル（Ｊｏｕｒｎａｌ　ｏｆ　Ｉｎｖｅｓｔｉｇａｔｉｖｅ　Ｄｅｒｍａｔｏｌｏｇｙ、１９９９年、第１１２巻、ｐ．４５６－４６２）、血管炎モデル（Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｃｌｉｎｉｃａｌ　Ｉｎｖｅｓｔｉｇａｔｉｏｎ、２００２年、第１１０巻、ｐ．９５５－９６３）、天疱瘡モデル（Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｃｌｉｎｉｃａｌ　Ｉｎｖｅｓｔｉｇａｔｉｏｎ、２０００年、第１０５巻、ｐ．６２５－６３１）、類天疱瘡モデル（Ｅｘｐｅｒｉｍｅｎｔａｌ　Ｄｅｒｍａｔｏｌｏｇｙ、２０１２年、第２１巻、ｐ．９０１－９０５）、皮膚筋炎モデル（Ａｍｅｒｉｃａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｐａｔｈｏｌｏｇｙ、１９８５年、第１２０巻、ｐ．３２３－３２５）、ざ瘡の自然発症モデル（Ｅｕｒｏｐｅａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｄｅｒｍａｔｏｌｏｇｙ、２００５年、第１５巻、ｐ．４５９－４６４）、白斑モデル（Ｐｉｇｍｅｎｔ　Ｃｅｌｌ　＆　Ｍｅｌａｎｏｍａ　Ｒｅｓｅａｒｃｈ、２０１４年、第２７巻、ｐ．１０７５－１０８５）又は、円形脱毛症モデル（Ｊｏｕｒｎａｌ　ｏｆ　Ｉｎｖｅｓｔｉｇａｔｉｖｅ　Ｄｅｒｍａｔｏｌｏｇｙ、２０１５年、第１３５巻、ｐ．２５３０－２５３２）が挙げられる。実験的自己免疫性脳脊髄炎モデルは、多発性硬化症のモデルとして一般的である。また、イミキモド誘発乾癬モデルは、乾癬のモデルとして一般的である。 The effectiveness of the cyclic amine derivative (I), its stereoisomer or hydrates thereof, or their pharmacologically acceptable salts for the treatment or prevention of autoimmune diseases can be determined using a pathological model It can be evaluated. As a pathological model, for example, experimental autoimmune encephalomyelitis model (Journal of Neuroscience Research, 2006, 84, pages 1225-1234), imiquimod-induced psoriasis model (Journal of Immunology, 2009, 182) , P. 5836-5845), collagen arthritis model (Annual Review of Immunology, 1984, Volume 2, 199-218), spontaneous lupus erythematosus model (Nature, volume 404, p. 2000). .995-999), TNBS-induced colitis model (European Journal of Pharmacology, 2001, 431, p. 103-110), ankylosing spondylitis Dell (Arthritis Research & Therapy, 2012, 14, p. 253-265), experimental autoimmune uveitis model (Journal of Immunology, 2006, 36, p. 3071-3081), strong Dermatosis model (Journal of Investigative Dermatology, 1999, 112, p. 456-462), vasculitis model (The Journal of Clinical Investigation, 2002, 110, p. 955-963), pemphigus model (The Journal of Clinical Investigation, 2000, 105, p. 625-631), pemphigoid model (Expe imental Dermatology, 2012, Vol. 21, p. 901-905), Dermatomyositis model (American Journal of Pathology, 1985, Vol. 120, p. 323-325), spontaneous onset model of acne (European Journal of Europe) Dermatology, 2005, vol. 15, p. 459-464, vitiligo model (Pigment Cell & Melanoma Research, 2014, vol. 27, p. 1075-1085), or alopecia areata model (Journal of Investigative Dermatology, Vol. 2015, Volume 135, pp. 2530-2532). The experimental autoimmune encephalomyelitis model is common as a model of multiple sclerosis. In addition, the imiquimod-induced psoriasis model is common as a model of psoriasis.
　また、環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩がアレルギー性疾患の治療又は予防に有効であることは、病態モデルを用いて評価できる。病態モデルとしては、例えば、ジニトロフルオロベンゼン（以下、ＤＮＦＢ）誘発アレルギー性皮膚炎モデル（Ｐｈａｒｍａｃｏｌｏｇｉｃａｌ　Ｒｅｐｏｒｔｓ、２０１３年、第６５巻、ｐ．１２３７－１２４６）、オキサゾロン誘発アトピー性皮膚炎モデル（Ｊｏｕｒｎａｌ　ｏｆ　Ｉｎｖｅｓｔｉｇａｔｉｖｅ　Ｄｅｒｍａｔｏｌｏｇｙ、２０１４年、第１３４巻、ｐ．２１２２－２１３０）、卵白アルブミン誘発アレルギー性鼻炎モデル（Ｊｏｕｒｎａｌ　ｏｆ　Ａｎｉｍａｌ　Ｓｃｉｅｎｃｅ、２０１０年、第８１巻、ｐ．６９９－７０５）、ＩｇＥ誘発アレルギー性結膜炎モデル（Ｂｒｉｔｉｓｈ　Ｊｏｕｒｎａｌ　ｏｆ　Ｏｐｈｔｈａｌｍｏｌｏｇｙ、２０１２年、第９６巻、ｐ．１３３２－１３３６）、アレルギー性胃腸炎モデル（Ｇａｓｔｒｏｅｎｔｅｒｏｌｏｇｙ、１９９７年、第１１３巻、ｐ．１５６０－１５６９）、卵白アルブミン誘発喘息モデル（Ａｍｅｒｉｃａｎ　Ｊｏｕｒｎａｌ　ｏｆ　Ｒｅｓｐｉｒａｔｏｒｙ　ａｎｄ　Ｃｒｉｔｉｃａｌ　Ｃａｒｅ　Ｍｅｄｉｃｉｎｅ、１９９７年、第１５６巻、ｐ．７６６－７７５）、又は、卵白アルブミン誘発食物アレルギーモデル（Ｃｌｉｎｉｃａｌ　＆　Ｅｘｐｅｒｉｍｅｎｔａｌ　Ａｌｌｅｒｇｙ、２００５年、第３５巻、ｐ．４６１－４６６）が挙げられる。ＤＮＦＢ誘発アレルギー性皮膚炎モデルは、アレルギー性皮膚炎のモデルとして、特に接触性皮膚炎モデルとして一般的である。また、オキサゾロン誘発アトピー性皮膚炎モデルは、アトピー性皮膚炎のモデルとして一般的である。 In addition, that the cyclic amine derivative (I), its stereoisomer or hydrate thereof, or pharmacologically acceptable salts thereof is effective for treatment or prevention of allergic diseases is a pathological model. It can be evaluated using. As a pathological model, for example, dinitrofluorobenzene (hereinafter, DNFB) -induced allergic dermatitis model (Pharmacological Reports, 2013, 65, p. 1237-1246), oxazolone-induced atopic dermatitis model (Journal of Investigative) Dermatology, 2014, vol. 134, p. 2122-2130), ovalbumin-induced allergic rhinitis model (Journal of Animal Science, 2010, vol. 81, p. 699-705), IgE-induced allergic conjunctivitis model (vol. British Journal of Ophthalmology, 2012, Vol. 96, p. 1332-1336), allergic gastroenteritis Dell (Gastroenterology, 1997, 113, p. 1560-1569), ovalbumin-induced asthma model (American Journal of Respiratory and Critical Care Medicine, 1997, 156, p. 766-775), or egg white An albumin-induced food allergy model (Clinical & Experimental Allergy, 2005, 35, 461-466) can be mentioned. The DNFB-induced allergic dermatitis model is common as a model of allergic dermatitis, in particular as a contact dermatitis model. In addition, the oxazolone-induced atopic dermatitis model is common as a model of atopic dermatitis.
　環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩の自己免疫疾患又はアレルギー性疾患の治療又は予防に対する有効性は、上記のｉｎ　ｖｉｔｒｏ試験を用いて、例えば、ＲＯＲγのリガンド結合ドメインとコアクチベーターとの結合量の低下、又は、ＲＯＲγの機能の指標であるＩＬ－１７産生量の低下を指標に評価することができる。また、多発性硬化症の治療又は予防に対する有効性は、上記の実験的自己免疫性脳脊髄炎モデルを用いて、例えば、多発性硬化症の特徴的指標である神経症状スコアの低下を指標に評価することができる。また、乾癬の治療又は予防に対する有効性は、上記のイミキモド誘発乾癬モデルを用いて、例えば、乾癬モデルの症状進行に伴って増加する耳介等の皮膚の厚みの低下を指標に評価することができる。また、アレルギー性皮膚炎、特に接触性皮膚炎の治療又は予防に対する有効性は、上記のＤＮＦＢ誘発アレルギー性皮膚炎モデルを用いて、例えば、皮膚炎症状の進行に伴って増加する耳介等の皮膚の厚みの低下を指標に評価することができる。また、アトピー性皮膚炎の治療又は予防に対する有効性は、上記のオキサゾロン誘発アトピー性皮膚炎モデルを用いて、例えば、皮膚炎症状の進行に伴って増加する耳介等の皮膚の厚みの低下を指標に評価することができる。 The efficacy of the cyclic amine derivative (I), a stereoisomer thereof or a hydrate of these or a pharmacologically acceptable salt thereof for the treatment or prevention of autoimmune diseases or allergic diseases is For example, a decrease in the amount of binding between the ligand binding domain of RORγ and the coactivator, or a decrease in the amount of IL-17 production, which is an indicator of the function of RORγ, can be evaluated using in vitro tests. In addition, the efficacy for treatment or prevention of multiple sclerosis can be evaluated using, for example, a decrease in neurological symptom score, which is a characteristic index of multiple sclerosis, using the above-mentioned experimental autoimmune encephalomyelitis model. It can be evaluated. In addition, the efficacy for treatment or prevention of psoriasis may be evaluated using, for example, the reduction in thickness of skin such as auricle or the like, which increases with the progression of symptoms of the psoriasis model, using the imiquimod-induced psoriasis model described above as an indicator. it can. Moreover, the efficacy for treatment or prevention of allergic dermatitis, particularly contact dermatitis, is increased using, for example, the above-mentioned DNFB-induced allergic dermatitis model, such as the auricle, etc., along with the progress of skin inflammation. The decrease in skin thickness can be evaluated as an index. Moreover, the efficacy for the treatment or prevention of atopic dermatitis is, for example, using the above-mentioned oxazolone-induced atopic dermatitis model to decrease the thickness of the skin such as the auricle that increases with the progress of skin inflammation. It can be evaluated on indicators.
　環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩は、哺乳動物（例えば、マウス、ラット、ハムスター、ウサギ、イヌ、ネコ、サル、ウシ、ヒツジ又はヒト）、特にヒトに対して投与した場合に、有用な医薬（特に、自己免疫疾患又はアレルギー性疾患の治療剤又は予防剤）として用いることができる。環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩を医薬として臨床で使用する際には、環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩を、そのまま若しくは薬理学的に許容される担体を配合して、経口的又は非経口的に投与することができる。上記医薬は、必要に応じて、結合剤、賦形剤、滑沢剤、崩壊剤、甘味剤、安定化剤、矯味剤、香料、着色剤、流動化剤、保存剤、緩衝剤、溶解補助剤、乳化剤、界面活性剤、懸濁化剤、希釈剤又は等張化剤等の添加剤が適宜混合されていてもよい。薬理学的に許容される担体としては、これらの添加剤が挙げられる。また、上記の医薬は、これらの薬剤用担体を適宜用いて、通常の方法によって製造することができる。上記の医薬の投与形態としては、例えば、錠剤、カプセル剤、顆粒剤、散剤若しくはシロップ剤等による経口剤、吸入剤、注射剤、座剤若しくは液剤等による非経口剤又は局所投与をするための軟膏剤、クリーム剤若しくは貼付剤が挙げられる。また、公知の持続型製剤としても構わない。 The cyclic amine derivative (I), its stereoisomer or a hydrate thereof, or a pharmacologically acceptable salt thereof is a mammal (eg, mouse, rat, hamster, rabbit, dog, cat, monkey, etc.) Can be used as useful medicaments (especially, therapeutic or prophylactic agents for autoimmune diseases or allergic diseases) when administered to cattle, sheep or humans), particularly humans. When the cyclic amine derivative (I), its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof is used clinically as a medicament, the cyclic amine derivative (I), its steric structure The isomers or their hydrates, or their pharmacologically acceptable salts can be administered orally or parenterally, as they are or in combination with pharmacologically acceptable carriers. . The above-mentioned medicines, if necessary, binders, excipients, lubricants, disintegrants, sweeteners, stabilizers, flavoring agents, flavors, coloring agents, fluidizers, preservatives, buffers, solution aids Additives such as an agent, an emulsifying agent, a surfactant, a suspending agent, a diluent or an isotonic agent may be appropriately mixed. Pharmaceutically acceptable carriers include these additives. Also, the above-mentioned medicament can be manufactured by a usual method using appropriately these pharmaceutical carriers. The dosage form of the above-mentioned medicine includes, for example, oral preparations such as tablets, capsules, granules, powders or syrups, parenteral preparations such as inhalants, injections, suppositories or solutions, or topical administration. An ointment, a cream or a patch may be mentioned. Also, it may be a known sustained release preparation.
　結合剤としては、例えば、シロップ、ゼラチン、アラビアゴム、ソルビトール、ポリビニルクロリド又はトラガントが挙げられる。 Binders include, for example, syrup, gelatin, gum arabic, sorbitol, polyvinyl chloride or tragacanth.
　賦形剤としては、例えば、砂糖、乳糖、コーンスターチ、リン酸カルシウム、ソルビトール又はグリシンが挙げられる。 Excipients include, for example, sugar, lactose, corn starch, calcium phosphate, sorbitol or glycine.
　滑沢剤としては、例えば、ステアリン酸マグネシウム、ステアリン酸カルシウム、ポリエチレングリコール、タルク又はシリカが挙げられる。 As the lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, talc or silica can be mentioned.
　崩壊剤としては、例えば、でんぷん又は炭酸カルシウムが挙げられる。 Disintegrants include, for example, starch or calcium carbonate.
　甘味剤としては、例えば、ブドウ糖、果糖、転化糖、ソルビトール、キシリトール、グリセリン又は単シロップが挙げられる。 Sweetening agents include, for example, glucose, fructose, invert sugar, sorbitol, xylitol, glycerin or simple syrup.
　上記の医薬は、環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩を０．００００１～９０重量％含有することが好ましく、０．０１～７０重量％含有することがより好ましい。用量は、患者の症状、年齢及び体重、並びに投与方法に応じて適宜選択されるが、成人に対する有効成分量として、注射剤の場合は１日あたり０．１μｇ～１ｇ、経口剤の場合は１日あたり１μｇ～１０ｇ、貼付剤の場合は１日あたり１μｇ～１０ｇが好ましく、それぞれ１回又は数回に分けて投与することができる。 The above-mentioned medicament preferably contains 0.00001 to 90% by weight of cyclic amine derivative (I), its stereoisomer or hydrate thereof, or pharmacologically acceptable salt thereof, and 0 More preferably, the content is from 0.1 to 70% by weight. The dose is appropriately selected according to the patient's condition, age and body weight, and administration method, but as an active ingredient amount for adults, 0.1 μg to 1 g per day for injections and 1 for oral preparations The amount is preferably 1 μg to 10 g per day, and in the case of a patch, 1 μg to 10 g per day, each of which can be administered once or several times.
　上記の医薬は、その治療若しくは予防効果の補完又は増強あるいは投与量の低減のために、他の薬剤と適量配合又は併用して使用しても構わない。 The above-mentioned medicines may be used together with other medicines in appropriate amounts or in combination for complementation or enhancement of their therapeutic or preventive effects or reduction of dosage.
　以下の参考例及び実施例により本発明をさらに詳細に説明するが、本発明は、これらによって限定されるものではない。 The present invention will be described in more detail by the following reference examples and examples, but the present invention is not limited thereto.
　参考例及び実施例の化合物の合成に使用される化合物で合成法の記載のないものについては、市販の化合物を使用した。以下の参考例及び実施例中の「室温」は通常約１０℃～約３５℃を示す。％は、収率についてはｍｏｌ／ｍｏｌ％を、カラムクロマトグラフィー及び高速液体クロマトグラフィーで用いられる溶媒については体積％を、その他については特に断らない限り重量％を示す。ＮＭＲデータ中に示される溶媒名は、測定に使用した溶媒を示している。また、４００　ＭＨｚ　ＮＭＲスペクトルは、ＪＮＭ－ＡＬ４００型核磁気共鳴装置（日本電子社）又はＪＮＭ－ＥＣＳ４００型核磁気共鳴装置（日本電子社）を用いて測定した。ケミカルシフトは、テトラメチルシランを基準として、δ（単位：ｐｐｍ）で表し、シグナルはそれぞれｓ（一重線）、ｄ（二重線）、ｔ（三重線）、ｑ（四重線）、ｑｕｉｎｔ（五重線）、ｓｅｐｔ（七重線）、ｍ（多重線）、ｂｒ（幅広）、ｄｄ（二重二重線）、ｄｔ（二重三重線）、ｄｄｄ（二重二重二重線）、ｄｑ（二重四重線）、ｔｄ（三重二重線）、ｔｔ（三重三重線）で表した。水酸基やアミノ基等のプロトンが非常に緩やかなピークであった場合は記載していない。ＥＳＩ－ＭＳスペクトルは、Ａｇｉｌｅｎｔ　Ｔｅｃｈｎｏｌｏｇｉｅｓ　１２００　Ｓｅｒｉｅｓ、Ｇ６１３０Ａ（ＡｇｉｌｅｎｔＴｅｃｈｎｏｌｏｇｙ社）を用いて測定した。シリカゲルはシリカゲル６０（メルク社）を用い、アミンシリカゲルはアミンシリカゲルＤＭ１０２０（富士シリシア化学社）を用い、クロマトグラフィーはＹＦＬＣ　Ｗ－ｐｒｅｐ２ＸＹ（山善社）を用いた。 The compounds used for the synthesis of the compounds of Reference Examples and Examples were commercially available compounds that were not described in the synthesis method. The “room temperature” in the following Reference Examples and Examples usually indicates about 10 ° C. to about 35 ° C. % Indicates mol / mol% for yield, volume% for solvents used in column chromatography and high performance liquid chromatography, and weight% unless otherwise specified. The solvent name shown in the NMR data indicates the solvent used for the measurement. In addition, the 400 MHz NMR spectrum was measured using a JNM-AL400 nuclear magnetic resonance apparatus (Nippon Denshi Co., Ltd.) or a JNM-ECS400 nuclear magnetic resonance apparatus (Nippon Denshi Co., Ltd.). Chemical shifts are expressed in δ (unit: ppm) relative to tetramethylsilane, and signals are s (singlet), d (doublet), t (triplet), q (quadruple), quint respectively (Quaternion), sept (seven), m (multiple), br (wide), dd (double double), dt (double triple), ddd (double double) , Dq (double quadruple), td (triple doublet), tt (triple triple). When protons such as a hydroxyl group and an amino group are very mild peaks, they are not described. The ESI-MS spectrum was measured using Agilent Technologies 1200 Series, G6130A (Agilent Technologies). Silica gel used silica gel 60 (Merck), amine silica gel used amine silica gel DM 1020 (Fuji Silysia Chemical Ltd.), and chromatography used YFLC W-prep 2 XY (Yamazen Co.).
（参考例１）２－クロロ－４－ニトロベンズアルデヒドの合成：
Figure JPOXMLDOC01-appb-C000018
 　２－クロロ－４－ニトロ安息香酸（１０．０ｇ，４９．６ｍｍｏｌ）をＴＨＦ（９９．２ｍＬ）に溶解し、ボランＴＨＦ錯体－ＴＨＦ溶液（０．９５Ｍ，６２．７ｍＬ，５９．５ｍｍｏｌ）を０℃で加え、室温に昇温した。５０℃で２時間撹拌した後、反応液を１Ｍ塩酸に加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物をクロロホルム（９９．２ｍＬ）に溶解し、二酸化マンガン（３２．３ｇ，３７２ｍｍｏｌ）を室温で加えた。５０℃で２４時間撹拌した後、反応液を濾過し、濾液を減圧濃縮し、表題化合物（以下、参考例１の化合物）（８．３７ｇ，４５．１ｍｍｏｌ，９１％）を淡黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：８．１１（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），８．２３（ｄｄ，Ｊ＝８．２，１．８Ｈｚ，１Ｈ），８．３６（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），１０．５５（ｓ，１Ｈ）． (Reference Example 1) Synthesis of 2-chloro-4-nitrobenzaldehyde:
Figure JPOXMLDOC01-appb-C000018
 Dissolve 2-chloro-4-nitrobenzoic acid (10.0 g, 49.6 mmol) in THF (99.2 mL), add borane THF complex-THF solution (0.95 M, 62.7 mL, 59.5 mmol) to 0. Add at ° C and warm to room temperature. After stirring for 2 hours at 50 ° C., the reaction solution was added to 1 M hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product was dissolved in chloroform (99.2 mL) and manganese dioxide (32.3 g, 372 mmol) was added at room temperature. After stirring at 50 ° C. for 24 hours, the reaction solution is filtered, and the filtrate is concentrated under reduced pressure to give the title compound (hereinafter, the compound of Reference Example 1) (8.37 g, 45.1 mmol, 91%) as a pale yellow solid. The
1 H-NMR (400 MHz, CDCl 3 ) δ: 8.11 (d, J = 8.2 Hz, 1 H), 8.23 (dd, J = 8.2, 1.8 Hz, 1 H), 8.36 ( d, J = 1.8 Hz, 1 H), 10. 55 (s, 1 H).
（参考例２）２－（２－クロロ－４－ニトロベンジル）－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000019
 　参考例１の化合物（０．１５０ｇ，０．８０８ｍｍｏｌ）をジクロロメタン（８．０８ｍＬ）に溶解し、１，２，３，４－テトラヒドロイソキノリン塩酸塩（０．１３７ｇ，０．８０８ｍｍｏｌ）及び水素化トリアセトキシホウ素ナトリウム（０．３９３ｇ，１．８６ｍｍｏｌ）を０℃で加えた。室温で１時間撹拌した後、反応液に蒸留水を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９０／１０）で精製し、表題化合物（以下、参考例２の化合物）（０．１４７ｇ，０．４８６ｍｍｏｌ，６０％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８３（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），２．９５（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．７３（ｓ，２Ｈ），３．８６（ｓ，２Ｈ），７．００（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），７．１５－７．１７（ｍ，３Ｈ），７．８３（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），８．１１（ｄｄ，Ｊ＝８．４，２．０Ｈｚ，１Ｈ），８．２５（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３０３（Ｍ＋Ｈ）＋． Reference Example 2 Synthesis of 2- (2-chloro-4-nitrobenzyl) -1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000019
 The compound of Reference Example 1 (0.150 g, 0.808 mmol) is dissolved in dichloromethane (8.08 mL), and 1,2,3,4-tetrahydroisoquinoline hydrochloride (0.137 g, 0.808 mmol) and hydrogenated tri Sodium acetoxyborohydride (0.393 g, 1.86 mmol) was added at 0 ° C. After stirring at room temperature for 1 hour, distilled water was added to the reaction solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10) to give the title compound (hereinafter, the compound of Reference Example 2) (0.147 g, 0.486 mmol, 60%) as colorless. Obtained as an oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.83 (t, J = 5.9 Hz, 2 H), 2.95 (t, J = 5.7 Hz, 2 H), 3.73 (s, 2 H) , 3.86 (s, 2 H), 7.00 (d, J = 6.8 Hz, 1 H), 7.15 to 7.17 (m, 3 H), 7.83 (d, J = 8.2 Hz, 1 H), 8.11 (dd, J = 8.4, 2.0 Hz, 1 H), 8. 25 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 303 (M + H) + .
（参考例３）（Ｒ）－２－（（３－クロロ－４－（（３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000020
 　参考例２の化合物（０．１４６ｇ，０．４８２ｍｍｏｌ）をＴＨＦ（２．４１ｍＬ）に溶解し、エタノール（２．４１ｍＬ）、蒸留水（２．４１ｍＬ）、鉄粉（０．１０８ｇ，１．９３ｍｍｏｌ）及び酢酸（０．２７６ｍＬ，４．８２ｍｍｏｌ）を室温で加えた。７０℃で３時間撹拌した後、反応液を濾過し、濾液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物をＤＭＦ（３．６７ｍＬ）に溶解し、ＨＡＴＵ（０．２０９ｇ，０．５５０ｍｍｏｌ）、（Ｒ）－Ｎ－Ｂｏｃ－ピペコリン酸（０．１０９ｇ，０．４７７ｍｍｏｌ）及びトリエチルアミン（０．１０２ｍＬ，０．７３３ｍｍｏｌ）を室温で加えた。同温度で１５時間撹拌した後、反応液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝７０／３０～５０／５０）で精製し、表題化合物（以下、参考例３の化合物）（０．１３６ｇ，０．２８１ｍｍｏｌ，５８％）を褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４８－１．５１（ｍ，３Ｈ），１．５２（ｓ，９Ｈ），１．６５－１．７０（ｍ，３Ｈ），２．２９－２．３１（ｍ，１Ｈ），２．７８－２．８７（ｍ，５Ｈ），３．６９（ｓ，２Ｈ），３．７５（ｓ，２Ｈ），４．０９－４．１１（ｍ，１Ｈ），４．８５（ｓ，１Ｈ），６．９９（ｄｄ，Ｊ＝７．５，２．０Ｈｚ，１Ｈ），７．１０（ｍ，２Ｈ），７．２５－７．２８（ｍ，２Ｈ），７．４９（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．７２（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）． Reference Example 3 (R) -2-((3-Chloro-4-((3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Composition of:
Figure JPOXMLDOC01-appb-C000020
 The compound of Reference Example 2 (0.146 g, 0.482 mmol) is dissolved in THF (2.41 mL), ethanol (2.41 mL), distilled water (2.41 mL), iron powder (0.108 g, 1.93 mmol) ) And acetic acid (0.276 mL, 4.82 mmol) were added at room temperature. After stirring at 70 ° C. for 3 hours, the reaction mixture was filtered, and to the filtrate was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product is dissolved in DMF (3.67 mL), HATU (0.209 g, 0.550 mmol), (R) -N-Boc-pipecolic acid (0.109 g, 0.477 mmol) and triethylamine (0) .102 mL, 0.733 mmol) was added at room temperature. After stirring for 15 hours at the same temperature, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 70/30 to 50/50) to give the title compound (hereinafter referred to as the compound of Reference Example 3) (0.136 g, 0.281 mmol, 58) %) As a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48-1.51 (m, 3 H), 1.52 (s, 9 H), 1.65-1.70 (m, 3 H), 2.29 -2.31 (m, 1 H), 2.78-2.87 (m, 5 H), 3.69 (s, 2 H), 3.75 (s, 2 H), 4.09-4.11 (m , 1 H), 4.85 (s, 1 H), 6.99 (dd, J = 7.5, 2.0 Hz, 1 H), 7.10 (m, 2 H), 7.25-7.28 (m , 2H), 7.49 (d, J = 8.2 Hz, 1 H), 7.72 (d, J = 2.3 Hz, 1 H).
（実施例１）（Ｒ）－Ｎ－（３－クロロ－４－（（３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）－１－（メチルスルホニル）ピペリジン－２－カルボキサミド　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000021
 　参考例３の化合物（０．１００ｇ，０．２０７ｍｍｏｌ）をジクロロメタン（２．０７ｍＬ）に溶解し、トリフルオロ酢酸（０．２３９ｍＬ，３．１０ｍｍｏｌ）を０℃で加えた。室温で１時間撹拌した後、反応液を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物をジクロロメタン（２．０６ｍＬ）に溶解し、トリエチルアミン（０．１４４ｍＬ，１．０３ｍｍｏｌ）及びメタンスルホニルクロリド（０．０２４２ｍＬ，０．３１０ｍｍｏｌ）を０℃で加えた。室温で１２時間撹拌した後、反応液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝３０／７０）で精製した。得られた精製物をジエチルエーテル（２．０ｍＬ）に溶解し、４Ｍ塩化水素－ジエチルエーテル溶液（１．０ｍＬ）を室温で加えた。析出した固体を濾取、乾燥し、表題化合物（以下、実施例１の化合物）（０．０３５０ｇ，０．０７０２ｍｍｏｌ，３４％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ３ＯＤ）δ：１．４７－１．６１（ｍ，２Ｈ），１．７０－１．８０（ｍ，２Ｈ），１．８７－１．９６（ｍ，１Ｈ），２．１８（ｄ，Ｊ＝１４．２Ｈｚ，１Ｈ），２．９４（ｓ，３Ｈ），３．２０（ｔ，Ｊ＝６．２Ｈｚ，２Ｈ），３．５９－３．７０（ｍ，４Ｈ），４．４５（ｄ，Ｊ＝６．９Ｈｚ，２Ｈ），４．５８（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），４．６７（ｄｄ，Ｊ＝５．９，２．３Ｈｚ，１Ｈ），７．１８（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．２４－７．３３（ｍ，３Ｈ），７．６２（ｓ，２Ｈ），７．９９（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４６２（Ｍ＋Ｈ）＋． Example 1 (R) -N- (3-Chloro-4-((3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) -1- (methylsulfonyl) piperidine-2-carboxamide Hydrochloride Synthesis:
Figure JPOXMLDOC01-appb-C000021
 The compound of Reference Example 3 (0.100 g, 0.207 mmol) was dissolved in dichloromethane (2.07 mL), and trifluoroacetic acid (0.239 mL, 3.10 mmol) was added at 0 ° C. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product was dissolved in dichloromethane (2.06 mL) and triethylamine (0.144 mL, 1.03 mmol) and methanesulfonyl chloride (0.0242 mL, 0.310 mmol) were added at 0 ° C. After stirring at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 30/70). The purified product obtained was dissolved in diethyl ether (2.0 mL), and 4 M hydrogen chloride-diethyl ether solution (1.0 mL) was added at room temperature. The precipitated solid was collected by filtration and dried to give the title compound (hereinafter, the compound of Example 1) (0.0350 g, 0.0702 mmol, 34%) as a white solid.
1 H-NMR (400 MHz, CD 3 OD) δ: 1.47-1.61 (m, 2 H), 1.70-1.80 (m, 2 H), 1.87-1. 96 (m, 1 H) ), 2.18 (d, J = 14.2 Hz, 1 H), 2.94 (s, 3 H), 3.20 (t, J = 6.2 Hz, 2 H), 3.59-3. 70 (m , 4H), 4.45 (d, J = 6.9 Hz, 2 H), 4.58 (d, J = 8.2 Hz, 2 H), 4.67 (dd, J = 5.9, 2.3 Hz, 1H), 7.18 (d, J = 7.8 Hz, 1H), 7.24-7.33 (m, 3H), 7.62 (s, 2H), 7.99 (s, 1H).
ESI-MS: m / z = 462 (M + H) <+> .
（参考例４）２，２，２－トリフルオロ－Ｎ－（４－メチルフェネチル）アセトアミドの合成：
Figure JPOXMLDOC01-appb-C000022
 　２－（４－メチルフェニル）エチルアミン（０．５３２ｍＬ，３．７０ｍｍｏｌ）をジクロロメタン（１２．３ｍＬ）に溶解し、トリフルオロ酢酸無水物（０．５７５ｍＬ，４．０７ｍｍｏｌ）を０℃で加えた。室温で２時間撹拌した後、反応液を減圧濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９５／５～８５／１５）で精製し、表題化合物（以下、参考例４の化合物）（０．５２５ｇ，２．２７ｍｍｏｌ，６１％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．３４（ｓ，３Ｈ），２．８５（ｔ，Ｊ＝６．９Ｈｚ，２Ｈ），３．６０（ｑ，Ｊ＝６．６Ｈｚ，２Ｈ），６．２８（ｂｒｓ，１Ｈ），７．０８（ｄ，Ｊ＝８，２Ｈｚ，２Ｈ），７．１５（ｄ，Ｊ＝７．８Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２３２（Ｍ＋Ｈ）＋． Reference Example 4 Synthesis of 2,2,2-trifluoro-N- (4-methylphenethyl) acetamide:
Figure JPOXMLDOC01-appb-C000022
 2- (4-Methylphenyl) ethylamine (0.532 mL, 3.70 mmol) was dissolved in dichloromethane (12.3 mL) and trifluoroacetic anhydride (0.575 mL, 4.07 mmol) was added at 0.degree. After stirring at room temperature for 2 hours, the reaction solution is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 85/15) to give the title compound The compound of Reference Example 4 (0.525 g, 2.27 mmol, 61%) was obtained as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.34 (s, 3 H), 2.85 (t, J = 6.9 Hz, 2 H), 3. 60 (q, J = 6.6 Hz, 2 H) , 6.28 (brs, 1 H), 7.08 (d, J = 8, 2 Hz, 2 H), 7.15 (d, J = 7.8 Hz, 2 H).
ESI-MS: m / z = 232 (M + H) + .
（参考例５）２，２，２－トリフルオロ－１－（７－メチル－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）エタン－１－オンの合成：
Figure JPOXMLDOC01-appb-C000023
 　濃硫酸（０．４５４ｍＬ）及び酢酸（２．２７ｍＬ）の混合液に、参考例４の化合物（０．５２５ｇ，２．２７ｍｍｏｌ）及びパラホルムアルデヒド（０．１０２ｇ，３．４１ｍｍｏｌ）を０℃で加えた。室温で３６時間撹拌した後、反応液を氷水に加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、蒸留水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９５／５～８０／２０）で精製し、表題化合物（以下、参考例５の化合物）（０．３３５ｇ，１．３８ｍｍｏｌ，６１％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．３３（ｓ，３Ｈ），２．９１（ｑ，Ｊ＝５．８Ｈｚ，２Ｈ），３．８３（ｔ，Ｊ＝５．９Ｈｚ，１．３Ｈ），３．８７（ｔ，Ｊ＝６．２Ｈｚ，０．７Ｈ），４．７１（ｓ，０．７Ｈ），４．７６（ｓ，１．３Ｈ），６．９５（ｄ，Ｊ＝１１．９Ｈｚ，１Ｈ），７．０６（ｄ，Ｊ＝１０．１Ｈｚ，２Ｈ）． Reference Example 5 Synthesis of 2,2,2-trifluoro-1- (7-methyl-3,4-dihydroisoquinolin-2 (1H) -yl) ethan-1-one:
Figure JPOXMLDOC01-appb-C000023
 The compound of Reference Example 4 (0.525 g, 2.27 mmol) and paraformaldehyde (0.102 g, 3.41 mmol) were added to a mixture of concentrated sulfuric acid (0.454 mL) and acetic acid (2.27 mL) at 0 ° C. The After stirring at room temperature for 36 hours, the reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, distilled water and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95 / 5-80 / 20) to give the title compound (hereinafter, the compound of Reference Example 5) (0.335 g, 1.38 mmol, 61) %) As a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.33 (s, 3 H), 2.91 (q, J = 5.8 Hz, 2 H), 3.83 (t, J = 5.9 Hz, 1. 3H), 3.87 (t, J = 6.2 Hz, 0.7 H), 4.71 (s, 0.7 H), 4.76 (s, 1.3 H), 6.95 (d, J = 11.9 Hz, 1 H), 7.06 (d, J = 10.1 Hz, 2 H).
（参考例６）７－メチル－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000024
 　参考例５の化合物（０．３３５ｇ，１．３８ｍｍｏｌ）をエタノール（４．１７ｍＬ）に溶解し、２Ｍ水酸化ナトリウム水溶液（３．７９ｍＬ）を０℃で加えた。室温で２時間撹拌した後、反応液を減圧濃縮し、蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮し、表題化合物（以下、参考例６の化合物）（０．１８５ｇ，１．２６ｍｍｏｌ，９１％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．２９（ｓ，３Ｈ），２．７５（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．１２（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），３．９８（ｓ，２Ｈ），６．８３（ｓ，１Ｈ），６．９５（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ），６．９９（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝１４８（Ｍ＋Ｈ）＋． Reference Example 6 Synthesis of 7-methyl-1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000024
 The compound of Reference Example 5 (0.335 g, 1.38 mmol) was dissolved in ethanol (4.17 mL), and 2 M aqueous sodium hydroxide solution (3.79 mL) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (hereinafter referred to as the compound of Reference Example 6) (0.185 g, 1.26 mmol, 91%) Obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.29 (s, 3 H), 2.75 (t, J = 5.7 Hz, 2 H), 3. 12 (t, J = 5.9 Hz, 2 H) , 3.98 (s, 2H), 6.83 (s, 1 H), 6.95 (d, J = 7.3 Hz, 1 H), 6.99 (d, J = 7.8 Hz, 1 H).
ESI-MS: m / z = 148 (M + H) + .
（参考例７）２－（２－クロロ－４－ニトロベンジル）－７－メチル－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000025
 　参考例６の化合物（０．１８４ｇ，１．２５ｍｍｏｌ）をジクロロメタン（３．７５ｍＬ）に溶解し、参考例１の化合物（０．２３０ｇ，１．２５ｍｍｏｌ）及び酢酸（０．０３５４ｍＬ）を室温で加えた。室温で１０分間撹拌した後、水素化トリアセトキシホウ素ナトリウム（０．３９３ｇ，１．８６ｍｍｏｌ）を０℃で加えた。室温で２時間撹拌した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９５／５～８５／１５）で精製し、表題化合物（以下、参考例７の化合物）（０．３４９ｇ，１．０１ｍｍｏｌ，８９％）を黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．２９（ｓ，３Ｈ），２．８１（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），２．９１（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．６９（ｓ，２Ｈ），３．８５（ｓ，２Ｈ），６．８３（ｓ，１Ｈ），６．９８（ｄ，Ｊ＝７．７Ｈｚ，１Ｈ），７．０４（ｄ，Ｊ＝７．７Ｈｚ，１Ｈ），７．８４（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），８．１１（ｄｄ，Ｊ＝８．６，２．３Ｈｚ，１Ｈ），８．２６（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３１７（Ｍ＋Ｈ）＋． Reference Example 7 Synthesis of 2- (2-chloro-4-nitrobenzyl) -7-methyl-1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000025
 The compound of Reference Example 6 (0.184 g, 1.25 mmol) is dissolved in dichloromethane (3.75 mL), and the compound of Reference Example 1 (0.230 g, 1.25 mmol) and acetic acid (0.0354 mL) are added at room temperature. The After stirring for 10 minutes at room temperature, sodium triacetoxyborohydride (0.393 g, 1.86 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 85/15) to give the title compound (hereinafter referred to as the compound of Reference Example 7) (0.349 g, 1.01 mmol, 89) %) As a yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.29 (s, 3 H), 2.81 (t, J = 5.9 Hz, 2 H), 2.91 (t, J = 5.7 Hz, 2 H) , 3.69 (s, 2H), 3.85 (s, 2H), 6.83 (s, 1H), 6.98 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.7 Hz, 1 H), 7.84 (d, J = 8.6 Hz, 1 H), 8.11 (dd, J = 8.6, 2.3 Hz, 1 H), 8. 26 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 317 (M + H) + .
（参考例８）３－クロロ－４－（（７－メチル－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000026
 　参考例７の化合物（０．３３５ｇ，１．０６ｍｍｏｌ）をＴＨＦ（１．０６ｍＬ）に溶解し、エタノール（１．０６ｍＬ）、蒸留水（１．０６ｍＬ）、鉄粉（０．２９５ｇ，５．２９ｍｍｏｌ）及び酢酸（０．３０３ｍＬ，５．２９ｍｍｏｌ）を室温で加えた。５０℃で２時間撹拌した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝８０／２０～６５／３５）で精製し、表題化合物（以下、参考例８の化合物）（０．２７１ｇ，０．９４５ｍｍｏｌ，８９％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．２７（ｓ，３Ｈ），２．７６（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），２．８５（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．６３（ｓ，２Ｈ），３．６８（ｓ，４Ｈ），６．５６（ｄｄ，Ｊ＝８．４，２．５Ｈｚ，１Ｈ），６．７１（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），６．８２（ｓ，１Ｈ），６．９３（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），６．９９（ｄ，Ｊ＝７．２Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２８７（Ｍ＋Ｈ）＋． Reference Example 8 Synthesis of 3-chloro-4-((7-methyl-3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline:
Figure JPOXMLDOC01-appb-C000026
 The compound of Reference Example 7 (0.335 g, 1.06 mmol) is dissolved in THF (1.06 mL), ethanol (1.06 mL), distilled water (1.06 mL), iron powder (0.295 g, 5.29 mmol) ) And acetic acid (0.303 mL, 5.29 mmol) were added at room temperature. After stirring at 50 ° C. for 2 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 65/35) to give the title compound (hereinafter, the compound of Reference Example 8) (0.271 g, 0.945 mmol, 89) %) As a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.27 (s, 3 H), 2.76 (t, J = 5.7 Hz, 2 H), 2.85 (t, J = 5.7 Hz, 2 H) , 3.63 (s, 2H), 3.68 (s, 4H), 6.56 (dd, J = 8.4, 2.5 Hz, 1 H), 6.71 (d, J = 2.3 Hz, 1H), 6.82 (s, 1 H), 6.93 (d, J = 8.2 Hz, 1 H), 6.99 (d, J = 7.2 Hz, 1 H), 7.28 (d, J = 8.6 Hz, 1 H).
ESI-MS: m / z = 287 (M + H) <+> .
（参考例９）（Ｒ）－２－（（３－クロロ－４－（（７－メチル－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000027
 　参考例８の化合物（０．０４００ｇ，０．１３９ｍｍｏｌ）及び（Ｒ）－Ｎ－Ｂｏｃ－ピペコリン酸（０．０３８４ｇ，０．１６７ｍｍｏｌ）をＤＭＦ（０．４６５ｍＬ）に溶解し、ＨＡＴＵ（０．０６３６ｇ，０．１６７ｍｍｏｌ）及びジイソプロピルエチルアミン（０．０３６５ｍＬ，０．２０９ｍｍｏｌ）を室温で加えた。同温度で１９時間撹拌した後、反応液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝８５／１５～７５／２５）で精製し、表題化合物（以下、参考例９の化合物）（０．０５５１ｇ，０．１１１ｍｍｏｌ，７９％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４７－１．７１（ｍ，１５Ｈ），２．２８（ｓ，３Ｈ），２．３３（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），２．７５－２．８７（ｍ，５Ｈ），３．６５（ｓ，２Ｈ），３．７４（ｓ，２Ｈ），４．０７（ｂｒｓ，１Ｈ），４．８５（ｓ，１Ｈ），６．８２（ｓ，１Ｈ），６．９４（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．００（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．２７（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．４９（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．７２（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４９８（Ｍ＋Ｈ）＋． Reference Example 9 (R) -2-((3-Chloro-4-((7-methyl-3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) carbamoyl) piperidine-1-carbon Synthesis of acid tert-butyl:
Figure JPOXMLDOC01-appb-C000027
 The compound of Reference Example 8 (0.0400 g, 0.139 mmol) and (R) -N-Boc-pipecolic acid (0.0384 g, 0.167 mmol) were dissolved in DMF (0.465 mL), and HATU (0.0636 g) , 0.167 mmol) and diisopropylethylamine (0.0365 mL, 0.209 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 mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 85/15 to 75/25) to give the title compound (hereinafter referred to as the compound of Reference Example 9) (0.0551 g, 0.111 mmol, 79) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.71 (m, 15 H), 2.28 (s, 3 H), 2. 33 (d, J = 13.7 Hz, 1 H), 2 .75-2.87 (m, 5 H), 3.65 (s, 2 H), 3.74 (s, 2 H), 4.07 (brs, 1 H), 4.85 (s, 1 H), 6. 82 (s, 1 H), 6.94 (d, J = 7.8 Hz, 1 H), 7.00 (d, J = 7.8 Hz, 1 H), 7.27 (dd, J = 8 2, 2 3 Hz, 1 H), 7.49 (d, J = 8.2 Hz, 1 H), 7.72 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 498 (M + H) + .
（実施例２）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（（７－メチル－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000028
 　参考例９の化合物（０．０５５０ｇ，０．１１０ｍｍｏｌ）をジクロロメタン（０．５５２ｍＬ）に溶解し、トリフルオロ酢酸（０．１２８ｍＬ，１．６６ｍｍｏｌ）を０℃で加えた。室温で１時間撹拌した後、反応液を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物をジクロロメタン（０．５５２ｍＬ）に溶解し、トリエチルアミン（０．０７７０ｍＬ，０．５５２ｍｍｏｌ）及び無水酢酸（０．０１５３ｍＬ，０．１６６ｍｍｏｌ）を０℃で加えた。室温で１時間撹拌した後、反応液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝３０／７０～１０／９０）で精製し、表題化合物（以下、実施例２の化合物）（０．０４２１ｇ，０．０９５７ｍｍｏｌ，８７％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４９－１．６０（ｍ，２Ｈ），１．７１－１．７９（ｍ，２Ｈ），１．９０－１．９８（ｍ，１Ｈ），２．２１（ｓ，３Ｈ），２．２７（ｓ，３Ｈ），２．２８（ｄ，Ｊ＝９．１Ｈｚ，１Ｈ），２．７６（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），２．８５（ｔ，Ｊ＝５．５Ｈｚ，２Ｈ），３．１５（ｔｄ，Ｊ＝１３．３，２．７Ｈｚ，１Ｈ），３．６４（ｓ，２Ｈ），３．７３（ｓ，２Ｈ），３．７７（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），５．２６（ｄ，Ｊ＝５．５Ｈｚ，１Ｈ），６．８１（ｓ，１Ｈ），６．９４（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．００（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．２８（ｄｄ，Ｊ＝８．９，２．５Ｈｚ，１Ｈ），７．４７（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．７０（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．４１（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４４０（Ｍ＋Ｈ）＋． Example 2 (R) -1-Acetyl-N- (3-chloro-4-((7-methyl-3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) piperidine-2- Carboxamide Synthesis:
Figure JPOXMLDOC01-appb-C000028
 The compound of Reference Example 9 (0.0550 g, 0.110 mmol) was dissolved in dichloromethane (0.552 mL), and trifluoroacetic acid (0.128 mL, 1.66 mmol) was added at 0 ° C. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product was dissolved in dichloromethane (0.552 mL) and triethylamine (0.0770 mL, 0.552 mmol) and acetic anhydride (0.0153 mL, 0.166 mmol) were added at 0 ° C. After stirring at room temperature for 1 hour, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 30/70 to 10/90) to give the title compound (compound of Example 2 below) (0.0421 g, 0.0957 mmol, 87) %) As a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49 to 1.60 (m, 2 H), 1.71 to 1. 79 (m, 2 H), 1.90 to 1. 98 (m, 1 H) , 2.21 (s, 3 H), 2. 27 (s, 3 H), 2. 28 (d, J = 9.1 Hz, 1 H), 2.76 (t, J = 5.7 Hz, 2 H), 2 .85 (t, J = 5.5 Hz, 2 H), 3. 15 (td, J = 13.3, 2.7 Hz, 1 H), 3.64 (s, 2 H), 3.73 (s, 2 H) , 3.77 (d, J = 13.7 Hz, 1 H), 5.26 (d, J = 5.5 Hz, 1 H), 6.81 (s, 1 H), 6.94 (d, J = 7. 6). 8 Hz, 1 H), 7.00 (d, J = 7.8 Hz, 1 H), 7. 28 (dd, J = 8.9, 2.5 Hz, 1 H), 7.47 (d, J = 8.7 Hz , 1H), 7.70 ( , J = 2.3Hz, 1H), 8.41 (brs, 1H).
ESI-MS: m / z = 440 (M + H) + .
（参考例１０）Ｎ－（４－クロロフェネチル）－２，２，２－トリフルオロアセトアミドの合成：
Figure JPOXMLDOC01-appb-C000029
 　２－（４－メチルフェニル）エチルアミンの代わりに２－（４－クロロフェニル）エチルアミンを用いて、それ以外は参考例４と同様の手順により、表題化合物（以下、参考例１０の化合物）（０．４１０ｇ，１．６３ｍｍｏｌ，５１％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８７（ｔ，Ｊ＝７．１Ｈｚ，２Ｈ），３．６１（ｑ，Ｊ＝６．７Ｈｚ，２Ｈ），６．２９（ｂｒｓ，１Ｈ），７．１３（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．３１（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２５２（Ｍ＋Ｈ）＋． Reference Example 10 Synthesis of N- (4-chlorophenethyl) -2,2,2-trifluoroacetamide:
Figure JPOXMLDOC01-appb-C000029
 Using 2- (4-chlorophenyl) ethylamine instead of 2- (4-methylphenyl) ethylamine and following the same procedure as in Reference Example 4 except for the above, to obtain the title compound (hereinafter referred to as the compound of Reference Example 10) (0. 1). 410 g, 1.63 mmol, 51%) were obtained as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.87 (t, J = 7.1 Hz, 2 H), 3.61 (q, J = 6.7 Hz, 2 H), 6.29 (brs, 1 H) , 7.13 (d, J = 8.2 Hz, 2 H), 7.31 (d, J = 8.2 Hz, 2 H).
ESI-MS: m / z = 252 (M + H) + .
（参考例１１）１－（７－クロロ－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）－２，２，２－トリフルオロエタン－１－オンの合成：
Figure JPOXMLDOC01-appb-C000030
 　参考例４の化合物の代わりに参考例１０の化合物を用いて、それ以外は参考例５と同様の手順により、表題化合物（以下、参考例１１の化合物）（０．３１１ｇ，１．１８ｍｍｏｌ，７２％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．９３（ｑ，Ｊ＝６．０Ｈｚ，２Ｈ），３．８４（ｔ，Ｊ＝５．７Ｈｚ，１．３Ｈ），３．８９（ｔ，Ｊ＝６．１Ｈｚ，０．７Ｈ），４．７１（ｓ，０．７Ｈ），４．７７（ｓ，１．３Ｈ），７．０９－７．２３（ｍ，３Ｈ）． Reference Example 11 Synthesis of 1- (7-chloro-3,4-dihydroisoquinolin-2 (1H) -yl) -2,2,2-trifluoroethan-1-one:
Figure JPOXMLDOC01-appb-C000030
 Using the compound of Reference Example 10 in place of the compound of Reference Example 4 and using the same procedure as in Reference Example 5 except the above, the title compound (compound of Reference Example 11 below) (0.311 g, 1.18 mmol, 72 %) As a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.93 (q, J = 6.0 Hz, 2 H), 3.84 (t, J = 5.7 Hz, 1.3 H), 3.89 (t, J = 6.1 Hz, 0.7 H), 4.71 (s, 0.7 H), 4.77 (s, 1.3 H), 7.09-7.23 (m, 3 H).
（参考例１２）７－クロロ－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000031
 　参考例５の化合物の代わりに参考例１１の化合物を用いて、それ以外は参考例６と同様の手順により、表題化合物（以下、参考例１２の化合物）（０．１９２ｇ，１．１５ｍｍｏｌ，９７％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．７５（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），３．１２（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），３．９８（ｓ，２Ｈ），７．００（ｓ，１Ｈ），７．０２（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．１０（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝１６８（Ｍ＋Ｈ）＋． Reference Example 12 Synthesis of 7-chloro-1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000031
 Using the compound of Reference Example 11 instead of the compound of Reference Example 5, and according to the same procedure as Reference Example 6 except the above, the title compound (hereinafter, the compound of Reference Example 12) (0.192 g, 1.15 mmol, 97 %) As a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.75 (t, J = 5.9 Hz, 2 H), 3. 12 (t, J = 5.9 Hz, 2 H), 3.98 (s, 2 H) , 7.00 (s, 1 H), 7.02 (d, J = 8.2 Hz, 1 H), 7. 10 (dd, J = 8.2, 2.3 Hz, 1 H).
ESI-MS: m / z = 168 (M + H) + .
（参考例１３）７－クロロ－２－（２－クロロ－４－ニトロベンジル）－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000032
 　参考例６の化合物の代わりに参考例１２の化合物を用いて、それ以外は参考例７と同様の手順により、表題化合物（以下、参考例１３の化合物）（０．３４２ｇ，１．０１ｍｍｏｌ，８９％）を黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８１（ｔ，Ｊ＝５．５Ｈｚ，２Ｈ），２．９０（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．６９（ｓ，２Ｈ），３．８６（ｓ，２Ｈ），７．００（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），７．０６（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．１３（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．８０（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），８．１２（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ）８．２７（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３３７（Ｍ＋Ｈ）＋． Reference Example 13 Synthesis of 7-chloro-2- (2-chloro-4-nitrobenzyl) -1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000032
 Using the compound of Reference Example 12 instead of the compound of Reference Example 6, and using the same procedure as Reference Example 7 except for this, the title compound (hereinafter, the compound of Reference Example 13) (0.342 g, 1.01 mmol, 89 %) As a yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.81 (t, J = 5.5 Hz, 2 H), 2.90 (t, J = 5.7 Hz, 2 H), 3.69 (s, 2 H) , 3.86 (s, 2 H), 7.00 (d, J = 2.3 Hz, 1 H), 7.06 (d, J = 8.2 Hz, 1 H), 7.13 (dd, J = 8). 2, 2.3 Hz, 1 H), 7. 80 (d, J = 8.7 Hz, 1 H), 8. 12 (dd, J = 8.2, 2.3 Hz, 1 H) 8. 27 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 337 (M + H) + .
（参考例１４）３－クロロ－４－（（７－クロロ－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000033
 　参考例７の化合物の代わりに参考例１３の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例１４の化合物）（０．２７０ｇ，０．８７９ｍｍｏｌ，８７％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．７６（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），２．８４（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．６３（ｓ，２Ｈ），３．６８（ｓ，２Ｈ），３．７０（ｓ，２Ｈ），６．５７（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），６．９９（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），７．０１（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．０８（ｄｄ，Ｊ＝８．２，１．８Ｈｚ，１Ｈ），７．２４（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３０７（Ｍ＋Ｈ）＋． Reference Example 14 Synthesis of 3-chloro-4-((7-chloro-3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline:
Figure JPOXMLDOC01-appb-C000033
 Using the compound of Reference Example 13 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 14) (0.270 g, 0.879 mmol, 87) %) As a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.76 (t, J = 5.9 Hz, 2 H), 2. 84 (t, J = 5.7 Hz, 2 H), 3.63 (s, 2 H) , 3.68 (s, 2H), 3.70 (s, 2H), 6.57 (dd, J = 8.2, 2.3 Hz, 1 H), 6.72 (d, J = 2.3 Hz, 1H), 6.99 (d, J = 2.3 Hz, 1 H), 7.01 (d, J = 8.2 Hz, 1 H), 7.08 (dd, J = 8.2, 1.8 Hz, 1 H) ), 7.24 (d, J = 8.2 Hz, 1 H).
ESI-MS: m / z = 307 (M + H) + .
（参考例１５）（Ｒ）－２－（（３－クロロ－４－（（７－クロロ－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000034
 　参考例８の化合物の代わりに参考例１４の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例１５の化合物）（０．０５３４ｇ，０．１０３ｍｍｏｌ，７９％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４３－１．７０（ｍ，１５Ｈ），２．３３（ｄ，Ｊ＝１２．３Ｈｚ，１Ｈ），２．７６－２．８６（ｍ，５Ｈ），３．６４（ｓ，２Ｈ），３．７４（ｓ，２Ｈ），４．０６（ｂｒｓ，１Ｈ），４．８５（ｓ，１Ｈ），６．９９（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），７．０３（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．０９（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．２８（ｄｄ，Ｊ＝８．５，２．１Ｈｚ，１Ｈ），７．４５（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．７３（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５１８（Ｍ＋Ｈ）＋． (Reference Example 15) (R) -2-((3-chloro-4-((7-chloro-3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) carbamoyl) piperidine-1-carbonide Synthesis of acid tert-butyl:
Figure JPOXMLDOC01-appb-C000034
 Using the compound of Reference Example 14 instead of the compound of Reference Example 8, and using the same procedure as Reference Example 9 except the above, the title compound (hereinafter, the compound of Reference Example 15) (0.0534 g, 0.103 mmol, 79 %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.43-1.70 (m, 15 H), 2.33 (d, J = 12.3 Hz, 1 H), 2.76-2.86 (m, 5H), 3.64 (s, 2H), 3.74 (s, 2H), 4.06 (brs, 1H), 4.85 (s, 1H), 6.99 (d, J = 2.3 Hz , 1H), 7.03 (d, J = 7.8 Hz, 1 H), 7.09 (dd, J = 8.2, 2.3 Hz, 1 H), 7.28 (dd, J = 8.5, 2.1 Hz, 1 H), 7. 45 (d, J = 8.2 Hz, 1 H), 7.73 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 518 (M + H) + .
（実施例３）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（（７－クロロ－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000035
 　参考例９の化合物の代わりに参考例１５の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例３の化合物）（０．０３９０ｇ，０．０８４７ｍｍｏｌ，８３％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４７－１．６１（ｍ，２Ｈ），１．７１－１．７８（ｍ，２Ｈ），１．９０－１．９９（ｍ，１Ｈ），２．２１（ｓ，３Ｈ），２．２８（ｄ，Ｊ＝１２．８Ｈｚ，１Ｈ），２．７６（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），２．８４（ｔ，Ｊ＝５．５Ｈｚ，２Ｈ），３．１４（ｔｄ，Ｊ＝１３．４，２．９Ｈｚ，１Ｈ），３．６４（ｓ，２Ｈ），３．７３（ｓ，２Ｈ），３．７７（ｄ，Ｊ＝１２．８Ｈｚ，１Ｈ），５．２６（ｄ，Ｊ＝５．５Ｈｚ，１Ｈ），６．９８（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），７．０２（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．０９（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．３０（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．４３（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．７１（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．４４（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４６０（Ｍ＋Ｈ）＋． Example 3 (R) -1-Acetyl-N- (3-chloro-4-((7-chloro-3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) piperidine-2- Carboxamide Synthesis:
Figure JPOXMLDOC01-appb-C000035
 Using the compound of Reference Example 15 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 3 below) (0.0390 g, 0.0847 mmol, 83) %) As a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.61 (m, 2H), 1.71-1.78 (m, 2H), 1.90-1.99 (m, 1H) , 2.21 (s, 3 H), 2.28 (d, J = 12.8 Hz, 1 H), 2.76 (t, J = 5.9 Hz, 2 H), 2.84 (t, J = 5. 5 Hz, 2 H), 3.14 (td, J = 13.4, 2.9 Hz, 1 H), 3.64 (s, 2 H), 3.73 (s, 2 H), 3.77 (d, J = 12.8 Hz, 1 H), 5.26 (d, J = 5.5 Hz, 1 H), 6.98 (d, J = 2.3 Hz, 1 H), 7.02 (d, J = 7.8 Hz, 1 H) , 7.09 (dd, J = 8.2, 2.3 Hz, 1 H), 7.30 (dd, J = 8.2, 2.3 Hz, 1 H), 7.43 (d, J = 8). 7 Hz, 1 H), 7. 1 (d, J = 2.3Hz, 1H), 8.44 (brs, 1H).
ESI-MS: m / z = 460 (M + H) + .
（参考例１６）２，２，２－トリフルオロ－Ｎ－（４－（トリフルオロメチル）フェネチル）アセトアミドの合成：
Figure JPOXMLDOC01-appb-C000036
 　２－（４－トリフルオロメチルフェニル）エチルアミン（１．６８ｍＬ，１０．６ｍｍｏｌ）をジクロロメタン（３５．２ｍＬ）に溶解し、トリフルオロ酢酸無水物（１．６４ｍＬ，１１．６ｍｍｏｌ）を０℃で加えた。室温で４時間撹拌した後、反応液を減圧濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝８５／１５～７５／２５）で精製し、表題化合物（以下、参考例１６の化合物）（２．６０ｇ，９．１２ｍｍｏｌ，８６％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．９７（ｔ，Ｊ＝７．１Ｈｚ，２Ｈ），３．６５（ｑ，Ｊ＝６．７Ｈｚ，２Ｈ），６．３０（ｂｒｓ，１Ｈ），７．３２（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．６０（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２８４（Ｍ－Ｈ）－． Reference Example 16 Synthesis of 2,2,2-trifluoro-N- (4- (trifluoromethyl) phenethyl) acetamide:
Figure JPOXMLDOC01-appb-C000036
 Dissolve 2- (4-trifluoromethylphenyl) ethylamine (1.68 mL, 10.6 mmol) in dichloromethane (35.2 mL) and add trifluoroacetic anhydride (1.64 mL, 11.6 mmol) at 0 ° C. The After stirring at room temperature for 4 hours, the reaction mixture is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (n-hexane / ethyl acetate = 85/15 to 75/25) to give the title compound (below) The compound of Reference Example 16 (2.60 g, 9.12 mmol, 86%) was obtained as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.97 (t, J = 7.1 Hz, 2 H), 3.65 (q, J = 6.7 Hz, 2 H), 6.30 (brs, 1 H) , 7.32 (d, J = 8.2 Hz, 2 H), 7. 60 (d, J = 8.2 Hz, 2 H).
ESI-MS: m / z = 284 (M-H) - .
（参考例１７）２，２，２－トリフルオロ－１－（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）エタン－１－オンの合成：
Figure JPOXMLDOC01-appb-C000037
 　濃硫酸（６．５４ｍＬ）及び酢酸（５．０２ｍＬ）の混合液に、参考例１６の化合物（１．００ｇ，３．５１ｍｍｏｌ）及びパラホルムアルデヒド（０．１５８ｇ，５．２６ｍｍｏｌ）を０℃で加えた。室温で１７時間撹拌した後、反応液を氷水に加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、蒸留水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９０／１０～７５／２５）で精製し、表題化合物（以下、参考例１７の化合物）（０．９６１ｇ，３．２３ｍｍｏｌ，９２％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．００－３．０４（ｍ，２Ｈ），３．８８（ｔ，Ｊ＝５．７Ｈｚ，１．３Ｈ），３．９３（ｔ，Ｊ＝６．２Ｈｚ，０．７Ｈｚ），４．８１（ｓ，０．７Ｈ），４．８５（ｓ，１．３Ｈ），７．３１（ｔ，Ｊ＝９．１Ｈｚ，１Ｈ），７．４２（ｄ，Ｊ＝１１．４Ｈｚ，１Ｈ），７．４９（ｔ，Ｊ＝９．４Ｈｚ，１Ｈ）． Reference Example 17 Synthesis of 2,2,2-trifluoro-1- (7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) ethan-1-one:
Figure JPOXMLDOC01-appb-C000037
 The compound of Reference Example 16 (1.00 g, 3.51 mmol) and paraformaldehyde (0.158 g, 5.26 mmol) were added to a mixture of concentrated sulfuric acid (6.54 mL) and acetic acid (5.02 mL) at 0 ° C. The After stirring at room temperature for 17 hours, the reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, distilled water and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90 / 10-75 / 25) to give the title compound (hereinafter, the compound of Reference Example 17) (0.961 g, 3.23 mmol, 92) %) As a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.00 to 3.04 (m, 2 H), 3.88 (t, J = 5.7 Hz, 1.3 H), 3.93 (t, J =) 6.2 Hz, 0.7 Hz), 4.81 (s, 0.7 H), 4.85 (s, 1.3 H), 7.31 (t, J = 9.1 Hz, 1 H), 7.42 ( d, J = 11.4 Hz, 1 H), 7.49 (t, J = 9.4 Hz, 1 H).
（参考例１８）７－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000038
 　参考例１７の化合物（０．４００ｇ，１．３５ｍｍｏｌ）をエタノール（４．０８ｍＬ）に溶解し、２Ｍ水酸化ナトリウム水溶液（３．７０ｍＬ）を０℃で加えた。室温で２時間撹拌した後、反応液を減圧濃縮し、蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮し、表題化合物（以下、参考例１８の化合物）（０．２５１ｇ，１．２５ｍｍｏｌ，９３％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８５（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．１６（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），４．０６（ｓ，２Ｈ），７．２０（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．２７（ｓ，１Ｈ），７．３７（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２０２（Ｍ＋Ｈ）＋． Reference Example 18 Synthesis of 7- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000038
 The compound of Reference Example 17 (0.400 g, 1.35 mmol) was dissolved in ethanol (4.08 mL), and a 2 M aqueous solution of sodium hydroxide (3.70 mL) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (hereinafter referred to as the compound of Reference Example 18) (0.251 g, 1.25 mmol, 93%) Obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.85 (t, J = 5.7 Hz, 2 H), 3.16 (t, J = 5.9 Hz, 2 H), 4.06 (s, 2 H) , 7.20 (d, J = 8.2 Hz, 1 H), 7. 27 (s, 1 H), 7. 37 (d, J = 8.2 Hz, 1 H).
ESI-MS: m / z = 202 (M + H) + .
（参考例１９）２－（２－クロロ－４－ニトロベンジル）－７－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000039
 　参考例１８の化合物（１０．０ｇ，４９．７ｍｍｏｌ）をジクロロメタン（１４８ｍＬ）に溶解し、参考例１の化合物（９．０４ｇ，４９．７ｍｍｏｌ）及び酢酸（１．４０ｍＬ）を室温で加えた。室温で１０分間撹拌した後、水素化トリアセトキシホウ素ナトリウム（１５．５ｇ，７３．１ｍｍｏｌ）を０℃で加えた。室温で１４時間撹拌した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣を再結晶（ｎ－ヘキサン／酢酸エチル）で精製し、表題化合物（以下、参考例１９の化合物）（１２．９ｇ，３４．８ｍｍｏｌ，７０％）を黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８５（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．００（ｔ，Ｊ＝５．５Ｈｚ，２Ｈ），３．７６（ｓ，２Ｈ），３．８８（ｓ，２Ｈ），７．２５（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．２７（ｓ，１Ｈ），７．４１（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．８０（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），８．１３（ｄｄ，Ｊ＝８．７，２．３Ｈｚ，１Ｈ），８．２７（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３７１（Ｍ＋Ｈ）＋． Reference Example 19 Synthesis of 2- (2-chloro-4-nitrobenzyl) -7- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000039
 The compound of Reference Example 18 (10.0 g, 49.7 mmol) was dissolved in dichloromethane (148 mL), and the compound of Reference Example 1 (9.04 g, 49.7 mmol) and acetic acid (1.40 mL) were added at room temperature. After stirring for 10 minutes at room temperature, sodium triacetoxyborohydride (15.5 g, 73.1 mmol) was added at 0 ° C. After stirring at room temperature for 14 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by recrystallization (n-hexane / ethyl acetate) to give the title compound (hereinafter, the compound of Reference Example 19) (12.9 g, 34.8 mmol, 70%) as a yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.85 (t, J = 5.7 Hz, 2 H), 3.00 (t, J = 5.5 Hz, 2 H), 3.76 (s, 2 H) , 3.88 (s, 2 H), 7. 25 (d, J = 7.8 Hz, 1 H), 7. 27 (s, 1 H), 7.41 (d, J = 7.8 Hz, 1 H), 7 80 (d, J = 8.7 Hz, 1 H), 8.13 (dd, J = 8.7, 2.3 Hz, 1 H), 8.27 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 371 (M + H) + .
（参考例２０）３－クロロ－４－（（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000040
 　参考例１９の化合物（１５．６ｇ，４２．１ｍｍｏｌ）をＴＨＦ（４２．１ｍＬ）に溶解し、エタノール（４２．１ｍＬ）、蒸留水（４２．１ｍＬ）、鉄粉（１１．８ｇ，２１０ｍｍｏｌ）及び酢酸（１２．０ｍＬ，２１０ｍｍｏｌ）を室温で加えた。５０℃で１．５時間撹拌した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝８０／２０～７０／３０）で精製し、表題化合物（以下、参考例２０の化合物）（１３．９ｇ，４０．８ｍｍｏｌ，９７％）を黄色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８０（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），２．９４（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．７０（ｄ，Ｊ＝２．７Ｈｚ，６Ｈ），６．５７（ｄｄ，Ｊ＝８．５，２．５Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），７．２０（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．２５（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ），７．２６（ｓ，１Ｈ），７．３６（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３４１（Ｍ＋Ｈ）＋． Reference Example 20 Synthesis of 3-chloro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline:
Figure JPOXMLDOC01-appb-C000040
 The compound of Reference Example 19 (15.6 g, 42.1 mmol) is dissolved in THF (42.1 mL), ethanol (42.1 mL), distilled water (42.1 mL), iron powder (11.8 g, 210 mmol) and Acetic acid (12.0 mL, 210 mmol) was added at room temperature. After stirring at 50 ° C. for 1.5 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20 to 70/30), and the title compound (hereinafter, the compound of Reference Example 20) (13.9 g, 40.8 mmol, 97) %) As a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.80 (t, J = 5.7 Hz, 2 H), 2.94 (t, J = 5.7 Hz, 2 H), 3.70 (d, J = 2.7 Hz, 6 H), 6.57 (dd, J = 8.5, 2.5 Hz, 1 H), 6.72 (d, J = 2.3 Hz, 1 H), 7.20 (d, J = 8 2 Hz, 1 H), 7. 25 (d, J = 8.7 Hz, 2 H), 7. 26 (s, 1 H), 7. 36 (d, J = 7.8 Hz, 1 H).
ESI-MS: m / z = 341 (M + H) <+> .
（参考例２１）（Ｒ）－２－（（３－クロロ－４－（（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000041
 　参考例２０の化合物（１３．５ｇ，３９．６ｍｍｏｌ）及び（Ｒ）－Ｎ－Ｂｏｃ－ピペコリン酸（１０．９ｇ，４７．５ｍｍｏｌ）をＤＭＦ（１３２ｍＬ）に溶解し、ＨＡＴＵ（１８．１ｇ，４７．５ｍｍｏｌ）及びジイソプロピルエチルアミン（１０．４ｍＬ，５９．４ｍｍｏｌ）を０℃で加えた。室温で１０時間撹拌した後、反応液に飽和塩化アンモニウム水溶液を加え、ｎ－ヘキサン／ジエチルエーテル（１：２）で抽出した。有機層を飽和炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝８５／１５～８０／２０）で精製し、表題化合物（以下、参考例２１の化合物）（１４．５ｇ，２６．３ｍｍｏｌ，６６％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４３－１．７０（ｍ，１５Ｈ），２．３２（ｄ，Ｊ＝１２．８Ｈｚ，１Ｈ），２．８０（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），２．８２－２．８６（ｍ，１Ｈ），２．９４（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．７１（ｓ，２Ｈ），３．７７（ｓ，２Ｈ），４．０８（ｂｒｓ，１Ｈ），４．８６（ｄ，Ｊ＝４．６Ｈｚ，１Ｈ），７．２１（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．２５（ｓ，１Ｈ），７．３０（ｄｄ，Ｊ＝８．２，１．８Ｈｚ，１Ｈ），７．３７（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．４５（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．７３（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５５２（Ｍ＋Ｈ）＋． Reference Example 21 (R) -2-((3-Chloro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl:
Figure JPOXMLDOC01-appb-C000041
 The compound of Reference Example 20 (13.5 g, 39.6 mmol) and (R) -N-Boc-pipecolic acid (10.9 g, 47.5 mmol) were dissolved in DMF (132 mL), and HATU (18.1 g, 47) was dissolved. .5 mmol) and diisopropylethylamine (10.4 mL, 59.4 mmol) were added at 0 ° C. After stirring at room temperature for 10 hours, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with n-hexane / diethyl ether (1: 2). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 85 / 15-80 / 20), and the title compound (hereinafter, the compound of Reference Example 21) (14.5 g, 26.3 mmol, 66) %) As a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.43-1.70 (m, 15 H), 2.32 (d, J = 12.8 Hz, 1 H), 2.80 (t, J = 5. 7 Hz, 2 H), 2.82-2.86 (m, 1 H), 2.94 (t, J = 5.7 Hz, 2 H), 3.71 (s, 2 H), 3.77 (s, 2 H) , 4.08 (brs, 1 H), 4.86 (d, J = 4.6 Hz, 1 H), 7.21 (d, J = 8.2 Hz, 1 H), 7.25 (s, 1 H), 7 30 (dd, J = 8.2, 1.8 Hz, 1 H), 7.37 (d, J = 7.8 Hz, 1 H), 7.45 (d, J = 8.2 Hz, 1 H), 7. 73 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 552 (M + H) + .
（参考例２２）（Ｒ）－Ｎ－（３－クロロ－４－（（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000042
 　参考例２１の化合物（１４．５ｇ，２６．３ｍｍｏｌ）をジクロロメタン（９７．０ｍＬ）に溶解し、トリフルオロ酢酸（２４．３ｍＬ，３１５ｍｍｏｌ）を０℃で加えた。室温で４時間撹拌した後、反応液に４Ｍ水酸化ナトリウム水溶液を加え中和し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣を再結晶（ｎ－ヘキサン／酢酸エチル）で精製し、表題化合物（以下、参考例２２の化合物）（１１．０ｇ，２４．４ｍｍｏｌ，９３％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４３－１．６２（ｍ，４Ｈ），１．７９－１．８４（ｍ，１Ｈ），１．９９－２．０５（ｍ，１Ｈ），２．７３－２．７９（ｍ，１Ｈ），２．８１（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），２．９４（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．０３－３．０８（ｍ，１Ｈ），３．３５（ｄｄ，Ｊ＝９．４，３．４Ｈｚ，１Ｈ），３．７１（ｓ，２Ｈ），３．７７（ｓ，２Ｈ），７．２１（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．２６（ｓ，１Ｈ），７．３７（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．４２（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．４６（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．７６（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），８．９２（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２２６（Ｍ＋Ｈ）＋／２． Reference Example 22 (R) -N- (3-Chloro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) piperidine-2- Carboxamide Synthesis:
Figure JPOXMLDOC01-appb-C000042
 The compound of Reference Example 21 (14.5 g, 26.3 mmol) was dissolved in dichloromethane (97.0 mL), and trifluoroacetic acid (24.3 mL, 315 mmol) was added at 0 ° C. After stirring at room temperature for 4 hours, the reaction solution was neutralized by adding 4 M aqueous sodium hydroxide solution, and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by recrystallization (n-hexane / ethyl acetate) to give the title compound (hereinafter, the compound of Reference Example 22) (11.0 g, 24.4 mmol, 93%) as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.43-1.62 (m, 4 H), 1.79-1.84 (m, 1 H), 1.99-2.05 (m, 1 H) , 2.73-2.79 (m, 1 H), 2.81 (t, J = 5.9 Hz, 2 H), 2.94 (t, J = 5.7 Hz, 2 H), 3.03-3. 08 (m, 1 H), 3. 35 (dd, J = 9.4, 3.4 Hz, 1 H), 3.71 (s, 2 H), 3.77 (s, 2 H), 7.21 (d, J = 8.2 Hz, 1 H), 7.26 (s, 1 H), 7. 37 (d, J = 8.2 Hz, 1 H), 7.42 (dd, J = 8.2, 2.3 Hz, 1 H ), 7.46 (d, J = 8.7 Hz, 1 H), 7.76 (d, J = 1.8 Hz, 1 H), 8.92 (s, 1 H).
ESI-MS: m / z = 226 (M + H) + / 2.
（実施例４）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000043
 　参考例９の化合物の代わりに参考例２１の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例４の化合物）（０．０３０７ｇ，０．０６２２ｍｍｏｌ，３４％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４９－１．５８（ｍ，３Ｈ），１．７３（ｄ，Ｊ＝１１．４Ｈｚ，２Ｈ），１．９６（ｄ，Ｊ＝１２．８Ｈｚ，１Ｈ），２．２１（ｓ，３Ｈ），２．２８（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），２．７９（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），２．９４（ｔ，Ｊ＝５．５Ｈｚ，２Ｈ），３．１５（ｔｄ，Ｊ＝１３．０，２．７Ｈｚ，１Ｈ），３．７０（ｓ，２Ｈ），３．７７（ｓ，２Ｈ），５．２６（ｄ，Ｊ＝５．５Ｈｚ，１Ｈ），７．２１－７．２５（ｍ，２Ｈ）７．３１（ｄｄ，Ｊ＝８．５，２．１Ｈｚ，１Ｈ），７．３７（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ），７．４３（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．７１（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．４６（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４９４（Ｍ＋Ｈ）＋． Example 4 (R) -1-Acetyl-N- (3-chloro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) Synthesis of piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000043
 Using the compound of Reference Example 21 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 4 below) (0.0307 g, 0.0622 mmol, 34) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49 to 1.58 (m, 3 H), 1.73 (d, J = 11.4 Hz, 2 H), 1.96 (d, J = 12. 8 Hz, 1 H), 2.21 (s, 3 H), 2. 28 (d, J = 13.3 Hz, 1 H), 2.79 (t, J = 5.7 Hz, 2 H), 2.94 (t, J = 5.5 Hz, 2H), 3.15 (td, J = 13.0, 2.7 Hz, 1 H), 3.70 (s, 2 H), 3.77 (s, 2 H), 5.26 ( d, J = 5.5 Hz, 1 H), 7.21-7. 25 (m, 2 H) 7.31 (dd, J = 8.5, 2.1 Hz, 1 H), 7.37 (d, J = 7.3 Hz, 1 H), 7.43 (d, J = 8.2 Hz, 1 H), 7.71 (d, J = 2.3 Hz, 1 H), 8.46 (brs, 1 H).
ESI-MS: m / z = 494 (M + H) <+> .
（実施例５）（Ｒ）－１－（２－（１Ｈ－テトラゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000044
 　参考例２２の化合物（１１．０ｇ，２４．３ｍｍｏｌ）をＤＭＦ（８１．０ｍＬ）に溶解し、２－（１Ｈ－テトラゾール－１－イル）酢酸（３．７４ｇ，２９．２ｍｍｏｌ）、ＨＡＴＵ（１１．１ｇ，２９．２ｍｍｏｌ）及びジイソプロピルエチルアミン（６．３８ｍＬ，３６．５ｍｍｏｌ）を０℃で加えた。室温で１６時間撹拌した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝５０／５０～０／１００）で精製し、表題化合物（以下、実施例５の化合物）（９．１７ｇ，１６．３ｍｍｏｌ，６７％）を白色アモルファスとして得た。キラルカラムを用いて分析したところ、得られた実施例５の化合物の保持時間は８．１分であり、そのときの光学純度は９９．８％ｅｅであった。キラルカラムを用いた分析条件は、以下の通りである。
測定機器；島津製作所　高速液体クロマトグラフ　ＬＣ－２０１０ＣＨＴ
カラム；ダイセル化学工業株式会社　ＣＨＩＲＡＬＣＥＬ　ＯＺ－３Ｒ　０．４６ｃｍφ×１５ｃｍ　粒子径　３μｍ
カラム温度；４０℃
移動相；（Ａ液）２０ｍＭ　リン酸二水素カリウム水溶液、（Ｂ液）アセトニトリル
移動相の組成；Ａ液：Ｂ液＝４５：５５で３０分間送液した。
流速；１．０ｍＬ／分
検出；ＵＶ（２１０ｎｍ）
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．６２－１．８２（ｍ，４Ｈ），１．９３（ｔ，Ｊ＝１３．０Ｈｚ，２Ｈ），２．２８（ｄ，Ｊ＝５．７Ｈｚ，１Ｈ），２．８０（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），２．９４（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．５０－３．５６（ｍ，１Ｈ），３．７０（ｓ，２Ｈ），３．７６（ｓ，２Ｈ），５．１７（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），５．３９（ｄ，Ｊ＝１６．５Ｈｚ，１Ｈ），５．４７（ｄ，Ｊ＝１６．５Ｈｚ，１Ｈ），７．２１（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．２５（ｓ，１Ｈ），７．２６（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．３７（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．４６（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．７１（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），７．９２（ｓ，１Ｈ），８．８５（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５６２（Ｍ＋Ｈ）＋． Example 5 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4-((7- (trifluoromethyl) -3,4-dihydro) Synthesis of isoquinolin-2 (1H) -yl) methyl) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000044
 The compound of Reference Example 22 (11.0 g, 24.3 mmol) is dissolved in DMF (81.0 mL), 2- (1H-tetrazol-1-yl) acetic acid (3.74 g, 29.2 mmol), HATU (11) 1 g, 29.2 mmol) and diisopropylethylamine (6.38 mL, 36.5 mmol) were added at 0.degree. After stirring at room temperature for 16 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/50 to 0/100) to give the title compound (compound of Example 5 below) (9.17 g, 16.3 mmol, 67) %) As a white amorphous. As a result of analysis using a chiral column, the retention time of the compound of Example 5 obtained was 8.1 minutes, and the optical purity at that time was 99.8% ee. The analysis conditions using a chiral column are as follows.
Measuring instrument; Shimadzu high performance liquid chromatograph LC-2010CHT
Column; Daicel Chemical Industries, Ltd. CHIRALCEL OZ-3R 0.46 cmφ × 15 cm particle diameter 3 μm
Column temperature: 40 ° C
Mobile phase: (Liquid A) 20 mM aqueous solution of potassium dihydrogen phosphate, (Liquid B) Composition of acetonitrile mobile phase; Liquid A: Liquid B = 45: 55 for 30 minutes.
Flow rate: 1.0 mL / min detection; UV (210 nm)
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.62-1.82 (m, 4 H), 1.93 (t, J = 13.0 Hz, 2 H), 2.28 (d, J = 5. 7 Hz, 1 H), 2.80 (t, J = 5.7 Hz, 2 H), 2.94 (t, J = 5.7 Hz, 2 H), 3.50 to 3.56 (m, 1 H), 70 (s, 2 H), 3.76 (s, 2 H), 5. 17 (d, J = 5.0 Hz, 1 H), 5. 39 (d, J = 16.5 Hz, 1 H), 5. 47 ( d, J = 16.5 Hz, 1 H), 7.21 (d, J = 7.8 Hz, 1 H), 7. 25 (s, 1 H), 7. 26 (dd, J = 8.2, 2.3 Hz) , 1H), 7.37 (d, J = 8.7 Hz, 1 H), 7.46 (d, J = 8.7 Hz, 1 H), 7.71 (d, J = 1.8 Hz, 1 H), 7 .92 (s, 1 H , 8.85 (s, 1H).
ESI-MS: m / z = 562 (M + H) + .
（実施例６）（Ｒ）－１－（２－（４Ｈ－１，２，４－トリアゾール－４－イル）アセチル）－Ｎ－（３－クロロ－４－（（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000045
 　２－（１Ｈ－テトラゾール－１－イル）酢酸の代わりに２－（４Ｈ－１，２，４－トリアゾール－４－イル）酢酸を用いて、それ以外は実施例５と同様の手順により、表題化合物（以下、実施例６の化合物）（０．０５７８ｇ，０．１０３ｍｍｏｌ，９３％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．５３－１．５８（ｍ，１Ｈ），１．６８－１．８８（ｍ，４Ｈ），２．２５－２．２８（ｍ，１Ｈ），２．７６－２．７９（ｍ，２Ｈ），２．９１－２．９４（ｍ，２Ｈ），３．５５－３．６２（ｍ，１Ｈ），３．６６－３．６８（ｍ，１Ｈ），３．６８（ｓ，２Ｈ），３．７３（ｓ，２Ｈ），４．９１（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），４．９８（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），５．１８－５．１９（ｍ，１Ｈ），７．２０（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．２４－７．２６（ｍ，２Ｈ），７．３６（ｄ，Ｊ＝７．７Ｈｚ，１Ｈ），７．４１（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．７０（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），８．１８（ｓ，２Ｈ），８．６８（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５５９（Ｍ－Ｈ）－． Example 6 (R) -1- (2- (4H-1,2,4-triazol-4-yl) acetyl) -N- (3-chloro-4-((7- (trifluoromethyl)) Synthesis of -3,4-Dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000045
 Using the same procedure as in Example 5 except for using 2- (4H-1,2,4-triazol-4-yl) acetic acid instead of 2- (1H-tetrazol-1-yl) acetic acid, The compound (hereinafter, the compound of Example 6) (0.0578 g, 0.103 mmol, 93%) was obtained as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.53-1.58 (m, 1 H), 1.68-1.88 (m, 4 H), 2.25-2.28 (m, 1 H) , 2.76-2.79 (m, 2H), 2.91-2.94 (m, 2H), 3.55-3.62 (m, 1 H), 3.66-3.68 (m, 2) 1H), 3.68 (s, 2H), 3.73 (s, 2H), 4.91 (d, J = 16.8 Hz, 1 H), 4.98 (d, J = 16.8 Hz, 1 H) , 5.18-5.19 (m, 1H), 7.20 (d, J = 8.2 Hz, 1 H), 7.24-7.26 (m, 2 H), 7.36 (d, J = 7.7 Hz, 1 H), 7.41 (d, J = 8.2 Hz, 1 H), 7. 70 (d, J = 1.8 Hz, 1 H), 8. 18 (s, 2 H), 8. 68 ( s, 1 H).
ESI-MS: m / z = 559 (M-H) - .
（実施例７）（Ｒ）－Ｎ－（３－クロロ－４－（（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）－１－（メチルスルホニル）ピペリジン－２－カルボキサミド　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000046
 　参考例３の化合物の代わりに参考例２１の化合物を用いて、それ以外は実施例１と同様の手順により、表題化合物（以下、実施例７の化合物）（０．０６９７ｇ，０．０９１９ｍｍｏｌ，７２％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ３ＯＤ）δ：１．４３－１．６４（ｍ，２Ｈ），１．６９－１．８０（ｍ，２Ｈ），１．８７－１．９７（ｍ，１Ｈ），２．１９（ｄ，Ｊ＝１５．１Ｈｚ，１Ｈ），２．９４（ｓ，３Ｈ），３．２７－３．３０（ｍ，２Ｈ），３．６０－３．７１（ｍ，４Ｈ），４．５８（ｓ，２Ｈ），４．６５（ｓ，２Ｈ），４．６８（ｄｄ，Ｊ＝５．９，１．８Ｈｚ，１Ｈ），７．４７（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．５９－７．６３（ｍ，３Ｈ），７．６９（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），８．０３（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５３０（Ｍ＋Ｈ）＋． Example 7 (R) -N- (3-Chloro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) -1- ( Synthesis of methylsulfonyl) piperidine-2-carboxamide hydrochloride:
Figure JPOXMLDOC01-appb-C000046
 Using the compound of Reference Example 21 instead of the compound of Reference Example 3, and using the same procedure as Example 1 except for the above, the title compound (the compound of Example 7 below) (0.0697 g, 0.0919 mmol, 72) %) As a white amorphous.
1 H-NMR (400 MHz, CD 3 OD) δ: 1.43-1.64 (m, 2 H), 1.69-1.80 (m, 2 H), 1.87-1. 97 (m, 1 H) ), 2.19 (d, J = 15.1 Hz, 1 H), 2.94 (s, 3 H), 3.27-3.30 (m, 2 H), 3.60-3.71 (m, 4 H) ), 4.58 (s, 2H), 4.65 (s, 2H), 4.68 (dd, J = 5.9, 1.8 Hz, 1 H), 7.47 (d, J = 7.8 Hz) , 1H), 7.59-7.63 (m, 3H), 7.69 (d, J = 8.2 Hz, 1 H), 8.03 (d, J = 1.8 Hz, 1 H).
ESI-MS: m / z = 530 (M + H) + .
（参考例２３）２，２，２－トリフルオロ－Ｎ－（３－（トリフルオロメチル）フェネチル）アセトアミドの合成：
Figure JPOXMLDOC01-appb-C000047
 　２－（３－トリフルオロメチルフェニル）エチルアミン（１．６７ｍＬ，１０．６ｍｍｏｌ）をジクロロメタン（３５．２ｍＬ）に溶解し、トリフルオロ酢酸無水物（１．６４ｍＬ，１１．６ｍｍｏｌ）を０℃で加えた。室温で４時間撹拌した後、反応液を減圧濃縮して、得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝８５／１５～７５／２５）で精製し、表題化合物（以下、参考例２３の化合物）（２．５２ｇ，８．８３ｍｍｏｌ，８４％）を薄黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．９７（ｔ，Ｊ＝７．１Ｈｚ，２Ｈ），３．６５（ｑ，Ｊ＝６．７Ｈｚ，２Ｈ），６．３１（ｂｒｓ，１Ｈ），７．３９（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．４５（ｓ，１Ｈ），７．４７（ｔ，Ｊ＝７．５Ｈｚ，１Ｈ），７．５４（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２８４（Ｍ－Ｈ）－． Reference Example 23 Synthesis of 2,2,2-trifluoro-N- (3- (trifluoromethyl) phenethyl) acetamide:
Figure JPOXMLDOC01-appb-C000047
 Dissolve 2- (3-trifluoromethylphenyl) ethylamine (1.67 mL, 10.6 mmol) in dichloromethane (35.2 mL) and add trifluoroacetic anhydride (1.64 mL, 11.6 mmol) at 0 ° C. The After stirring at room temperature for 4 hours, the reaction mixture is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (n-hexane / ethyl acetate = 85/15 to 75/25) to give the title compound The compound of Reference Example 23 (2.52 g, 8.83 mmol, 84%) was obtained as a pale yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.97 (t, J = 7.1 Hz, 2 H), 3.65 (q, J = 6.7 Hz, 2 H), 6.31 (brs, 1 H) , 7.39 (d, J = 7.8 Hz, 1 H), 7.45 (s, 1 H), 7.47 (t, J = 7.5 Hz, 1 H), 7.54 (d, J = 7. 8 Hz, 1 H).
ESI-MS: m / z = 284 (M-H) - .
（参考例２４）２，２，２－トリフルオロ－１－（６－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）エタン－１－オン：
Figure JPOXMLDOC01-appb-C000048
 及び、
（参考例２５）２，２，２－トリフルオロ－１－（８－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）エタン－１－オンの合成：
Figure JPOXMLDOC01-appb-C000049
 　濃硫酸（６．５４ｍＬ）及び酢酸（５．０２ｍＬ）の混合液に、参考例２３の化合物（１．００ｇ，３．５１ｍｍｏｌ）及びパラホルムアルデヒド（０．１５８ｇ，５．２６ｍｍｏｌ）を０℃で加えた。室温で１７時間撹拌した後、反応液を氷水に加え、酢酸エチルで抽出した。有機層を飽和炭酸水素ナトリウム水溶液、蒸留水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９０／１０～７５／２５）で精製し、先に溶出した表題化合物（以下、参考例２４の化合物）（０．５０２ｇ，１．６９ｍｍｏｌ，４８％）及び後に溶出した表題化合物（以下、参考例２５の化合物）（０．３７９ｇ，１．２８ｍｍｏｌ，３６％）をそれぞれ白色固体として得た。
（参考例２４の化合物）：
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．０２（ｑ，Ｊ＝６．１Ｈｚ，２Ｈ），３．８８（ｔ，Ｊ＝５．９Ｈｚ，１．３Ｈ），３．９３（ｔ，Ｊ＝６．２Ｈｚ，０．７Ｈｚ），４．８０（ｓ，０．７Ｈ），４．８５（ｓ，１．３Ｈ），７．２３－７．３０（ｍ，１Ｈ），７．４５（ｄ，Ｊ＝９．６Ｈｚ，１Ｈ），７．５０（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ）．
（参考例２５の化合物）：
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．０３－３．０６（ｍ，２Ｈ），３．８８（ｔ，Ｊ＝５．９Ｈｚ，１．１Ｈ），３．９２（ｔ，Ｊ＝６．２Ｈｚ，０．９Ｈｚ），４．９３（ｓ，０．９Ｈ），５．００（ｓ，１．１Ｈ），７．３３－７．３８（ｍ，２Ｈ），７．５６－７．５９（ｍ，１Ｈ）． Reference Example 24 2,2,2-Trifluoro-1- (6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) ethan-1-one:
Figure JPOXMLDOC01-appb-C000048
 as well as,
Reference Example 25 Synthesis of 2,2,2-trifluoro-1- (8- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) ethan-1-one:
Figure JPOXMLDOC01-appb-C000049
 The compound of Reference Example 23 (1.00 g, 3.51 mmol) and paraformaldehyde (0.158 g, 5.26 mmol) were added to a mixture of concentrated sulfuric acid (6.54 mL) and acetic acid (5.02 mL) at 0 ° C. The After stirring at room temperature for 17 hours, the reaction solution was added to ice water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, distilled water and saturated brine, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 90/10 to 75/25), and the title compound eluted in advance (hereinafter, the compound of Reference Example 24) (0.502 g, 1) .69 mmol, 48%) and the later eluted title compound (hereinafter, the compound of Reference Example 25) (0.379 g, 1.28 mmol, 36%) were respectively obtained as a white solid.
(Compound of Reference Example 24):
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.02 (q, J = 6.1 Hz, 2 H), 3.88 (t, J = 5.9 Hz, 1.3 H), 3.93 (t, J = 6.2 Hz, 0.7 Hz), 4.80 (s, 0.7 H), 4.85 (s, 1.3 H), 7.23-7.30 (m, 1 H), 7.45 ( d, J = 9.6 Hz, 1 H), 7. 50 (d, J = 8.7 Hz, 1 H).
(Compound of Reference Example 25):
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.03-3.06 (m, 2 H), 3.88 (t, J = 5.9 Hz, 1.1 H), 3.92 (t, J = 6.2 Hz, 0.9 Hz), 4.93 (s, 0.9 H), 5.00 (s, 1.1 H), 7.33-7. 38 (m, 2 H), 7.56-7. 59 (m, 1 H).
（参考例２６）６－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000050
 　参考例２４の化合物（０．３００ｇ，１．０１ｍｍｏｌ）をエタノール（３．０６ｍＬ）に溶解し、２Ｍ水酸化ナトリウム水溶液（２．７８ｍＬ）を０℃で加えた。室温で７時間撹拌した後、反応液を減圧濃縮し、蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮し、表題化合物（以下、参考例２６の化合物）（０．１８５ｇ，０．９２０ｍｍｏｌ，９１％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８５（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），３．１６（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），４．０５（ｓ，２Ｈ），７．１１（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．３５（ｓ，１Ｈ），７．３６（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２０２（Ｍ＋Ｈ）＋． Reference Example 26 Synthesis of 6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000050
 The compound of Reference Example 24 (0.300 g, 1.01 mmol) was dissolved in ethanol (3.06 mL), and a 2 M aqueous solution of sodium hydroxide (2.78 mL) was added at 0 ° C. After stirring at room temperature for 7 hours, the reaction mixture was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure to give the title compound (hereinafter, a compound of Reference Example 26) (0.185 g, 0.920 mmol, 91%) Obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.85 (t, J = 5.9 Hz, 2 H), 3.16 (t, J = 5.9 Hz, 2 H), 4.05 (s, 2 H) , 7.11 (d, J = 7.8 Hz, 1 H), 7. 35 (s, 1 H), 7. 36 (d, J = 8.7 Hz, 1 H).
ESI-MS: m / z = 202 (M + H) + .
（参考例２７）２－（２－クロロ－４－ニトロベンジル）－６－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000051
 　参考例２６の化合物（７．５０ｇ，３７．３ｍｍｏｌ）をジクロロメタン（１１３ｍＬ）に溶解し、参考例１の化合物（６．９２ｇ，３７．３ｍｍｏｌ）及び酢酸（１．０７ｍＬ）を室温で加えた。室温で１５分間撹拌した後、水素化トリアセトキシホウ素ナトリウム（１１．９ｇ，５５．９ｍｍｏｌ）を０℃で加えた。室温で４時間撹拌した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９５／５～８５／１５）で精製し、表題化合物（以下、参考例２７の化合物）（１２．１ｇ，３２．５ｍｍｏｌ，８７％）を黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８５（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．００（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．７７（ｓ，２Ｈ），３．８８（ｓ，２Ｈ），７．１２（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．３９（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．４０（ｓ，１Ｈ），７．８０（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），８．１３（ｄｄ，Ｊ＝８．７，２．３Ｈｚ，１Ｈ）８．２７（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３７１（Ｍ＋Ｈ）＋． Reference Example 27 Synthesis of 2- (2-chloro-4-nitrobenzyl) -6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000051
 The compound of Reference Example 26 (7.50 g, 37.3 mmol) was dissolved in dichloromethane (113 mL), and the compound of Reference Example 1 (6.92 g, 37.3 mmol) and acetic acid (1.07 mL) were added at room temperature. After stirring for 15 minutes at room temperature, sodium triacetoxyborohydride (11.9 g, 55.9 mmol) was added at 0 ° C. After stirring at room temperature for 4 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 85/15), and the title compound (hereinafter, the compound of Reference Example 27) (12.1 g, 32.5 mmol, 87) %) As a yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.85 (t, J = 5.7 Hz, 2 H), 3.00 (t, J = 5.7 Hz, 2 H), 3.77 (s, 2 H) , 3.88 (s, 2H), 7.12 (d, J = 7.8 Hz, 1 H), 7.39 (d, J = 8.7 Hz, 1 H), 7.40 (s, 1 H), 7 80 (d, J = 8.7 Hz, 1 H), 8.13 (dd, J = 8.7, 2.3 Hz, 1 H) 8.27 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 371 (M + H) + .
（参考例２８）３－クロロ－４－（（６－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000052
 　参考２７の化合物（１１．５ｇ，３１．０ｍｍｏｌ）をＴＨＦ（３８．８ｍＬ）に溶解し、エタノール（３８．８ｍＬ）、蒸留水（３８．８ｍＬ）、鉄粉（８．６６ｇ，１５５ｍｍｏｌ）及び酢酸（８．８８ｍＬ，１５５ｍｍｏｌ）を室温で加えた。５０℃で２．５時間撹拌した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝８５／１５～７０／３０）で精製し、表題化合物（以下、参考例２８の化合物）（１０．６ｇ，４０．８ｍｍｏｌ，定量的）を黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８０（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），２．９３（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．７０（ｓ，６Ｈ），６．５７（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），７．１０（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ），７．２５（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．３４（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．３５（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３４１（Ｍ＋Ｈ）＋． Reference Example 28 Synthesis of 3-chloro-4-((6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline:
Figure JPOXMLDOC01-appb-C000052
 Reference 27 compound (11.5 g, 31.0 mmol) is dissolved in THF (38.8 mL), ethanol (38.8 mL), distilled water (38.8 mL), iron powder (8.66 g, 155 mmol) and acetic acid (8.88 mL, 155 mmol) was added at room temperature. After stirring at 50 ° C. for 2.5 hours, a saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 85/15 to 70/30), and the title compound (hereinafter, the compound of Reference Example 28) (10.6 g, 40.8 mmol, quantitative) ) As a yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.80 (t, J = 5.7 Hz, 2 H), 2.93 (t, J = 5.7 Hz, 2 H), 3.70 (s, 6 H) , 6.57 (dd, J = 8.2, 2.3 Hz, 1 H), 6.72 (d, J = 2.3 Hz, 1 H), 7. 10 (d, J = 7.3 Hz, 1 H), 7.25 (d, J = 8.2 Hz, 1 H), 7.34 (d, J = 8.2 Hz, 1 H), 7. 35 (s, 1 H).
ESI-MS: m / z = 341 (M + H) <+> .
（参考例２９）（Ｒ）－２－（（３－クロロ－４－（（６－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000053
 　参考例８の化合物の代わりに参考例２８の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例２９の化合物）（０．１０６ｇ，０．１９２ｍｍｏｌ，９４％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．５２－１．７２（ｍ，１５Ｈ），２．３３（ｓ，１Ｈ），２．８１（ｔ，Ｊ＝５．７Ｈｚ，３Ｈ），２．９４（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．７１（ｓ，２Ｈ），３．７７（ｓ，２Ｈ），４．０８（ｂｒｓ，１Ｈ），４．８５（ｓ，１Ｈ），７．１０（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ），７．３０（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．３５（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．３６（ｓ，１Ｈ），７．４６（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．７３（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５５２（Ｍ＋Ｈ）＋． Reference Example 29 (R) -2-((3-Chloro-4-((6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl:
Figure JPOXMLDOC01-appb-C000053
 Using the compound of Reference Example 28 instead of the compound of Reference Example 8, and according to the same procedure as Reference Example 9 except the above, the title compound (hereinafter, the compound of Reference Example 29) (0.106 g, 0.192 mmol, 94 %) As a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.52-1.72 (m, 15 H), 2.33 (s, 1 H), 2.81 (t, J = 5.7 Hz, 3 H), 2 .94 (t, J = 5.7 Hz, 2 H), 3.71 (s, 2 H), 3.77 (s, 2 H), 4.08 (brs, 1 H), 4. 85 (s, 1 H), 7.10 (d, J = 7.3 Hz, 1 H), 7.30 (dd, J = 8.2, 2.3 Hz, 1 H), 7.35 (d, J = 8.7 Hz, 1 H), 7 36 (s, 1 H), 7.46 (d, J = 8.7 Hz, 1 H), 7.73 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 552 (M + H) + .
（実施例８）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（（６－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）ピペリジン－２－カルボキサミド　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000054
 　参考例２９の化合物（０．０５００ｇ，０．０９０６ｍｍｏｌ）をジクロロメタン（０．９０６ｍＬ）に溶解し、トリフルオロ酢酸（０．１０５ｍＬ，１．３６ｍｍｏｌ）を０℃で加えた。室温で２時間撹拌した後、反応液を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物をジクロロメタン（０．９０６ｍＬ）に溶解し、トリエチルアミン（０．０６３１ｍＬ，０．４５３ｍｍｏｌ）及びアセチルクロリド（０．０１２８ｍＬ，０．１３６ｍｍｏｌ）を０℃で加えた。室温で１２時間撹拌した後、反応液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝５０／５０～５／９５）で精製した。得られた精製物を酢酸エチル（１．０ｍＬ）に溶解し、１０重量％塩化水素－メタノール溶液（１．０ｍＬ）を室温で加えた。反応液を減圧濃縮した後、晶析（酢酸エチル／ジエチルエーテル）、濾過し、濾取した固体を乾燥し、表題化合物（以下、実施例８の化合物）（０．０１９６ｇ，０．０３７０ｍｍｏｌ，４１％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ３ＯＤ）δ：１．５２－１．６７（ｍ，２Ｈ），１．７４－１．８８（ｍ，３Ｈ），２．１９－２．２６（ｍ，４Ｈ），３．３０（ｔ，Ｊ＝６．２Ｈｚ，２Ｈ），３．５８（ｔｄ，Ｊ＝１２．８，３．２Ｈｚ，１Ｈ），３．７０（ｂｒｓ，２Ｈ），３．９０（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），４．５５（ｓ，２Ｈ），４．６２（ｓ，２Ｈ），５．２２（ｄｄ，Ｊ＝６．２，２．５Ｈｚ，１Ｈ），７．４３（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．６０（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．６４－７．７１（ｍ，３Ｈ），８．００（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４９４（Ｍ＋Ｈ）＋． Example 8 (R) -1-Acetyl-N- (3-chloro-4-((6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) Synthesis of piperidine-2-carboxamide hydrochloride:
Figure JPOXMLDOC01-appb-C000054
 The compound of Reference Example 29 (0.0500 g, 0.0906 mmol) was dissolved in dichloromethane (0.906 mL), and trifluoroacetic acid (0.105 mL, 1.36 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product was dissolved in dichloromethane (0.906 mL) and triethylamine (0.0631 mL, 0.453 mmol) and acetyl chloride (0.0128 mL, 0.136 mmol) were added at 0 ° C. After stirring at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/50 to 5/95). The purified product obtained was dissolved in ethyl acetate (1.0 mL), and 10 wt% hydrogen chloride-methanol solution (1.0 mL) was added at room temperature. The reaction mixture is concentrated under reduced pressure, crystallized (ethyl acetate / diethyl ether), filtered, and the solid collected by filtration is dried, and the title compound (hereinafter, the compound of Example 8) (0.0196 g, 0.0370 mmol, 41) %) As a white solid.
1 H-NMR (400 MHz, CD 3 OD) δ: 1.52-1.67 (m, 2 H), 1.74-1. 88 (m, 3 H), 2.19-2.26 (m, 4 H) ), 3.30 (t, J = 6.2 Hz, 2 H), 3.58 (td, J = 12.8, 3.2 Hz, 1 H), 3.70 (brs, 2 H), 3. 90 (d , J = 13.3 Hz, 1 H), 4.55 (s, 2 H), 4.62 (s, 2 H), 5.22 (dd, J = 6.2, 2.5 Hz, 1 H), 7.43 (D, J = 8.2 Hz, 1 H), 7.60 (d, J = 8.2 Hz, 1 H), 7.64-7.71 (m, 3 H), 8.00 (s, 1 H).
ESI-MS: m / z = 494 (M + H) <+> .
（参考例３０）８－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000055
 　参考例５の化合物の代わりに参考例２５の化合物を用いて、それ以外は参考例６と同様の手順により、表題化合物（以下、参考例３０の化合物）（０．１９０ｇ，０．９４４ｍｍｏｌ，９４％）を黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８７（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），３．１５（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），４．１７（ｓ，２Ｈ），７．２２（ｔ，Ｊ＝７．５Ｈｚ，１Ｈ），７．２７（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ），７．４６（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２０２（Ｍ＋Ｈ）＋． Reference Example 30 Synthesis of 8- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000055
 Using the compound of Reference Example 25 instead of the compound of Reference Example 5, and according to the same procedure as Reference Example 6 except the above, the title compound (hereinafter, the compound of Reference Example 30) (0.190 g, 0.944 mmol, 94 %) As a yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.87 (t, J = 5.9 Hz, 2 H), 3. 15 (t, J = 5.9 Hz, 2 H), 4. 17 (s, 2 H) , 7.22 (t, J = 7.5 Hz, 1 H), 7. 27 (d, J = 7.3 Hz, 1 H), 7.46 (d, J = 7.8 Hz, 1 H).
ESI-MS: m / z = 202 (M + H) + .
（参考例３１）２－（２－クロロ－４－ニトロベンジル）－８－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000056
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例３０の化合物を用いて、それ以外は参考例２と同様の手順により、表題化合物（以下、参考例３１の化合物）（０．２９６ｇ，０．７９８ｍｍｏｌ，８７％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８２（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），３．０１（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），３．９０（ｓ，２Ｈ），３．９１（ｓ，２Ｈ），７．２６（ｔ，Ｊ＝７．８Ｈｚ，１Ｈ），７．３２（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．８０（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），８．１２（ｄｄ，Ｊ＝８．７，２．３Ｈｚ，１Ｈ），８．２７（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３７１（Ｍ＋Ｈ）＋． Reference Example 31 Synthesis of 2- (2-chloro-4-nitrobenzyl) -8- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000056
 Using the compound of Reference Example 30 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 2 except for the above, the title compound (hereinafter referred to as the compound of Reference Example 31) (0. 1). 296 g (0.798 mmol, 87%) were obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.82 (t, J = 5.9 Hz, 2 H), 3.01 (t, J = 5.9 Hz, 2 H), 3. 90 (s, 2 H) , 3.91 (s, 2H), 7.26 (t, J = 7.8 Hz, 1 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.48 (d, J = 7. 6). 8 Hz, 1 H), 7. 80 (d, J = 8.7 Hz, 1 H), 8. 12 (dd, J = 8.7, 2.3 Hz, 1 H), 8. 27 (d, J = 2.3 Hz) , 1 H).
ESI-MS: m / z = 371 (M + H) + .
（参考例３２）３－クロロ－４－（（８－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000057
 　参考例７の化合物の代わりに参考例３１の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例３２の化合物）（０．１９２ｇ，０．５６３ｍｍｏｌ，８４％）を黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８０（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），２．９３（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．７０（ｓ，６Ｈ），６．５７（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），７．１０（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ），７．２５（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．３４（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．３５（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３４１（Ｍ＋Ｈ）＋． Reference Example 32 Synthesis of 3-chloro-4-((8- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline:
Figure JPOXMLDOC01-appb-C000057
 Using the compound of Reference Example 31 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 32) (0.192 g, 0.563 mmol, 84 %) As a yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.80 (t, J = 5.7 Hz, 2 H), 2.93 (t, J = 5.7 Hz, 2 H), 3.70 (s, 6 H) , 6.57 (dd, J = 8.2, 2.3 Hz, 1 H), 6.72 (d, J = 2.3 Hz, 1 H), 7. 10 (d, J = 7.3 Hz, 1 H), 7.25 (d, J = 8.2 Hz, 1 H), 7.34 (d, J = 8.2 Hz, 1 H), 7. 35 (s, 1 H).
ESI-MS: m / z = 341 (M + H) <+> .
（参考例３３）（Ｒ）－２－（（３－クロロ－４－（（８－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000058
 　参考例８の化合物の代わりに参考例３２の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例３３の化合物）（０．１００ｇ，０．１８１ｍｍｏｌ，８８％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４６－１．７３（ｍ，１５Ｈ），２．３５（ｓ，１Ｈ），２．７６（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），２．８２（ｔｄ，Ｊ＝１３．４，２．９Ｈｚ，１Ｈ），２．９５（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），３．７９（ｓ，２Ｈ），３．８９（ｓ，２Ｈ），４．０８（ｂｒｓ，１Ｈ），４．８５（ｓ，１Ｈ），７．２２（ｔ，Ｊ＝７．５Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．３０（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．４６（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．７３（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５５２（Ｍ＋Ｈ）＋． Reference Example 33 (R) -2-((3-Chloro-4-((8- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl:
Figure JPOXMLDOC01-appb-C000058
 Using the compound of Reference Example 32 instead of the compound of Reference Example 8, and according to the same procedure as Reference Example 9 except the above, the title compound (hereinafter, the compound of Reference Example 33) (0. 100 g, 0.181 mmol, 88) %) As a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.46 to 1.73 (m, 15 H), 2.35 (s, 1 H), 2.76 (t, J = 5.9 Hz, 2 H), 2 .82 (td, J = 13.4, 2.9 Hz, 1 H), 2.95 (t, J = 5.9 Hz, 2 H), 3.79 (s, 2 H), 3.89 (s, 2 H) , 4.08 (brs, 1 H), 4.85 (s, 1 H), 7.22 (t, J = 7.5 Hz, 1 H), 7.28 (d, J = 8.7 Hz, 1 H), 7 30 (dd, J = 8.2, 2.3 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 2 H), 7.73 (d, J = 1.8 Hz, 1 H).
ESI-MS: m / z = 552 (M + H) + .
（実施例９）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（（８－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）ピペリジン－２－カルボキサミド　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000059
 　参考例２９の化合物の代わりに参考例３３の化合物を用いて、それ以外は実施例８と同様の手順により、表題化合物（以下、実施例９の化合物）（０．０３７５ｇ，０．０７０７ｍｍｏｌ，７８％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ３ＯＤ）δ：１．５２－１．６０（ｍ，２Ｈ），１．７２－１．７９（ｍ，３Ｈ），２．１８－２．２３（ｍ，４Ｈ），３．２８（ｔ，Ｊ＝６．４Ｈｚ，２Ｈ），３．５５（ｔｄ，Ｊ＝１２．７，３．４Ｈｚ，１Ｈ），３．６５（ｂｒｓ，２Ｈ），３．８６（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），４．５９（ｓ，２Ｈ），４．６３（ｓ，２Ｈ），５．１９（ｄｄ，Ｊ＝６．４，２．３Ｈｚ，１Ｈ），７．４８－７．５６（ｍ，２Ｈ），７．６０－７．６７（ｍ，３Ｈ），７．９７（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４９４（Ｍ＋Ｈ）＋． Example 9 (R) -1-Acetyl-N- (3-chloro-4-((8- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) Synthesis of piperidine-2-carboxamide hydrochloride:
Figure JPOXMLDOC01-appb-C000059
 Using the compound of Reference Example 33 instead of the compound of Reference Example 29, and using the same procedure as Example 8 except for the above, the title compound (the compound of Example 9 below) (0.0375 g, 0.0707 mmol, 78) %) As a white solid.
1 H-NMR (400 MHz, CD 3 OD) δ: 1.52-1.60 (m, 2 H), 1.72-1. 79 (m, 3 H), 2.18-2.23 (m, 4 H) ), 3.28 (t, J = 6.4 Hz, 2 H), 3.55 (td, J = 12.7, 3.4 Hz, 1 H), 3.65 (brs, 2 H), 3.86 (d) , J = 13.7 Hz, 1 H), 4.59 (s, 2 H), 4.63 (s, 2 H), 5. 19 (dd, J = 6.4, 2.3 Hz, 1 H), 7.48 -7.56 (m, 2H), 7.60-7.67 (m, 3H), 7.97 (d, J = 1.8 Hz, 1 H).
ESI-MS: m / z = 494 (M + H) <+> .
（参考例３４）２－フルオロ－４－ニトロベンズアルデヒドの合成：
Figure JPOXMLDOC01-appb-C000060
 　２－フルオロ－４－ニトロ安息香酸（１．００ｇ，５．４０ｍｍｏｌ）をＴＨＦ（１０．１ｍＬ）に溶解し、ボランＴＨＦ錯体－ＴＨＦ溶液（０．９０Ｍ，９．００ｍＬ，８．１０ｍｍｏｌ）を０℃で加えた。室温で２時間撹拌した後、反応液に蒸留水を加え、酢酸エチルで抽出した。有機層を炭酸水素ナトリウム水溶液及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物をジクロロメタン（１５．２ｍＬ）に溶解し、飽和炭酸水素ナトリウム水溶液（１５．２ｍＬ）、臭化カリウム（０．１８１ｇ，１．５２ｍｍｏｌ）、ＴＥＭＰＯ（０．００４８ｇ，０．０３０ｍｍｏｌ）及び６重量％次亜塩素酸ナトリウム水溶液（１．８９ｍＬ）を０℃で加えた。同温度で３時間撹拌した後、反応液に蒸留水を加え、クロロホルムで抽出した。有機層を飽和チオ硫酸ナトリウム水溶液、蒸留水及び飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９５／５～９０／１０）で精製し、表題化合物（以下、参考例３４の化合物）（０．１２８ｇ，０．７５７ｍｍｏｌ，１４％）を黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：８．０７－８．１１（ｍ，２Ｈ），８．１４－８．１７（ｍ，１Ｈ），１０．４５（ｓ，１Ｈ）． (Reference Example 34) Synthesis of 2-fluoro-4-nitrobenzaldehyde:
Figure JPOXMLDOC01-appb-C000060
 Dissolve 2-fluoro-4-nitrobenzoic acid (1.00 g, 5.40 mmol) in THF (10.1 mL) and add borane THF complex-THF solution (0.90 M, 9.00 mL, 8.10 mmol) to 0. Added at ° C. After stirring at room temperature for 2 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product is dissolved in dichloromethane (15.2 mL), saturated aqueous sodium hydrogen carbonate solution (15.2 mL), potassium bromide (0.181 g, 1.52 mmol), TEMPO (0.0048 g, 0.030 mmol) And 6 wt% aqueous sodium hypochlorite solution (1.89 mL) were added at 0.degree. After stirring for 3 hours at the same temperature, distilled water was added to the reaction solution, and extracted with chloroform. The organic layer was washed with saturated aqueous sodium thiosulfate solution, distilled water and saturated brine, then dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5 to 90/10), and the title compound (hereinafter, the compound of Reference Example 34) (0.128 g, 0.757 mmol, 14) %) As a yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 8.07-8.11 (m, 2H), 8.14-8.17 (m, 1H), 10.45 (s, 1H).
（参考例３５）２－（２－フルオロ－４－ニトロベンジル）－７－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000061
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の化合物の代わりに参考例１８の化合物を、参考例１の化合物の代わりに参考例３４の化合物を用いて、それ以外は参考例２と同様の手順により、表題化合物（以下、参考例３５の化合物）（０．１２６ｇ，０．３５６ｍｍｏｌ，７９％）を薄褐色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８２（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），２．９８（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．７３（ｓ，２Ｈ），３．８５（ｓ，２Ｈ），７．２３（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．２６（ｓ，１Ｈ），７．４０（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．７３（ｔ，Ｊ＝７．８Ｈｚ，１Ｈ），７．９５（ｄｄ，Ｊ＝９．６，２．３Ｈｚ，１Ｈ），８．０４（ｄｄ，Ｊ＝８．５，１．６Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３５５（Ｍ＋Ｈ）＋． Reference Example 35 Synthesis of 2- (2-fluoro-4-nitrobenzyl) -7- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000061
 The compound of Reference Example 18 is used in place of the compound of 1,2,3,4-tetrahydroisoquinoline hydrochloride, and the compound of Reference Example 34 is used in place of the compound of Reference Example 1; Through the procedure, the title compound (hereinafter, the compound of Reference Example 35) (0.126 g, 0.356 mmol, 79%) was obtained as a pale brown solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.82 (t, J = 5.9 Hz, 2 H), 2.98 (t, J = 5.7 Hz, 2 H), 3.73 (s, 2 H) , 3.85 (s, 2H), 7.23 (d, J = 7.8 Hz, 1 H), 7.26 (s, 1 H), 7.40 (d, J = 8.7 Hz, 1 H), 7 .73 (t, J = 7.8 Hz, 1 H), 7.95 (dd, J = 9.6, 2.3 Hz, 1 H), 8.04 (dd, J = 8.5, 1.6 Hz, 1 H) ).
ESI-MS: m / z = 355 (M + H) + .
（参考例３６）３－フルオロ－４－（（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000062
 　参考例７の化合物の代わりに参考例３５の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例３６の化合物）（０．０６９５ｇ，０．２１４ｍｍｏｌ，６１％）を黄色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．７７（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），２．９３（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．６６（ｓ，４Ｈ），３．７５（ｂｒｓ，２Ｈ），６．３９（ｄｄ，Ｊ＝１１．９，２．３Ｈｚ，１Ｈ），６．４４（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．１５（ｔ，Ｊ＝８．２Ｈｚ，１Ｈ），７．１８（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ），７．２５（ｓ，１Ｈ），７．３５（ｄｄ，Ｊ＝８．２，１．４Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３２５（Ｍ＋Ｈ）＋． Reference Example 36 Synthesis of 3-fluoro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) aniline:
Figure JPOXMLDOC01-appb-C000062
 Using the compound of Reference Example 35 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 36) (0.0695 g, 0.214 mmol, 61) %) As a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.77 (t, J = 5.9 Hz, 2 H), 2.93 (t, J = 5.7 Hz, 2 H), 3.66 (s, 4 H) , 3.75 (brs, 2H), 6.39 (dd, J = 11.9, 2.3 Hz, 1 H), 6.44 (dd, J = 8.2, 2.3 Hz, 1 H), 7. 15 (t, J = 8.2 Hz, 1 H), 7. 18 (d, J = 7.3 Hz, 1 H), 7. 25 (s, 1 H), 7. 35 (dd, J = 8.2, 1 .4 Hz, 1 H).
ESI-MS: m / z = 325 (M + H) + .
（参考例３７）（Ｒ）－２－（（３－フルオロ－４－（（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000063
 　参考例８の化合物の代わりに参考例３６の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例３７の化合物）（０．０４８５ｇ，０．０９０６ｍｍｏｌ，７３％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４６－１．７２（ｍ，１５Ｈ），２．３３（ｄ，Ｊ＝１１．９Ｈｚ，１Ｈ），２．７７－２．８４（ｍ，３Ｈ），２．９４（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．６７（ｓ，２Ｈ），３．７２（ｓ，２Ｈ），４．０７（ｂｒｓ，１Ｈ），４．８５（ｓ，１Ｈ），７．０８（ｄｄ，Ｊ＝８．２，１．８Ｈｚ，１Ｈ），７．１９（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．２５－７．２６（ｍ，１Ｈ），７．３４－７．３８（ｍ，２Ｈ），７．５４（ｄｄ，Ｊ＝１１．７，２．１Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５３６（Ｍ＋Ｈ）＋． Reference Example 37 (R) -2-((3-fluoro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) carbamoyl) piperidine Synthesis of -1-carboxylic acid tert-butyl:
Figure JPOXMLDOC01-appb-C000063
 Using the compound of Reference Example 36 instead of the compound of Reference Example 8, and using the same procedure as Reference Example 9 except the above, the title compound (hereinafter, the compound of Reference Example 37) (0.0485 g, 0.0906 mmol, 73 %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.46 to 1.72 (m, 15 H), 2.33 (d, J = 11.9 Hz, 1 H), 2.77 to 2.84 (m, 5) 3H), 2.94 (t, J = 5.7 Hz, 2H), 3.67 (s, 2H), 3.72 (s, 2H), 4.07 (brs, 1H), 4.85 (s) , 1 H), 7.08 (dd, J = 8.2, 1.8 Hz, 1 H), 7.19 (d, J = 7.8 Hz, 1 H), 7.25-7.26 (m, 1 H) , 7.34-7.38 (m, 2H), 7.54 (dd, J = 11.7, 2.1 Hz, 1 H).
ESI-MS: m / z = 536 (M + H) + .
（実施例１０）（Ｒ）－１－アセチル－Ｎ－（３－フルオロ－４－（（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）メチル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000064
 　参考例９の化合物の代わりに参考例３７の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例１０の化合物）（０．０１４０ｇ，０．０２９３ｍｍｏｌ，７９％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４９－１．６１（ｍ，２Ｈ），１．７２－１．７８（ｍ，２Ｈ），１．９０－２．０１（ｍ，１Ｈ），２．２１（ｓ，３Ｈ），２．２８（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），２．７７（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），２．９３（ｔ，Ｊ＝５．５Ｈｚ，２Ｈ），３．１５（ｔｄ，Ｊ＝１３．３，２．７Ｈｚ，１Ｈ），３．６７（ｓ，２Ｈ），３．７１（ｓ，２Ｈ），３．７６（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），５．２６（ｄ，Ｊ＝５．５Ｈｚ，１Ｈ），７．０８（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．１９（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．２４（ｓ，１Ｈ），７．３４（ｔ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５２（ｄｄ，Ｊ＝１１．９，１．８Ｈｚ，１Ｈ），８．４９（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４６０（Ｍ＋Ｈ）＋． Example 10 (R) -1-Acetyl-N- (3-fluoro-4-((7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) methyl) phenyl) Synthesis of piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000064
 Using the compound of Reference Example 37 instead of the compound of Reference Example 9, and according to the same procedure as Example 2 except the above, the title compound (the compound of Example 10) (0.0140 g, 0.0293 mmol, 79) %) As a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49-1.61 (m, 2 H), 1.72-1. 78 (m, 2 H), 1.90-2.01 (m, 1 H) , 2.21 (s, 3 H), 2. 28 (d, J = 13.7 Hz, 1 H), 2.77 (t, J = 5.9 Hz, 2 H), 2.93 (t, J = 5. 5 Hz, 2H), 3.15 (td, J = 13.3, 2.7 Hz, 1 H), 3.67 (s, 2 H), 3.71 (s, 2 H), 3.76 (d, J = 13.7 Hz, 1 H), 5.26 (d, J = 5.5 Hz, 1 H), 7.08 (dd, J = 8.2, 2.3 Hz, 1 H), 7.19 (d, J = 8) .2 Hz, 1 H), 7.24 (s, 1 H), 7.34 (t, J = 8.2 Hz, 2 H), 7.52 (dd, J = 11.9, 1.8 Hz, 1 H), 8 .49 (brs, H).
ESI-MS: m / z = 460 (M + H) + .
（参考例３８）１－（２－クロロ－４－ニトロベンジル）インドリンの合成：
Figure JPOXMLDOC01-appb-C000065
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりにインドリンを用いて、それ以外は参考例２と同様の手順により、表題化合物（以下、参考例３８の化合物）（０．４０６ｇ，１．４１ｍｍｏｌ，８４％）を褐色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．０９（ｔ，Ｊ＝８．２Ｈｚ，２Ｈ），３．４９（ｔ，Ｊ＝８．２Ｈｚ，２Ｈ），４．３９（ｓ，２Ｈ），６．３３（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），６．７４（ｔｄ，Ｊ＝７．３，０．９Ｈｚ，１Ｈ），７．０５（ｔｄ，Ｊ＝７．８，１．４Ｈｚ，１Ｈ），７．１５（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．６８（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），８．１０（ｄｄ，Ｊ＝８．７，２．３Ｈｚ，１Ｈ），８．２９（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２８９（Ｍ＋Ｈ）＋． (Reference Example 38) Synthesis of 1- (2-chloro-4-nitrobenzyl) indoline:
Figure JPOXMLDOC01-appb-C000065
 Using indoline instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as in Reference Example 2 except for the above, the title compound (hereinafter, the compound of Reference Example 38) (0.406 g, 41 mmol, 84%) were obtained as a brown solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.09 (t, J = 8.2 Hz, 2 H), 3.49 (t, J = 8.2 Hz, 2 H), 4.39 (s, 2 H) , 6.33 (d, J = 7.8 Hz, 1 H), 6. 74 (td, J = 7.3, 0.9 Hz, 1 H), 7.05 (td, J = 7.8, 1.4 Hz , 1 H), 7.15 (d, J = 7.8 Hz, 1 H), 7.68 (d, J = 8.2 Hz, 1 H), 8. 10 (dd, J = 8.7, 2.3 Hz, 1H), 8.29 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 289 (M + H) + .
（参考例３９）３－クロロ－４－（インドリン－１－イルメチル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000066
 　参考例７の化合物の代わりに参考例３８の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例３９の化合物）（０．１３９ｇ，０．５３７ｍｍｏｌ，５２％）を無色油状物として得た
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．９８（ｔ，Ｊ＝８．２Ｈｚ，２Ｈ），３．３６（ｔ，Ｊ＝８．２Ｈｚ，２Ｈ），３．６９（ｂｒｓ，２Ｈ），４．２３（ｓ，２Ｈ），６．５０（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），６．５４（ｄｄ，Ｊ＝８．２，２．７Ｈｚ，１Ｈ），６．６６（ｔｄ，Ｊ＝７．３，０．９Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），７．０５（ｔｄ，Ｊ＝７．８，１．４Ｈｚ，１Ｈ），７．０９（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．１９（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２５９（Ｍ＋Ｈ）＋． Reference Example 39 Synthesis of 3-chloro-4- (indoline-1-ylmethyl) aniline:
Figure JPOXMLDOC01-appb-C000066
 Using the compound of Reference Example 38 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 39) (0.139 g, 0.537 mmol, 52) %) As a colorless oil
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.98 (t, J = 8.2 Hz, 2 H), 3.36 (t, J = 8.2 Hz, 2 H), 3.69 (brs, 2 H) , 4.23 (s, 2 H), 6.50 (d, J = 7.8 Hz, 1 H), 6.54 (dd, J = 8.2, 2.7 Hz, 1 H), 6.66 (td, J = 7.3, 0.9 Hz, 1 H, 6.73 (d, J = 2.3 Hz, 1 H), 7.05 (td, J = 7.8, 1.4 Hz, 1 H), 7.09 (D, J = 7.8 Hz, 1 H), 7.19 (d, J = 8.2 Hz, 1 H).
ESI-MS: m / z = 259 (M + H) + .
（参考例４０）（Ｒ）－２－（（３－クロロ－４－（インドリン－１－イルメチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000067
 　参考例８の化合物の代わりに参考例３９の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例４０の化合物）（０．０８８７ｇ，０．１８９ｍｍｏｌ，９８％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４５－１．７３（ｍ，１５Ｈ），２．３３（ｄ，Ｊ＝１１．４Ｈｚ，１Ｈ），２．８２（ｔ，Ｊ＝１１．４Ｈｚ，１Ｈ），３．０１（ｔ，Ｊ＝８．５Ｈｚ，２Ｈ），３．４０（ｔ，Ｊ＝８．２Ｈｚ，２Ｈ），４．０７（ｂｒｓ，１Ｈ），４．２９（ｓ，２Ｈ），４．８５（ｂｒｓ，１Ｈ），６．４４（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），６．６８（ｔ，Ｊ＝７．３Ｈｚ，１Ｈ），７．０４（ｔ，Ｊ＝７．５Ｈｚ，１Ｈ），７．１０（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ），７．２３（ｄｄ，Ｊ＝８．２，１．８Ｈｚ，１Ｈ），７．３７（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．７８（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４７０（Ｍ＋Ｈ）＋． Reference Example 40 Synthesis of tert-butyl (R) -2-((3-chloro-4- (indoline-1-ylmethyl) phenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000067
 The title compound (hereinafter, the compound of Reference Example 40) (0.0887 g, 0.189 mmol, 98) was prepared by using the compound of Reference Example 39 instead of the compound of Reference Example 8 and using the same procedure as in Reference Example 9 except the above. %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.45-1.73 (m, 15 H), 2.33 (d, J = 11.4 Hz, 1 H), 2.82 (t, J = 11. 4 Hz, 1 H), 3.01 (t, J = 8.5 Hz, 2 H), 3. 40 (t, J = 8.2 Hz, 2 H), 4.07 (brs, 1 H), 4. 29 (s, 2H), 4.85 (brs, 1 H), 6.44 (d, J = 7.8 Hz, 1 H), 6.68 (t, J = 7.3 Hz, 1 H), 7.04 (t, J = 7.5 Hz, 1 H), 7. 10 (d, J = 7.3 Hz, 1 H), 7.23 (dd, J = 8.2, 1.8 Hz, 1 H), 7.37 (d, J = 8 .7 Hz, 1 H), 7.78 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 470 (M + H) + .
（実施例１１）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（インドリン－１－イルメチル）フェニル）ピペリジン－２－カルボキサミド　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000068
 　参考例２９の化合物の代わりに参考例４０の化合物を用いて、それ以外は実施例８と同様の手順により、表題化合物（以下、実施例１１の化合物）（０．０３１３ｇ，０．０７６０ｍｍｏｌ，８９％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＤＭＳＯ－ｄ６）δ：１．３２－１．４５（ｍ，２Ｈ），１．５８－１．６８（ｍ，３Ｈ），２．０６（ｓ，３Ｈ），２．１２（ｄ，Ｊ＝１４．２Ｈｚ，１Ｈ），２．９０（ｔ，Ｊ＝８．０Ｈｚ，２Ｈ），３．２９（ｔ，Ｊ＝８．５Ｈｚ，２Ｈ），３．４１（ｓ，１Ｈ），３．７５（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），４．２６（ｓ，２Ｈ），５．１０（ｄ，Ｊ＝４．１Ｈｚ，１Ｈ），６．５２（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），６．６０（ｔ，Ｊ＝７．３Ｈｚ，１Ｈ），６．９８（ｔ，Ｊ＝７．８Ｈｚ，１Ｈ），７．０５（ｄ，Ｊ＝６．９Ｈｚ，１Ｈ），７．３８－７．５３（ｍ，２Ｈ），７．８５－７．９０（ｍ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４１２（Ｍ＋Ｈ）＋． Example 11 Synthesis of (R) -1-Acetyl-N- (3-chloro-4- (indoline-1-ylmethyl) phenyl) piperidine-2-carboxamide hydrochloride:
Figure JPOXMLDOC01-appb-C000068
 Using the compound of Reference Example 40 instead of the compound of Reference Example 29, and using the same procedure as Example 8 except for the above, the title compound (the compound of Example 11 below) (0.0313 g, 0.0760 mmol, 89) %) As a white amorphous.
1 H-NMR (400 MHz, DMSO-d 6 ) δ: 1.32-1.45 (m, 2 H), 1.58-1.68 (m, 3 H), 2.06 (s, 3 H), 2 .12 (d, J = 14. 2 Hz, 1 H), 2. 90 (t, J = 8.0 Hz, 2 H), 3. 29 (t, J = 8.5 Hz, 2 H), 3.41 (s, 1H), 3.75 (d, J = 13.3 Hz, 1 H), 4.26 (s, 2 H), 5. 10 (d, J = 4.1 Hz, 1 H), 6.52 (d, J = 7.8 Hz, 1 H), 6.60 (t, J = 7.3 Hz, 1 H), 6.98 (t, J = 7.8 Hz, 1 H), 7.05 (d, J = 6.9 Hz, 1 H) ], 7.38-7.53 (m, 2H), 7.85-7.90 (m, 1H).
ESI-MS: m / z = 412 (M + H) + .
（参考例４１）１－（２－クロロ－４－ニトロベンジル）－５－（トリフルオロメチル）インドリンの合成：
Figure JPOXMLDOC01-appb-C000069
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに５－（トリフルオロメチル）インドリンを用いて、それ以外は参考例２と同様の手順により、表題化合物（以下、参考例４１の化合物）（０．０５７６ｇ，０．１６１ｍｍｏｌ，２０％）を黄色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．１４（ｔ，Ｊ＝８．５Ｈｚ，２Ｈ），３．６０（ｔ，Ｊ＝８．７Ｈｚ，２Ｈ），４．４７（ｓ，２Ｈ），６．３１（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．３０（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．３４（ｓ，１Ｈ），７．５７（ｄ，Ｊ＝９．１Ｈｚ，１Ｈ），８．１１（ｄｄ，Ｊ＝８．５，２．１Ｈｚ，１Ｈ），８．３０（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３５７（Ｍ＋Ｈ）＋． Reference Example 41 Synthesis of 1- (2-chloro-4-nitrobenzyl) -5- (trifluoromethyl) indoline:
Figure JPOXMLDOC01-appb-C000069
 Title compound (following, compound of Reference Example 41) in the same manner as in Reference Example 2 except for using 5- (trifluoromethyl) indoline instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride (0.0576 g, 0.161 mmol, 20%) was obtained as a yellow solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.14 (t, J = 8.5 Hz, 2 H), 3.60 (t, J = 8.7 Hz, 2 H), 4.47 (s, 2 H) , 6.31 (d, J = 8.2 Hz, 1 H), 7.30 (d, J = 7.8 Hz, 1 H), 7.34 (s, 1 H), 7.57 (d, J = 9. 1 Hz, 1 H), 8.11 (dd, J = 8.5, 2.1 Hz, 1 H), 8.30 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 357 (M + H) + .
（参考例４２）３－クロロ－４－（（５－（トリフルオロメチル）インドリン－１－イル）メチル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000070
 　参考例７の化合物の代わりに参考例４１の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例４２の化合物）（０．０３０４ｇ，０．０９３０ｍｍｏｌ，５８％）を薄褐色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．０３（ｔ，Ｊ＝８．５Ｈｚ，２Ｈ），３．４８（ｔ，Ｊ＝８．５Ｈｚ，２Ｈ），３．７２（ｓ，２Ｈ），４．２９（ｓ，２Ｈ），６．４４（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），６．５４（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），６．７４（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），７．０９（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．２６（ｓ，１Ｈ），７．２９（ｄ，Ｊ＝９．１Ｈｚ，１Ｈ）． Reference Example 42 Synthesis of 3-chloro-4-((5- (trifluoromethyl) indoline-1-yl) methyl) aniline:
Figure JPOXMLDOC01-appb-C000070
 Using the compound of Reference Example 41 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 42) (0.0304 g, 0.0930 mmol, 58 %) As a light brown solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.03 (t, J = 8.5 Hz, 2 H), 3.48 (t, J = 8.5 Hz, 2 H), 3.72 (s, 2 H) , 4.29 (s, 2H), 6.44 (d, J = 8.2 Hz, 1 H), 6.54 (dd, J = 8.2, 2.3 Hz, 1 H), 6.74 (d, J) J = 2.3 Hz, 1 H), 7.09 (d, J = 8.2 Hz, 1 H), 7.26 (s, 1 H), 7. 29 (d, J = 9.1 Hz, 1 H).
（参考例４３）（Ｒ）－２－（（３－クロロ－４－（（５－（トリフルオロメチル）インドリン－１－イル）メチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000071
 　参考例８の化合物の代わりに参考例４２の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例４３の化合物）（０．０３２４ｇ，０．０６０２ｍｍｏｌ，６８％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４５－１．７３（ｍ，１５Ｈ），２．３２（ｄ，Ｊ＝１４．２Ｈｚ，１Ｈ），２．８１（ｔ，Ｊ＝１２．８Ｈｚ，１Ｈ），３．０６（ｔ，Ｊ＝８．５Ｈｚ，２Ｈ），３．５２（ｔ，Ｊ＝８．５Ｈｚ，２Ｈ），４．０７（ｂｒｓ，１Ｈ），４．３６（ｓ，２Ｈ），４．８５（ｂｒｓ，１Ｈ），６．３９（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．２５－７．３０（ｍ，４Ｈ），７．８０（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５３６（Ｍ－Ｈ）－． (Reference Example 43) (R) -2-((3-chloro-4-((5- (trifluoromethyl) indoline-1-yl) methyl) phenyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Synthesis:
Figure JPOXMLDOC01-appb-C000071
 The title compound (hereinafter, the compound of Reference Example 43) (0.0324 g, 0.0602 mmol, 68) was prepared by using the compound of Reference Example 42 instead of the compound of Reference Example 8 and using the same procedure as in Reference Example 9 except the above. %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.45-1.73 (m, 15 H), 2.32 (d, J = 14.2 Hz, 1 H), 2.81 (t, J = 12. 8 Hz, 1 H), 3.06 (t, J = 8.5 Hz, 2 H), 3.52 (t, J = 8.5 Hz, 2 H), 4.07 (brs, 1 H), 4.36 (s, 2H), 4.85 (brs, 1 H), 6.39 (d, J = 8.2 Hz, 1 H), 7.25-7.30 (m, 4 H), 7.80 (s, 1 H).
ESI-MS: m / z = 536 (M-H) - .
（実施例１２）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（（５－（トリフルオロメチル）インドリン－１－イル）メチル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000072
 　参考例９の化合物の代わりに参考例４３の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例１２の化合物）（０．０１０６ｇ，０．０２２１ｍｍｏｌ，６０％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４８－１．６２（ｍ，２Ｈ），１．７１－１．８０（ｍ，２Ｈ），１．９０－２．０１（ｍ，１Ｈ），２．２１（ｓ，３Ｈ），２．２７（ｄ，Ｊ＝１４．２Ｈｚ，１Ｈ），３．０５（ｔ，Ｊ＝８．５Ｈｚ，２Ｈ），３．１５（ｔｄ，Ｊ＝１３．２，２．６Ｈｚ，１Ｈ），３．５０（ｔ，Ｊ＝８．５Ｈｚ，２Ｈ），３．７７（ｄ，Ｊ＝１２．８Ｈｚ，１Ｈ），４．３５（ｓ，２Ｈ），５．２５（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．３９（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．２５－７．２９（ｍ，４Ｈ），７．７６（ｓ，１Ｈ），８．４９（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４７８（Ｍ－Ｈ）－． Example 12 Synthesis of (R) -1-acetyl-N- (3-chloro-4-((5- (trifluoromethyl) indoline-1-yl) methyl) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000072
 Using the compound of Reference Example 43 instead of the compound of Reference Example 9, and according to the same procedure as Example 2 except the above, the title compound (the compound of Example 12 below) (0.0106 g, 0.0221 mmol, 60) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.48-1.62 (m, 2 H), 1.71-1.80 (m, 2 H), 1.90-2.01 (m, 1 H) , 2.21 (s, 3 H), 2.27 (d, J = 14.2 Hz, 1 H), 3.05 (t, J = 8.5 Hz, 2 H), 3.15 (td, J = 13. 2, 2.6 Hz, 1 H), 3.50 (t, J = 8.5 Hz, 2 H), 3.77 (d, J = 12.8 Hz, 1 H), 4. 35 (s, 2 H), 5. 25 (d, J = 5.0 Hz, 1 H), 6.39 (d, J = 8.7 Hz, 1 H), 7.25-7. 29 (m, 4 H), 7.76 (s, 1 H), 8.49 (brs, 1 H).
ESI-MS: m / z = 478 (M-H) - .
（実施例１３）（Ｒ）－１－（２－（１Ｈ－テトラゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（（５－（トリフルオロメチル）インドリン－１－イル）メチル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000073
 　参考例４３の化合物（０．０１５０ｇ，０．０２７９ｍｍｏｌ）をジクロロメタン（０．２７９ｍＬ）に溶解し、トリフルオロ酢酸（０．０３２２ｍＬ，０．４１８ｍｍｏｌ）を０℃で加えた。室温で５時間撹拌した後、反応液を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物をＤＭＦ（０．２７９ｍＬ）に溶解し、２－（１Ｈ－テトラゾール－１－イル）酢酸（０．００５４ｇ，０．０４２ｍｍｏｌ）、ＨＡＴＵ（０．０１５９ｇ，０．０４１８ｍｍｏｌ）及びジイソプロピルエチルアミン（０．０２４４ｍＬ，０．１３９ｍｍｏｌ）を０℃で加えた。室温で１５時間撹拌した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝３０／７０～１０／９０）で精製し、表題化合物（以下、実施例１３の化合物）（０．００６６ｇ，０．０１２ｍｍｏｌ，４３％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．５８－１．６４（ｍ，１Ｈ），１．７２－１．８３（ｍ，２Ｈ），１．８８－１．９６（ｍ，２Ｈ），２．２９（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），３．０６（ｔ，Ｊ＝８．６Ｈｚ，２Ｈ），３．４７－３．５３（ｍ，３Ｈ），３．７４（ｄ，Ｊ＝１３．１Ｈｚ，１Ｈ），４．３５（ｓ，２Ｈ），５．１７（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），５．４０（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），５．４６（ｄ，Ｊ＝１６．３Ｈｚ，１Ｈ），６．３８（ｄ，Ｊ＝９．１Ｈｚ，１Ｈ），７．２１（ｄｄ，Ｊ＝８．４，２．０Ｈｚ，１Ｈ），７．２６－７．３０（ｍ，３Ｈ），７．７８（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），７．８７（ｓ，１Ｈ），８．８４（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５４８（Ｍ＋Ｈ）＋． Example 13 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4-((5- (trifluoromethyl) indoline-1-yl) Synthesis of methyl) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000073
 The compound of Reference Example 43 (0.0150 g, 0.0279 mmol) was dissolved in dichloromethane (0.279 mL), and trifluoroacetic acid (0.0322 mL, 0.418 mmol) was added at 0 ° C. After stirring for 5 hours at room temperature, the reaction solution was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product is dissolved in DMF (0.279 mL), 2- (1H-tetrazol-1-yl) acetic acid (0.0054 g, 0.042 mmol), HATU (0.0159 g, 0.0418 mmol) and diisopropyl Ethylamine (0.0244 mL, 0.139 mmol) was added at 0.degree. After stirring at room temperature for 15 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 30/70 to 10/90) to give the title compound (compound of Example 13 below) (0.0066 g, 0.012 mmol, 43) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.58-1.64 (m, 1 H), 1.72-1. 83 (m, 2 H), 1.88-1. 96 (m, 2 H) , 2.29 (d, J = 13.6 Hz, 1 H), 3.06 (t, J = 8.6 Hz, 2 H), 3.47-3. 53 (m, 3 H), 3.74 (d, 7) J = 13.1 Hz, 1 H), 4. 35 (s, 2 H), 5. 17 (d, J = 5.0 Hz, 1 H), 5. 40 (d, J = 16.8 Hz, 1 H), 5. 46 (d, J = 16.3 Hz, 1 H), 6.38 (d, J = 9.1 Hz, 1 H), 7.21 (dd, J = 8.4, 2.0 Hz, 1 H), 7.26 -7.30 (m, 3H), 7.78 (d, J = 1.8 Hz, 1 H), 7.87 (s, 1 H), 8.84 (s, 1 H).
ESI-MS: m / z = 548 (M + H) <+> .
（参考例４４）２－（２－クロロ－４－ニトロベンジル）－５－（トリフルオロメチル）イソインドリンの合成：
Figure JPOXMLDOC01-appb-C000074
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに５－（トリフルオロメチル）イソインドリンを用いて、それ以外は参考例２と同様の手順により、表題化合物（以下、参考例４４の化合物）（０．１０６ｇ，０．２９７ｍｍｏｌ，７９％）を褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：４．０９（ｓ，４Ｈ），４．１３（ｓ，２Ｈ），７．３２（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．４７（ｓ，１Ｈ），７．５０（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．８０（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），８．１５（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），８．２８（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３５７（Ｍ＋Ｈ）＋． Reference Example 44 Synthesis of 2- (2-chloro-4-nitrobenzyl) -5- (trifluoromethyl) isoindoline:
Figure JPOXMLDOC01-appb-C000074
 Using 5- (trifluoromethyl) isoindoline instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as in Reference Example 2 except for the title compound (the compound of Reference Example 44 below) ) (0.106 g, 0.297 mmol, 79%) was obtained as a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 4.09 (s, 4 H), 4. 13 (s, 2 H), 7.32 (d, J = 7.8 Hz, 1 H), 7.47 (s , 1 H), 7.50 (d, J = 7.8 Hz, 1 H), 7. 80 (d, J = 8.2 Hz, 1 H), 8. 15 (dd, J = 8.2, 2.3 Hz, 1H), 8.28 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 357 (M + H) + .
（参考例４５）３－クロロ－４－（（５－（トリフルオロメチル）イソインドリン－２－イル）メチル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000075
 　参考例７の化合物の代わりに参考例４４の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例４５の化合物）（０．０５６８ｇ，０．１７４ｍｍｏｌ，５９％）を褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．７１（ｓ，２Ｈ），３．９３（ｓ，２Ｈ），４．００（ｓ，４Ｈ），６．５８（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），７．２５（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．２７（ｄ，Ｊ＝７．３Ｈｚ，１Ｈ），７．４３（ｓ，１Ｈ），７．４４（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３２７（Ｍ＋Ｈ）＋． Reference Example 45 Synthesis of 3-chloro-4-((5- (trifluoromethyl) isoindolin-2-yl) methyl) aniline:
Figure JPOXMLDOC01-appb-C000075
 Using the compound of Reference Example 44 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 45) (0.0568 g, 0.174 mmol, 59) %) As a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.71 (s, 2 H), 3.93 (s, 2 H), 4.00 (s, 4 H), 6.58 (dd, J = 8.2 , 2.3 Hz, 1 H), 6.73 (d, J = 2.3 Hz, 1 H), 7. 25 (d, J = 8.2 Hz, 1 H), 7.27 (d, J = 7.3 Hz, 1H), 7.43 (s, 1 H), 7.44 (d, J = 8.2 Hz, 1 H).
ESI-MS: m / z = 327 (M + H) + .
（参考例４６）（Ｒ）－２－（（３－クロロ－４－（（５－（トリフルオロメチル）イソインドリン－２－イル）メチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000076
 　参考例８の化合物の代わりに参考例４５の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例４６の化合物）（０．０３３５ｇ，０．０６２３ｍｍｏｌ，７３％）を褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４６－１．７１（ｍ，１５Ｈ），２．３３（ｄ，Ｊ＝１２．８Ｈｚ，１Ｈ），２．８２（ｔ，Ｊ＝１１．７Ｈｚ，１Ｈ），４．００（ｓ，２Ｈ），４．０２（ｓ，４Ｈ），４．０７（ｂｒｓ，１Ｈ），４．８６（ｄ，Ｊ＝４．６Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝９．６Ｈｚ，１Ｈ），７．３２（ｄｄ，Ｊ＝８．５，２．１Ｈｚ，１Ｈ），７．４３（ｓ，１Ｈ），７．４６（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．７３（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５３８（Ｍ＋Ｈ）＋． (Reference Example 46) (R) -2-((3-Chloro-4-((5- (trifluoromethyl) isoindoline-2-yl) methyl) phenyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Composition of:
Figure JPOXMLDOC01-appb-C000076
 The title compound (hereinafter, the compound of Reference Example 46) (0.0335 g, 0.0623 mmol, 73) was prepared by using the compound of Reference Example 45 instead of the compound of Reference Example 8 and using the same procedure as in Reference Example 9 except the above. %) As a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.46 to 1.71 (m, 15 H), 2.33 (d, J = 12.8 Hz, 1 H), 2.82 (t, J = 11. 7 Hz, 1 H), 4.00 (s, 2 H), 4.02 (s, 4 H), 4.07 (brs, 1 H), 4.86 (d, J = 4.6 Hz, 1 H), 7.28 (D, J = 9.6 Hz, 1 H), 7.32 (dd, J = 8.5, 2.1 Hz, 1 H), 7.43 (s, 1 H), 7.46 (d, J = 8. 2 Hz, 2 H), 7.73 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 538 (M + H) + .
（実施例１４）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（（５－（トリフルオロメチル）イソインドリン－２－イル）メチル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000077
 　参考例９の化合物の代わりに参考例４６の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例１４の化合物）（０．０１２６ｇ，０．０２６３ｍｍｏｌ，４３％）を淡赤色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．５５－１．５７（ｍ，１Ｈ），１．７２－１．８０（ｍ，２Ｈ），１．９１－１．９９（ｍ，１Ｈ），２．２０－２．２２（ｍ，１Ｈ），２．２２（ｓ，３Ｈ），２．２６－２．３１（ｍ，１Ｈ），３．１５（ｔｄ，Ｊ＝１３．２，２．６Ｈｚ，１Ｈ），３．７７（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），３．９９（ｓ，２Ｈ），４．０１（ｓ，４Ｈ），５．２６（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．３３（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．４３－７．４７（ｍ，３Ｈ），７．７１（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），８．４６（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４８０（Ｍ＋Ｈ）＋． Example 14 Synthesis of (R) -1-Acetyl-N- (3-chloro-4-((5- (trifluoromethyl) isoindoline-2-yl) methyl) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000077
 Using the compound of Reference Example 46 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 14 below) (0.0126 g, 0.0263 mmol, 43) %) Was obtained as pale red amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.55-1.57 (m, 1 H), 1.72-1. 80 (m, 2 H), 1.91-1.99 (m, 1 H) , 2.20-2.22 (m, 1 H), 2.22 (s, 3 H), 2.26-2.31 (m, 1 H), 3.15 (td, J = 13.2, 2. 6 Hz, 1 H), 3.77 (d, J = 13.7 Hz, 1 H), 3.99 (s, 2 H), 4.01 (s, 4 H), 5.26 (d, J = 5.0 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1 H), 7.33 (dd, J = 8.2, 2.3 Hz, 1 H), 7.43-7.47 (m, 3 H), 7.71 (d, J = 1.8 Hz, 1 H), 8.46 (s, 1 H).
ESI-MS: m / z = 480 (M + H) + .
（参考例４７）２－（２－クロロ－４－ニトロフェニル）－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000078
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩（１．００ｇ，５．８９ｍｍｏｌ）をＤＭＳＯ（１１．８ｍＬ）に溶解し、３－クロロ－４－フルオロニトロベンゼン（１．０４ｇ，５．８９ｍｍｏｌ）及びＮ－メチルモルホリン（１．１９ｇ，１１．８ｍｍｏｌ）を室温で加えた。１１０℃で１６時間撹拌した後、反応液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９５／５）で精製し、表題化合物（以下、参考例４７の化合物）（１．０５ｇ，３．６４ｍｍｏｌ，６２％）を黄褐色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．０７（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．６２（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），４．４３（ｓ，２Ｈ），７．１３（ｔ，Ｊ＝６．８Ｈｚ，２Ｈ），７．２１－７．２７（ｍ，３Ｈ），８．１１（ｔｄ，Ｊ＝５．７，２．７Ｈｚ，１Ｈ），８．２９（ｄ，Ｊ＝２．５Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２８９（Ｍ＋Ｈ）＋． Reference Example 47 Synthesis of 2- (2-chloro-4-nitrophenyl) -1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000078
 Dissolve 1,2,3,4-tetrahydroisoquinoline hydrochloride (1.00 g, 5.89 mmol) in DMSO (11.8 mL), 3-chloro-4-fluoronitrobenzene (1.04 g, 5.89 mmol) and N-methyl morpholine (1.19 g, 11.8 mmol) was added at room temperature. After stirring at 110 ° C. for 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 95/5), and the title compound (hereinafter, the compound of Reference Example 47) (1.05 g, 3.64 mmol, 62%) was yellowed. Obtained as a brown solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.07 (t, J = 5.7 Hz, 2 H), 3.62 (t, J = 5.7 Hz, 2 H), 4.43 (s, 2 H) , 7.13 (t, J = 6.8 Hz, 2 H), 7.21-7. 27 (m, 3 H), 8.11 (td, J = 5.7, 2.7 Hz, 1 H), 8. 29 (d, J = 2.5 Hz, 1 H).
ESI-MS: m / z = 289 (M + H) + .
（参考例４８）３－クロロ－４－（３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000079
 　参考例７の化合物の代わりに参考例４７の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例４８の化合物）（０．８７２ｇ，３．３７ｍｍｏｌ，９７％）を薄赤色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．００（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．２７（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），３．５５（ｓ，２Ｈ），４．１７（ｓ，２Ｈ），６．５６（ｄｄ，Ｊ＝８．６，２．７Ｈｚ，１Ｈ），６．７８（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），６．９６（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．０９－７．１１（ｍ，１Ｈ），７．１５－７．２０（ｍ，３Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２５９（Ｍ＋Ｈ）＋． Reference Example 48 Synthesis of 3-chloro-4- (3,4-dihydroisoquinolin-2 (1H) -yl) aniline:
Figure JPOXMLDOC01-appb-C000079
 Using the compound of Reference Example 47 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 48) (0.872 g, 3.37 mmol, 97 %) As a pale red oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.00 (t, J = 5.7 Hz, 2 H), 3.27 (t, J = 5.9 Hz, 2 H), 3.55 (s, 2 H) , 4.17 (s, 2 H), 6.56 (dd, J = 8.6, 2.7 Hz, 1 H), 6.78 (d, J = 2.7 Hz, 1 H), 6.96 (d, J = 8.6 Hz, 1 H), 7.09-7.11 (m, 1 H), 7.15-7.20 (m, 3 H).
ESI-MS: m / z = 259 (M + H) + .
（参考例４９）（Ｒ）－２－（（３－クロロ－４－（３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000080
 　参考例８の化合物の代わりに参考例４８の化合物を、ジイソプロピルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例４９の化合物）（０．７６６ｇ，１．６３ｍｍｏｌ，８４％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４９（ｓ，９Ｈ），１．５６－１．６９（ｍ，６Ｈ），２．３３（ｄ，Ｊ＝１２．０Ｈｚ，１Ｈ），２．８３（ｔ，Ｊ＝１２．０Ｈｚ，１Ｈ），３．０１（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），３．３５（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），４．１２－４．１５（ｍ，１Ｈ），４．２３（ｓ，２Ｈ），４．８５（ｓ，１Ｈ），７．０４－７．１０（ｍ，２Ｈ），７．１１－７．１３（ｍ，３Ｈ），７．３１（ｄｄ，Ｊ＝８．６，２．３Ｈｚ，１Ｈ），７．６８（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４７０（Ｍ＋Ｈ）＋． Reference Example 49 Synthesis of tert-butyl (R) -2-((3-chloro-4- (3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000080
 The title compound (hereinafter, the compound of Reference Example 49) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 48 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. .766 g, 1.63 mmol, 84%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49 (s, 9 H), 1.56-1.69 (m, 6 H), 2.33 (d, J = 12.0 Hz, 1 H), 2 .83 (t, J = 12.0 Hz, 1 H), 3.01 (t, J = 5.9 Hz, 2 H), 3.35 (t, J = 5.9 Hz, 2 H), 4.12-4. 15 (m, 1 H), 4.23 (s, 2 H), 4. 85 (s, 1 H), 7.04-7. 10 (m, 2 H), 7.11-7. 13 (m, 3 H) , 7.31 (dd, J = 8.6, 2.3 Hz, 1 H), 7.68 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 470 (M + H) + .
（実施例１５）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000081
 　参考例９の化合物の代わりに参考例４９の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例１５の化合物）（０．０１２６ｇ，０．０２６３ｍｍｏｌ，４３％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．５５－１．５７（ｍ，１Ｈ），１．７２－１．８０（ｍ，２Ｈ），１．９１－１．９９（ｍ，１Ｈ），２．２０－２．２２（ｍ，１Ｈ），２．２２（ｓ，３Ｈ），２．２６－２．３１（ｍ，１Ｈ），３．１５（ｔｄ，Ｊ＝１３．２，２．６Ｈｚ，１Ｈ），３．７７（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），３．９９（ｓ，２Ｈ），４．０１（ｓ，４Ｈ），５．２６（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．３３（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．４３－７．４７（ｍ，３Ｈ），７．７１（ｄ，Ｊ＝１．８Ｈｚ，１Ｈ），８．４６（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４８０（Ｍ＋Ｈ）＋． EXAMPLE 15 Synthesis of (R) -1-acetyl-N- (3-chloro-4- (3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000081
 Using the compound of Reference Example 49 instead of the compound of Reference Example 9, and using the procedure of Example 2 except for the above, the title compound (the compound of Example 15 below) (0.0126 g, 0.0263 mmol, 43 %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.55-1.57 (m, 1 H), 1.72-1. 80 (m, 2 H), 1.91-1.99 (m, 1 H) , 2.20-2.22 (m, 1 H), 2.22 (s, 3 H), 2.26-2.31 (m, 1 H), 3.15 (td, J = 13.2, 2. 6 Hz, 1 H), 3.77 (d, J = 13.7 Hz, 1 H), 3.99 (s, 2 H), 4.01 (s, 4 H), 5.26 (d, J = 5.0 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1 H), 7.33 (dd, J = 8.2, 2.3 Hz, 1 H), 7.43-7.47 (m, 3 H), 7.71 (d, J = 1.8 Hz, 1 H), 8.46 (s, 1 H).
ESI-MS: m / z = 480 (M + H) + .
（実施例１６）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000082
 　参考例４９の化合物（０．３００ｇ，０．６３８ｍｍｏｌ）をジクロロメタン（６．３８ｍＬ）に溶解し、トリフルオロ酢酸（０．７３８ｍＬ，９．５７ｍｍｏｌ）を０℃で加えた。室温で２時間撹拌した後、反応液を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物をＤＭＦ（６．３８ｍＬ）に溶解し、１－イミダゾール酢酸（０．０９７０ｇ，０．７６９ｍｍｏｌ）、ＨＡＴＵ（０．３６４ｇ，０．９５７ｍｍｏｌ）及びトリエチルアミン（０．４４５ｍＬ，３．１９ｍｍｏｌ）を０℃で加えた。室温で１８時間撹拌した後、反応液を減圧濃縮し、得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝９０／１０）で精製し、表題化合物（以下、実施例１６の化合物）（０．２５７ｇ，０．５３８ｍｍｏｌ，８４％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４４－１．８４（ｍ，３Ｈ），１．９６（ｄ，Ｊ＝１０．９Ｈｚ，１Ｈ），２．２４（ｄ，Ｊ＝１４．５Ｈｚ，１Ｈ），３．００（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．３２－３．４５（ｍ，４Ｈ），３．６８（ｄ，Ｊ＝１１．８Ｈｚ，１Ｈ），４．２２（ｓ，２Ｈ），４．８３－４．９２（ｍ，２Ｈ），５．１７（ｄ，Ｊ＝５．４Ｈｚ，１Ｈ），６．９８（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），７．０２－７．２１（ｍ，７Ｈ），７．５１（ｓ，１Ｈ），７．６６（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），８．１３（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４７８（Ｍ＋Ｈ）＋． Example 16 (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (3-chloro-4- (3,4-dihydroisoquinolin-2 (1H) -yl) Synthesis of Phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000082
 The compound of Reference Example 49 (0.300 g, 0.638 mmol) was dissolved in dichloromethane (6.38 mL), and trifluoroacetic acid (0.738 mL, 9.57 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product is dissolved in DMF (6.38 mL), 1-imidazoleacetic acid (0.0970 g, 0.769 mmol), HATU (0.364 g, 0.957 mmol) and triethylamine (0.445 mL, 3.19 mmol) ) Was added at 0 ° C. After stirring at room temperature for 18 hours, the reaction mixture is concentrated under reduced pressure, and the obtained residue is purified by silica gel column chromatography (chloroform / methanol = 90/10) to give the title compound (hereinafter, a compound of Example 16) (0 .257 g, 0.538 mmol, 84%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.44-1.84 (m, 3 H), 1.96 (d, J = 10.9 Hz, 1 H), 2.24 (d, J = 14. 5 Hz, 1 H), 3.00 (t, J = 5.7 Hz, 2 H), 3.32-3. 45 (m, 4 H), 3.68 (d, J = 11.8 Hz, 1 H), 4. 22 (s, 2 H), 4.83-4. 92 (m, 2 H), 5. 17 (d, J = 5.4 Hz, 1 H), 6.98 (d, J = 6.8 Hz, 1 H), 7.02-7.21 (m, 7 H), 7.51 (s, 1 H), 7.66 (d, J = 2.7 Hz, 1 H), 8.13 (s, 1 H).
ESI-MS: m / z = 478 (M + H) <+> .
（参考例５０）３－クロロ－４－（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000083
 　７－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリン塩酸塩（０．５００ｇ，２．１０ｍｍｏｌ）をＤＭＳＯ（１０．５ｍＬ）に溶解し、３－クロロ－４－フルオロニトロベンゼン（０．３６９ｇ，２．１０ｍｍｏｌ）及びＮ－メチルモルホリン（０．４２６ｇ，４．２１ｍｍｏｌ）を室温で加えた。１１０℃で１６時間撹拌した後、反応液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物をＴＨＦ（７．０１ｍＬ）に溶解し、エタノール（７．０１ｍＬ）、蒸留水（７．０１ｍＬ）、鉄粉（０．３１３ｇ，５．６１ｍｍｏｌ）及び酢酸（０．８０２ｍＬ，１４．０ｍｍｏｌ）を室温で加えた。７０℃で３時間撹拌した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝８０／２０）で精製し、表題化合物（以下、参考例５０の化合物）（０．３８９ｇ，１．１９ｍｍｏｌ，５７％）を橙赤色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．０３（ｔ，Ｊ＝５．４Ｈｚ，２Ｈ），３．２５（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．５７（ｓ，２Ｈ），４．１５（ｓ，２Ｈ），６．５４（ｄｄ，Ｊ＝８．６，２．７Ｈｚ，１Ｈ），６．７６（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），６．９２（ｔ，Ｊ＝４．１Ｈｚ，１Ｈ），７．２４（ｔ，Ｊ＝４．１Ｈｚ，１Ｈ），７．３２（ｓ，１Ｈ），７．４０（ｄ，Ｊ＝７．７Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３２７（Ｍ＋Ｈ）＋． Reference Example 50 Synthesis of 3-chloro-4- (7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) aniline:
Figure JPOXMLDOC01-appb-C000083
 Dissolve 7- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride (0.500 g, 2.10 mmol) in DMSO (10.5 mL), 3-chloro-4-fluoronitrobenzene (0 .369 g, 2.10 mmol) and N-methylmorpholine (0.426 g, 4.21 mmol) were added at room temperature. After stirring at 110 ° C. for 16 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product is dissolved in THF (7.01 mL), ethanol (7.01 mL), distilled water (7.01 mL), iron powder (0.313 g, 5.61 mmol) and acetic acid (0.802 mL, 14) .0 mmol) was added at room temperature. After stirring at 70 ° C. for 3 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20), and the title compound (hereinafter, the compound of Reference Example 50) (0.389 g, 1.19 mmol, 57%) was orange Obtained as a red oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.03 (t, J = 5.4 Hz, 2 H), 3.25 (t, J = 5.7 Hz, 2 H), 3.57 (s, 2 H) , 4.15 (s, 2H), 6.54 (dd, J = 8.6, 2.7 Hz, 1 H), 6.76 (d, J = 2.7 Hz, 1 H), 6.92 (t, J = 4.1 Hz, 1 H), 7.24 (t, J = 4.1 Hz, 1 H), 7.32 (s, 1 H), 7.40 (d, J = 7.7 Hz, 1 H).
ESI-MS: m / z = 327 (M + H) + .
（参考例５１）（Ｒ）－２－（（３－クロロ－４－（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000084
 　参考例８の化合物の代わりに参考例５０の化合物を、ジイソプロピルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例５１の化合物）（０．２４２ｇ，０．４５０ｍｍｏｌ，９９％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．５２（ｓ，９Ｈ），１．６０（ｄ，Ｊ＝２．７Ｈｚ，３Ｈ），１．６５（ｄ，Ｊ＝１６．３Ｈｚ，３Ｈ），２．３１（ｄ，Ｊ＝１２．０Ｈｚ，１Ｈ），２．８８（ｔ，Ｊ＝１２．０Ｈｚ，１Ｈ），３．０５－３．０８（ｍ，２Ｈ），３．２９－３．３８（ｍ，２Ｈ），４．０８－４．１１（ｍ，１Ｈ），４．２３（ｓ，２Ｈ），４．８６（ｓ，１Ｈ），７．０１（ｔ，Ｊ＝６．８Ｈｚ，１Ｈ），７．２３－７．２７（ｍ，２Ｈ），７．３４（ｓ，１Ｈ），７．４０（ｄ，Ｊ＝７．７Ｈｚ，１Ｈ），７．７３（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５３８（Ｍ＋Ｈ）＋． (Reference Example 51) (R) -2-((3-Chloro-4- (7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) carbamoyl) piperidine-1- (R) Synthesis of tert-butyl carboxylic acid:
Figure JPOXMLDOC01-appb-C000084
 The title compound (hereinafter, the compound of Reference Example 51) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 50 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. .242 g, 0.450 mmol, 99%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.52 (s, 9 H), 1.60 (d, J = 2.7 Hz, 3 H), 1.65 (d, J = 16.3 Hz, 3 H) , 2.31 (d, J = 1 2.0 Hz, 1 H), 2.88 (t, J = 1 2.0 Hz, 1 H), 3.05-3. 08 (m, 2 H), 3.29-3. 38 (m, 2 H), 4.08-4.11 (m, 1 H), 4.23 (s, 2 H), 4.86 (s, 1 H), 7.01 (t, J = 6.8 Hz, 1H), 7.23-7.27 (m, 2H), 7.34 (s, 1H), 7.40 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 2. 0 Hz, 1 H).
ESI-MS: m / z = 538 (M + H) + .
（実施例１７）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000085
 　参考例９の化合物の代わりに参考例５１の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例１７の化合物）（０．０８５１ｇ，０．１７７ｍｍｏｌ，９６％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４７－１．７９（ｍ，４Ｈ），１．９１（ｄｄ，Ｊ＝１７．２，７．７Ｈｚ，１Ｈ），２．３１（ｓ，３Ｈ），２．２７（ｔ，Ｊ＝６．８Ｈｚ，１Ｈ），３．０５（ｄ，Ｊ＝５．４Ｈｚ，２Ｈ），３．２０－３．３８（ｍ，３Ｈ），３．７７（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），４．２４（ｓ，２Ｈ），５．２６（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），７．００（ｄｄ，Ｊ＝８．６，１．４Ｈｚ，１Ｈ），７．２４－７．３０（ｍ，２Ｈ），７．３４（ｓ，１Ｈ），７．４０（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．７２（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．５０（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４８０（Ｍ＋Ｈ）＋． Example 17 (R) -1-Acetyl-N- (3-chloro-4- (7- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) piperidine-2 -Synthesis of carboxamide:
Figure JPOXMLDOC01-appb-C000085
 Using the compound of Reference Example 51 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 17 below) (0.0851 g, 0.177 mmol, 96) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.79 (m, 4 H), 1.91 (dd, J = 17.2, 7.7 Hz, 1 H), 2.31 (s, s, 3H), 2.27 (t, J = 6.8 Hz, 1 H), 3.05 (d, J = 5.4 Hz, 2 H), 3.20-3.38 (m, 3 H), 3.77 ( d, J = 13.6 Hz, 1 H), 4.24 (s, 2 H), 5. 26 (d, J = 5.0 Hz, 1 H), 7.00 (dd, J = 8.6, 1.4 Hz , 1H), 7.24-7.30 (m, 2H), 7.34 (s, 1H), 7.40 (d, J = 8.2 Hz, 1 H), 7.72 (d, J = 2) .3 Hz, 1 H), 8. 50 (s, 1 H).
ESI-MS: m / z = 480 (M + H) + .
（実施例１８）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（７－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000086
 　参考例４９の化合物の代わりに参考例５１の化合物を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例１８の化合物）（０．１２３ｇ，０．２２５ｍｍｏｌ，８７％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．６０－１．７４（ｍ，３Ｈ），２．１６（ｄ，Ｊ＝１６．５Ｈｚ，１Ｈ），２．６３（ｑ，Ｊ＝７．１Ｈｚ，１Ｈ），２．８８－３．０５（ｍ，２Ｈ），３．１６（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），３．３２－３．４９（ｍ，２Ｈ），３．５１－３．６５（ｍ，２Ｈ），４．１３（ｄｄ，Ｊ＝１９．１，１３．１Ｈｚ，２Ｈ），４．７８－４．９０（ｍ，２Ｈ），５．１４（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．８８－７．０６（ｍ，４Ｈ），７．１７（ｄ，Ｊ＝７．７Ｈｚ，１Ｈ），７．２４－７．３９（ｍ，２Ｈ），７．５０（ｓ，１Ｈ），７．７４（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），９．１２（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５４６（Ｍ＋Ｈ）＋． Example 18 (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (3-chloro-4- (7- (trifluoromethyl) -3,4-dihydroisoquinoline Synthesis of -2 (1H) -yl) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000086
 Using the compound of Reference Example 51 instead of the compound of Reference Example 49, and using the procedure of Example 16 except the above, the title compound (the compound of Example 18 below) (0.123 g, 0.225 mmol, 87) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.60 to 1.74 (m, 3 H), 2.16 (d, J = 16.5 Hz, 1 H), 2.63 (q, J = 7. 1 Hz, 1 H), 2.88-3. 05 (m, 2 H), 3. 16 (d, J = 5.0 Hz, 1 H), 3.32-3. 49 (m, 2 H), 3.51- 3.65 (m, 2H), 4.13 (dd, J = 19.1, 13.1 Hz, 2H), 4.78-4.90 (m, 2H), 5.14 (d, J = 5 .0 Hz, 1 H), 6.88-7.06 (m, 4 H), 7.17 (d, J = 7.7 Hz, 1 H), 7.24-7. 39 (m, 2 H), 7.50 (S, 1 H), 7.74 (d, J = 2.3 Hz, 1 H), 9.12 (s, 1 H).
ESI-MS: m / z = 546 (M + H) <+> .
（参考例５２）２－（２－クロロ－４－ニトロフェニル）－６－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリンの合成：
Figure JPOXMLDOC01-appb-C000087
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに６－（トリフルオロメチル）－１，２，３，４－テトラヒドロイソキノリン塩酸塩を用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例５２の化合物）（１．１０ｇ，３．０８ｍｍｏｌ，８５％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．１３（ｔ，Ｊ＝５．９Ｈｚ，２Ｈ），３．６１（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），４．４５（ｓ，２Ｈ），７．１３（ｔ，Ｊ＝８．７Ｈｚ，１Ｈ），７．２４－７．２７（ｍ，１Ｈ），７．４５－７．４７（ｍ，２Ｈ），８．１３（ｄｄ，Ｊ＝９．１，２．７Ｈｚ，１Ｈ），８．３０（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３５７（Ｍ＋Ｈ）＋． Reference Example 52 Synthesis of 2- (2-chloro-4-nitrophenyl) -6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline:
Figure JPOXMLDOC01-appb-C000087
 A procedure similar to Reference Example 47 is used, except that 6- (trifluoromethyl) -1,2,3,4-tetrahydroisoquinoline hydrochloride is used instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride. The title compound (hereinafter, the compound of Reference Example 52) (1.10 g, 3.08 mmol, 85%) was obtained as a yellow-brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.13 (t, J = 5.9 Hz, 2 H), 3.61 (t, J = 5.7 Hz, 2 H), 4.45 (s, 2 H) , 7.13 (t, J = 8.7 Hz, 1 H), 7.24-7. 27 (m, 1 H), 7.45-7.47 (m, 2 H), 8.13 (dd, J = 9.1, 2.7 Hz, 1 H), 8.30 (d, J = 2.7 Hz, 1 H).
ESI-MS: m / z = 357 (M + H) + .
（参考例５３）３－クロロ－４－（６－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000088
 　参考例７の化合物の代わりに参考例５２の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例５３の化合物）（０．９４０ｇ，２．８８ｍｍｏｌ，９９％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．０５（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．２８（ｔ，Ｊ＝５．７Ｈｚ，２Ｈ），３．５８（ｓ，２Ｈ），４．１９（ｓ，２Ｈ），６．５７（ｄｄ，Ｊ＝８．７，２．７Ｈｚ，１Ｈ），６．７９（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），６．９４（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．１８（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．３８－７．４２（ｍ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３２７（Ｍ＋Ｈ）＋． Reference Example 53 Synthesis of 3-chloro-4- (6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) aniline:
Figure JPOXMLDOC01-appb-C000088
 Using the compound of Reference Example 52 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 53) (0.940 g, 2.88 mmol, 99 %) As a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.05 (t, J = 5.7 Hz, 2 H), 3.28 (t, J = 5.7 Hz, 2 H), 3.58 (s, 2 H) , 4.19 (s, 2 H), 6.57 (dd, J = 8.7, 2.7 Hz, 1 H), 6.79 (d, J = 2.7 Hz, 1 H), 6.94 (d, 7 J = 8.7 Hz, 1 H), 7.18 (d, J = 7.8 Hz, 1 H), 7.38-7.42 (m, 2 H).
ESI-MS: m / z = 327 (M + H) + .
（参考例５４）（Ｒ）－２－（（３－クロロ－４－（６－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000089
 　参考例８の化合物の代わりに参考例５３の化合物を、ジイソプロピルエチルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例５４の化合物）（０．３２６ｇ，０．６０６ｍｍｏｌ，９９％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．５３（ｓ，９Ｈ），１．６７－１．７５（ｍ，５Ｈ），２．３２－２．９５（ｍ，１Ｈ），３．０１－３．０９（ｍ，３Ｈ），３．２５－３．３２（ｍ，３Ｈ），４．１０－４．１２（ｍ，１Ｈ），４．２１（ｓ，２Ｈ），４．８８（ｓ，１Ｈ），６．７１－６．９６（ｍ，１Ｈ），７．１４－７．１７（ｍ，２Ｈ），７．３５－７．４１（ｍ，２Ｈ），７．７５（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５３８（Ｍ＋Ｈ）＋． (Reference Example 54) (R) -2-((3-chloro-4- (6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) carbamoyl) piperidine-1- (R) Synthesis of tert-butyl carboxylic acid:
Figure JPOXMLDOC01-appb-C000089
 The title compound (hereinafter, the compound of Reference Example 54) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 53 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylethylamine. .326 g, 0.606 mmol, 99%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.53 (s, 9 H), 1.67-1.75 (m, 5 H), 2.32-2.95 (m, 1 H), 3.01 -3.09 (m, 3H), 3.25-3.32 (m, 3H), 4.10-4.12 (m, 1H), 4.21 (s, 2H), 4.88 (s) , 1H), 6.71 to 6.96 (m, 1H), 7.14 to 7.17 (m, 2H), 7.35 to 7.41 (m, 2H), 7.75 (s, 1H) ).
ESI-MS: m / z = 538 (M + H) + .
（実施例１９）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（６－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000090
 　参考例９の化合物の代わりに参考例５４の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例１９の化合物）（０．０５７６ｇ，０．１２０ｍｍｏｌ，８１％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４７－１．６３（ｍ，２Ｈ），１．６５－１．７８（ｍ，２Ｈ），１．９２（ｔｔ，Ｊ＝１７．６，４．７Ｈｚ，１Ｈ），２．１９（ｓ，３Ｈ），２．２７（ｔ，Ｊ＝７．８Ｈｚ，１Ｈ），３．０１（ｄｄ，Ｊ＝２３．６，１７．６Ｈｚ，２Ｈ），３．２０－３．３８（ｍ，３Ｈ），３．７７（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），４．２５（ｓ，２Ｈ），５．２６（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），７．０４（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．１８（ｔ，Ｊ＝７．１Ｈｚ，１Ｈ），７．２９（ｄｄ，Ｊ＝８．７，２．７Ｈｚ，１Ｈ），７．４０－７．４５（ｍ，２Ｈ），７．７１（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），８．５２（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４８０（Ｍ＋Ｈ）＋． Example 19 (R) -1-Acetyl-N- (3-chloro-4- (6- (trifluoromethyl) -3,4-dihydroisoquinolin-2 (1H) -yl) phenyl) piperidine-2 -Synthesis of carboxamide:
Figure JPOXMLDOC01-appb-C000090
 Using the compound of Reference Example 54 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 19 below) (0.0576 g, 0.120 mmol, 81) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.63 (m, 2H), 1.65-1.78 (m, 2H), 1.92 (tt, J = 17.6, 4.7 Hz, 1 H), 2.19 (s, 3 H), 2. 27 (t, J = 7.8 Hz, 1 H), 3.01 (dd, J = 23.6, 17.6 Hz, 2 H), 3.20-3.38 (m, 3 H), 3.77 (d, J = 13.3 Hz, 1 H), 4. 25 (s, 2 H), 5. 26 (d, J = 5.0 Hz, 1 H ), 7.04 (d, J = 8.7 Hz, 1 H), 7.18 (t, J = 7.1 Hz, 1 H), 7. 29 (dd, J = 8.7, 2.7 Hz, 1 H) , 7.40-7.45 (m, 2H), 7.71 (d, J = 2.7 Hz, 1 H), 8.52 (s, 1 H).
ESI-MS: m / z = 480 (M + H) + .
（実施例２０）（Ｒ）－１－（２－（１Ｈ－テトラゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（６－（トリフルオロメチル）－３，４－ジヒドロイソキノリン－２（１Ｈ）－イル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000091
 　参考例４９の化合物の代わりに参考例５４の化合物を、１－イミダゾール酢酸の代わりに２－（１Ｈ－テトラゾール－１－イル）酢酸を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例２０の化合物）（０．０９８７ｇ，０．１８０ｍｍｏｌ，９７％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４０－１．７１（ｍ，４Ｈ），１．８３（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），２．１１－２．２５（ｍ，１Ｈ），２．９２－２．９７（ｍ，２Ｈ），３．２５－３．２９（ｍ，２Ｈ），３．６４（ｄｑ，Ｊ＝２８．４，６．９Ｈｚ，２Ｈ），４．１８（ｓ，２Ｈ），５．０８（ｓ，１Ｈ），５．３５－５．４０（ｍ，２Ｈ），６．９４（ｔ，Ｊ＝１２．１Ｈｚ，１Ｈ），７．１４（ｄ，Ｊ＝１６．９，５．６Ｈｚ，２Ｈ），７．３２－７．３９（ｍ，２Ｈ），７．７０（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），８．５０（ｓ，１Ｈ），８．８５（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５４８（Ｍ＋Ｈ）＋． Example 20 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4- (6- (trifluoromethyl) -3,4-dihydroisoquinoline Synthesis of -2 (1H) -yl) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000091
 The procedure of Example 16 is repeated using the compound of Reference Example 54 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 20) (0.0987 g, 0.180 mmol, 97%) was obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.40 to 1.71 (m, 4 H), 1.83 (d, J = 13.3 Hz, 1 H), 2.11 to 2.25 (m, 4) 1H), 2.92-2.97 (m, 2H), 3.25-3.29 (m, 2H), 3.64 (dq, J = 28.4, 6.9 Hz, 2H), 4. 18 (s, 2H), 5.08 (s, 1H), 5.35-5. 40 (m, 2H), 6.94 (t, J = 12.1 Hz, 1H), 7.14 (d, J = 16.9, 5.6 Hz, 2 H), 7.32-7.39 (m, 2 H), 7. 70 (d, J = 2.7 Hz, 1 H), 8. 50 (s, 1 H), 8.85 (s, 1 H).
ESI-MS: m / z = 548 (M + H) <+> .
（参考例５５）Ｎ－ベンジルプロパン－１－アミンの合成：
Figure JPOXMLDOC01-appb-C000092
 　ベンズアルデヒド（５．００ｇ，４７．１ｍｍｏｌ）をジクロロメタン（９４．０ｍＬ）に溶解し、プロピルアミン（２．７９ｇ，４７．１ｍｍｏｌ）及び硫酸ナトリウム（１３．４ｇ，９４．２ｍｍｏｌ）を室温で加えた。同温度で３０分間撹拌した後、水素化ホウ素ナトリウム（１．７８ｇ，４７．１ｍｍｏｌ）を０℃で加え、ゆっくりとメタノールを加えた。室温で１時間撹拌した後、反応液に蒸留水を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝９５／５）で精製し、表題化合物（以下、参考例５５の化合物）（６．１０ｇ，４０．９ｍｍｏｌ，８７％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９２（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．５４（ｔｄ，Ｊ＝１４．７，７．２Ｈｚ，２Ｈ），２．６０（ｄｄ，Ｊ＝８．６，６．３Ｈｚ，２Ｈ），３．７９（ｓ，２Ｈ），７．２３－７．２８（ｍ，１Ｈ），７．３１（ｔｄ，Ｊ＝７．６，３．２Ｈｚ，４Ｈ）． Reference Example 55 Synthesis of N-benzylpropan-1-amine:
Figure JPOXMLDOC01-appb-C000092
 Benzaldehyde (5.00 g, 47.1 mmol) was dissolved in dichloromethane (94.0 mL) and propylamine (2.79 g, 47.1 mmol) and sodium sulfate (13.4 g, 94.2 mmol) were added at room temperature. After stirring for 30 minutes at the same temperature, sodium borohydride (1.78 g, 47.1 mmol) was added at 0 ° C., and methanol was slowly added. After stirring at room temperature for 1 hour, distilled water was added to the reaction solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 95/5) to give the title compound (hereinafter, the compound of Reference Example 55) (6.10 g, 40.9 mmol, 87%) as a colorless oil Obtained.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (t, J = 7.5 Hz, 3 H), 1.54 (td, J = 14.7, 7.2 Hz, 2 H), 2.60 dd, J = 8.6, 6.3 Hz, 2H), 3.79 (s, 2H), 7.23-7.28 (m, 1H), 7.31 (td, J = 7.6, 3 .2 Hz, 4 H).
（参考例５６）Ｎ－ベンジル－２－クロロ－４－ニトロ－Ｎ－プロピルアニリンの合成：
Figure JPOXMLDOC01-appb-C000093
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例５５の化合物を用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例５６の化合物）（１．２２ｇ，４．００ｍｍｏｌ，６０％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８６（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．５９（ｄｄ，Ｊ＝１４．７，７．５Ｈｚ，２Ｈ），３．１７－３．２０（ｍ，２Ｈ），４．４７（ｓ，２Ｈ），６．９９（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．２４－７．３４（ｍ，５Ｈ），８．００（ｄｄ，Ｊ＝８．８，２．５Ｈｚ，１Ｈ），８．２６（ｄ，Ｊ＝２．５Ｈｚ，１Ｈ）． Reference Example 56 Synthesis of N-benzyl-2-chloro-4-nitro-N-propylaniline:
Figure JPOXMLDOC01-appb-C000093
 Using the compound of Reference Example 55 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 56) (1. 22 g, 4.00 mmol, 60%) were obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.86 (t, J = 7.2 Hz, 3 H), 1.59 (dd, J = 14.7, 7.5 Hz, 2 H), 3.17- 3.20 (m, 2 H), 4.47 (s, 2 H), 6.99 (d, J = 8.8 Hz, 1 H), 7.24-7. 34 (m, 5 H), 8.00 ( dd, J = 8.8, 2.5 Hz, 1 H), 8.26 (d, J = 2.5 Hz, 1 H).
（参考例５７）Ｎ１－ベンジル－２－クロロ－Ｎ１－プロピルベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000094
 　参考例７の化合物の代わりに参考例５６の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例５７の化合物）（０．４１５ｇ，１．５１ｍｍｏｌ，９２％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．３９（ｄｄ，Ｊ＝１４．５，７．２Ｈｚ，２Ｈ），２．８５（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．５３（ｂｒｓ，２Ｈ），４．０７（ｓ，２Ｈ），６．５０（ｄｄ，Ｊ＝８．６，２．７Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），６．８８（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．２２（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），７．２９（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），７．３６（ｄ，Ｊ＝７．２Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２７５（Ｍ＋Ｈ）＋． (Reference Example 57) Synthesis of N 1 -benzyl 2-chloro-N 1 -propylbenzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000094
 Using the compound of Reference Example 56 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 57) (0.415 g, 1.51 mmol, 92) %) As a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.2 Hz, 3 H), 1.39 (dd, J = 14.5, 7.2 Hz, 2 H), 2.85 ( t, J = 7.2 Hz, 2 H), 3.53 (brs, 2 H), 4.07 (s, 2 H), 6. 50 (dd, J = 8.6, 2.7 Hz, 1 H), 6. 75 (d, J = 2.7 Hz, 1 H), 6.88 (d, J = 8.6 Hz, 1 H), 7.22 (d, J = 6.8 Hz, 1 H), 7. 29 (t, J = 7.2 Hz, 2 H), 7. 36 (d, J = 7.2 Hz, 2 H).
ESI-MS: m / z = 275 (M + H) + .
（参考例５８）（Ｒ）－２－（（４－（ベンジル（プロピル）アミノ）－３－クロロフェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000095
 　参考例８の化合物の代わりに参考例５７の化合物を、ジイソプロピルエチルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例５８の化合物）（０．６４０ｇ，１．３２ｍｍｏｌ，８０％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．３８－１．４９（ｍ，３Ｈ），１．５１（ｓ，９Ｈ），１．５５－１．６８（ｍ，５Ｈ），２．３３（ｄ，Ｊ＝１２．７Ｈｚ，１Ｈ），２．８２（ｔ，Ｊ＝１２．０Ｈｚ，１Ｈ），２．９１－２．９４（ｍ，２Ｈ），４．１２－４．２１（ｍ，１Ｈ），４．１６（ｓ，２Ｈ），４．８４（ｓ，１Ｈ），６．９８（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．２０－７．３０（ｍ，４Ｈ），７．３２－７．３５（ｍ，２Ｈ），７．６６（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）． Reference Example 58 Synthesis of tert-butyl (R) -2-((4- (benzyl (propyl) amino) -3-chlorophenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000095
 The title compound (hereinafter, the compound of Reference Example 58) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 57 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylethylamine. .640 g, 1.32 mmol, 80%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.2 Hz, 3 H), 1.38-1.49 (m, 3 H), 1.51 (s, 9 H), 1 .55-1.68 (m, 5H), 2.33 (d, J = 12.7 Hz, 1 H), 2.82 (t, J = 1 2.0 Hz, 1 H), 2.91-2.94 ( m, 2H), 4.12-4. 21 (m, 1H), 4.16 (s, 2H), 4.84 (s, 1H), 6.98 (d, J = 8.6 Hz, 1H) , 7.20-7.30 (m, 4H), 7.32-7.35 (m, 2H), 7.66 (d, J = 2.3 Hz, 1 H).
（実施例２１）（Ｒ）－１－アセチル－Ｎ－（４－（ベンジル（プロピル）アミノ）－３－クロロフェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000096
 　参考例９の化合物の代わりに参考例５８の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例２１の化合物）（０．１２２ｇ，０．２８５ｍｍｏｌ，３６％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．３６－１．４４（ｍ，４Ｈ），１．７５－１．９３（ｍ，３Ｈ），２．１７（ｓ，３Ｈ），２．２６（ｄ，Ｊ＝１２．７Ｈｚ，１Ｈ），２．９１（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．２１（ｄｄ，Ｊ＝１８．３，７．９Ｈｚ，１Ｈ），３．７４（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），４．１５（ｓ，２Ｈ），５．２５（ｄ，Ｊ＝５．４Ｈｚ，１Ｈ），６．９５（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．１９－７．３４（ｍ，６Ｈ），７．６６（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），８．４５（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４２８（Ｍ＋Ｈ）＋． Example 21 Synthesis of (R) -1-Acetyl-N- (4- (benzyl (propyl) amino) -3-chlorophenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000096
 Using the compound of Reference Example 58 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 21 below) (0.122 g, 0.285 mmol, 36) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.2 Hz, 3 H), 1.36 to 1.44 (m, 4 H), 1.75-1. 93 (m, 5) 3H), 2.17 (s, 3H), 2.26 (d, J = 12.7 Hz, 1 H), 2.91 (t, J = 7.2 Hz, 2 H), 3.21 (dd, J =) 18.3, 7.9 Hz, 1 H), 3.74 (d, J = 13.6 Hz, 1 H), 4.15 (s, 2 H), 5.25 (d, J = 5.4 Hz, 1 H), 6.95 (d, J = 8.6 Hz, 1 H), 7. 19-7. 34 (m, 6 H), 7. 66 (d, J = 2.7 Hz, 1 H), 8. 45 (s, 1 H) ).
ESI-MS: m / z = 428 (M + H) + .
（実施例２２）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（４－（ベンジル（プロピル）アミノ）－３－クロロフェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000097
 　参考例４９の化合物の代わりに参考例５８の化合物を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例２２の化合物）（０．１２０ｇ，０．２４３ｍｍｏｌ，５９％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．４０－１．８３（ｍ，６Ｈ），１．９８（ｄ，Ｊ＝１２．７Ｈｚ，１Ｈ），２．２４（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），２．９３（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），３．３７（ｔ，Ｊ＝１１．８Ｈｚ，１Ｈ），３．６７（ｄ，Ｊ＝１２．７Ｈｚ，１Ｈ），４．１６（ｓ，２Ｈ），４．８１－４．９１（ｍ，２Ｈ），５．１６（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．９５－６．９７（ｍ，２Ｈ），７．１３－７．１６（ｍ，２Ｈ），７．２０－７．３０（ｍ，３Ｈ），７．３３（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），７．５２（ｓ，１Ｈ）７．６５（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），７．９９（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４９５（Ｍ＋Ｈ）＋． Example 22 Synthesis of (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (4- (benzyl (propyl) amino) -3-chlorophenyl) piperidine-2-carboxamide :
Figure JPOXMLDOC01-appb-C000097
 Using the compound of Reference Example 58 instead of the compound of Reference Example 49, and using the procedure of Example 16 except the above, the title compound (the compound of Example 22) (0.120 g, 0.243 mmol, 59 %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.2 Hz, 3 H), 1.40 to 1.83 (m, 6 H), 1.98 (d, J = 12. 7 Hz, 1 H), 2.24 (d, J = 13.6 Hz, 1 H), 2.93 (t, J = 7.5 Hz, 2 H), 3.37 (t, J = 11.8 Hz, 1 H), 3.67 (d, J = 12.7 Hz, 1 H), 4.16 (s, 2 H), 4.81-4. 91 (m, 2 H), 5. 16 (d, J = 5.0 Hz, 1 H ), 6.95-6.97 (m, 2H), 7.13-7.16 (m, 2H), 7.20-7.30 (m, 3H), 7.33 (d, J = 6) .8 Hz, 1 H), 7.52 (s, 1 H) 7.65 (d, J = 2.7 Hz, 1 H), 7.99 (s, 1 H).
ESI-MS: m / z = 495 (M + H) <+> .
（実施例２３）（Ｒ）－Ｎ－（４－（ベンジル（プロピル）アミノ）－３－クロロフェニル）－１－（メチルスルホニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000098
 　参考例５８の化合物（０．０６００ｇ，０．１２３ｍｍｏｌ）をジクロロメタン（１．２３ｍＬ）に溶解し、トリフルオロ酢酸（０．１４３ｍＬ，１．８５ｍｍｏｌ）を０℃で加えた。室温で２時間撹拌した後、を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物をジクロロメタン（１．２３ｍＬ）に溶解し、トリエチルアミン（０．０８６０ｍＬ，０．６１７ｍｍｏｌ）及びメタンスルホニルクロリド（０．０１４４ｍＬ，０．１８５ｍｍｏｌ）を０℃で加えた。室温で１２時間撹拌した後、反応液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝３０／７０）で精製し、表題化合物（以下、実施例２３の化合物）（０．０４７０ｇ，０．１０１ｍｍｏｌ，８２％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８７（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．４０－１．７９（ｍ，７Ｈ），２．３９（ｄ，Ｊ＝１３．１Ｈｚ，１Ｈ），３．００（ｓ，３Ｈ），３．２０（ｔ，Ｊ＝１２．９Ｈｚ，１Ｈ），３．４６（ｔ，Ｊ＝７．０Ｈｚ，２Ｈ），３．８７（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），４．５９（ｄ，Ｊ＝７．７Ｈｚ，３Ｈ），７．１８－７．３１（ｍ，７Ｈ），７．８６（ｓ，１Ｈ），８．４６（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４６５（Ｍ＋Ｈ）＋． Example 23 Synthesis of (R) -N- (4- (benzyl (propyl) amino) -3-chlorophenyl) -1- (methylsulfonyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000098
 The compound of Reference Example 58 (0.0600 g, 0.123 mmol) was dissolved in dichloromethane (1.23 mL), and trifluoroacetic acid (0.143 mL, 1.85 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product was dissolved in dichloromethane (1.23 mL) and triethylamine (0.0860 mL, 0.617 mmol) and methanesulfonyl chloride (0.0144 mL, 0.185 mmol) were added at 0 ° C. After stirring at room temperature for 12 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 30/70) to give the title compound (hereinafter, the compound of Example 23) (0.0470 g, 0.101 mmol, 82%) as a white Obtained as amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.87 (t, J = 7.2 Hz, 3 H), 1.40-1. 79 (m, 7 H), 2.39 (d, J = 13. 1 Hz, 1 H), 3.00 (s, 3 H), 3. 20 (t, J = 12.9 Hz, 1 H), 3.46 (t, J = 7.0 Hz, 2 H), 3.87 (d, J = 13.6 Hz, 1 H), 4.59 (d, J = 7.7 Hz, 3 H), 7.18-7.31 (m, 7 H), 7.86 (s, 1 H), 8.46 (m s, 1 H).
ESI-MS: m / z = 465 (M + H) <+> .
（参考例５９）Ｎ－（４－フルオロベンジル）プロパン－１－アミンの合成：
Figure JPOXMLDOC01-appb-C000099
 　ベンズアルデヒドの代わりに４－フルオロベンズアルデヒドを用いて、それ以外は参考例５５と同様の手順により、表題化合物（以下、参考例５９の化合物）（３．９４ｇ，２３．６ｍｍｏｌ，９７％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９２（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．５３（ｄｄ，Ｊ＝１４．７，７．５Ｈｚ，２Ｈ），２．５８（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．７５（ｓ，２Ｈ），７．００（ｄｄ，Ｊ＝８．６，５．７Ｈｚ，２Ｈ），７．２８（ｄｄ，Ｊ＝８．６，５．７Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝１６８（Ｍ＋Ｈ）＋． Reference Example 59 Synthesis of N- (4-fluorobenzyl) propan-1-amine:
Figure JPOXMLDOC01-appb-C000099
 Using 4-fluorobenzaldehyde instead of benzaldehyde, and using the same procedure as in Reference Example 55 except for the above, the title compound (the compound of Reference Example 59 below) (3.94 g, 23.6 mmol, 97%) as a colorless oil I got it as a thing.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (t, J = 7.2 Hz, 3 H), 1.53 (dd, J = 14.7, 7.5 Hz, 2 H), 2.58 ( t, J = 7.2 Hz, 2 H), 3. 75 (s, 2 H), 7.00 (dd, J = 8.6, 5.7 Hz, 2 H), 7. 28 (dd, J = 8.6) , 5.7 Hz, 2 H).
ESI-MS: m / z = 168 (M + H) + .
（参考例６０）２－クロロ－Ｎ－（４－フルオロベンジル）－４－ニトロ－Ｎ－プロピルアニリンの合成：
Figure JPOXMLDOC01-appb-C000100
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例５９の化合物を用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例６０の化合物）（１．２０ｇ，３．７２ｍｍｏｌ，３１％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８６（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．５３－１．６０（ｍ，２Ｈ），３．１３－３．１７（ｍ，２Ｈ），４．４２（ｓ，２Ｈ），６．９８－７．０２（ｍ，３Ｈ），７．２５（ｄｄ，Ｊ＝８．７，５．５Ｈｚ，２Ｈ），８．０１（ｄｄ，Ｊ＝８．９，２．５Ｈｚ，１Ｈ），８．２７（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ）． Reference Example 60 Synthesis of 2-Chloro-N- (4-fluorobenzyl) -4-nitro-N-propylaniline:
Figure JPOXMLDOC01-appb-C000100
 Using the compound of Reference Example 59 in place of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 60) (1. 20 g, 3.72 mmol, 31%) were obtained as a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.86 (t, J = 7.3 Hz, 3 H), 1.53-1.60 (m, 2 H), 3.13-3.17 (m, 2H), 4.42 (s, 2 H), 6.98-7.02 (m, 3 H), 7. 25 (dd, J = 8.7, 5.5 Hz, 2 H), 8.01 (dd, J = 8.9, 2.5 Hz, 1 H, 8. 27 (d, J = 2.7 Hz, 1 H).
（参考例６１）２－クロロ－Ｎ１－（４－フルオロベンジル）－Ｎ１－プロピルベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000101
 　参考例７の化合物の代わりに参考例６０の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例６１の化合物）（１．０２ｇ，３．４８ｍｍｏｌ，９４％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３８（ｔｄ，Ｊ＝１４．６，７．３Ｈｚ，２Ｈ），２．８２（ｄｄ，Ｊ＝８．３，６．６Ｈｚ，２Ｈ），３．５４（ｓ，２Ｈ），４．０２（ｓ，２Ｈ），６．５０（ｄｄ，Ｊ＝８．２，２．７Ｈｚ，１Ｈ），６．７４（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），６．８６（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），６．９３－６．９６（ｍ，２Ｈ），７．２９－７．３３（ｍ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２９３（Ｍ＋Ｈ）＋． Reference Example 61 Synthesis of 2-chloro-N 1- (4-fluorobenzyl) -N 1 -propylbenzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000101
 Using the compound of Reference Example 60 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 61) (1.02 g, 3.48 mmol, 94 %) As a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.3 Hz, 3 H), 1.38 (td, J = 14.6, 7.3 Hz, 2 H), 2.82 dd, J = 8.3, 6.6 Hz, 2 H), 3.54 (s, 2 H), 4.02 (s, 2 H), 6. 50 (dd, J = 8.2, 2.7 Hz, 1 H) ), 6.74 (d, J = 2.7 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 1 H), 6.93-6.96 (m, 2 H), 7.29-7 .33 (m, 2H).
ESI-MS: m / z = 293 (M + H) + .
（参考例６２）（Ｒ）－２－（（３－クロロ－４－（（４－フルオロベンジル）（プロピル）アミノ）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000102
 　参考例８の化合物の代わりに参考例６１の化合物を、ジイソプロピルエチルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例６２の化合物）（０．４８１ｇ，０．９５４ｍｍｏｌ，７０％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３７－１．４８（ｍ，２Ｈ），１．５１（ｓ，９Ｈ），１．５２－１．７２（ｍ，６Ｈ），２．３２（ｄ，Ｊ＝１２．３Ｈｚ，１Ｈ），２．８３－２．９２（ｍ，３Ｈ），４．１０－４．１２（ｍ，１Ｈ），４．１２（ｓ，２Ｈ），４．８３－４．８６（ｍ，１Ｈ），６．９２－６．９８（ｍ，３Ｈ），７．２３－７．３２（ｍ，３Ｈ），７．６７（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ）． Reference Example 62 Synthesis of tert-butyl (R) -2-((3-chloro-4-((4-fluorobenzyl) (propyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000102
 Using the compound of Reference Example 61 in place of the compound of Reference Example 8 and triethylamine in place of diisopropylethylamine and following the same procedure as in Reference Example 9 except for the above, the title compound (hereinafter referred to as Compound of Reference Example 62) (0 .481 g, 0.954 mmol, 70%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.3 Hz, 3 H), 1.37-1.48 (m, 2 H), 1.51 (s, 9 H), 1 .52-1.72 (m, 6H), 2.32 (d, J = 12.3 Hz, 1H), 2.83-2.92 (m, 3H), 4.10-4.12 (m, 6) 1H), 4.12 (s, 2 H), 4.83-4. 86 (m, 1 H), 6. 9-6. 98 (m, 3 H), 7.2 3-7. 32 (m, 3 H) , 7.67 (d, J = 2.7 Hz, 1 H).
（実施例２４）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（（４－フルオロベンジル）（プロピル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000103
 　参考例９の化合物の代わりに参考例６２の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例２４の化合物）（０．０８５１ｇ，０．１９１ｍｍｏｌ，９６％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８０（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３８－１．５９（ｍ，４Ｈ），１．７０－１．７７（ｍ，２Ｈ），１．９２（ｔ，Ｊ＝１２．８Ｈｚ，１Ｈ），２．１９（ｓ，３Ｈ），２．２６（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），２．９０（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．１７（ｔ，Ｊ＝１３．３Ｈｚ，１Ｈ），３．７５（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），４．１１（ｓ，２Ｈ），５．２５（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．９３－６．９８（ｍ，３Ｈ），７．２４（ｄｄ，Ｊ＝８．７，２．７Ｈｚ，１Ｈ），７．２９（ｄｄ，Ｊ＝８．７，５．５Ｈｚ，２Ｈ），７．６６（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．３８（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４４６（Ｍ＋Ｈ）＋． Example 24 Synthesis of (R) -1-Acetyl-N- (3-chloro-4-((4-fluorobenzyl) (propyl) amino) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000103
 Using the compound of Reference Example 62 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 24 below) (0.0851 g, 0.191 mmol, 96) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.80 (t, J = 7.3 Hz, 3 H), 1.38-1.59 (m, 4 H), 1.70-1. 77 (m, 2H), 1.92 (t, J = 12.8 Hz, 1 H), 2.19 (s, 3 H), 2.26 (d, J = 13.3 Hz, 1 H), 2.90 (t, J = 7.3 Hz, 2 H), 3. 17 (t, J = 13.3 Hz, 1 H), 3. 75 (d, J = 13.7 Hz, 1 H), 4.1 1 (s, 2 H), 5.25 ( d, J = 5.0 Hz, 1 H), 6.93-6.98 (m, 3 H), 7.24 (dd, J = 8.7, 2.7 Hz, 1 H), 7.29 (dd, J) = 8.7, 5.5 Hz, 2 H), 7.66 (d, J = 2.3 Hz, 1 H), 8. 38 (s, 1 H).
ESI-MS: m / z = 446 (M + H) + .
（実施例２５）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（（４－フルオロベンジル）（プロピル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000104
 　参考例４９の化合物の代わりに参考例６２の化合物を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例２５の化合物）（０．１４０ｇ，０．２７３ｍｍｏｌ，６９％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３７－１．５１（ｍ，２Ｈ），１．６３－１．７８（ｍ，４Ｈ），１．９４（ｄ，Ｊ＝１２．８Ｈｚ，１Ｈ），２．２３（ｄ，Ｊ＝１４．２Ｈｚ，１Ｈ），２．９０（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．３３－３．４３（ｍ，１Ｈ），３．６７（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），４．１１（ｓ，２Ｈ），４．８１－４．９１（ｍ，２Ｈ），５．１６（ｄ，Ｊ＝５．５Ｈｚ，１Ｈ），６．６６－６．９９（ｍ，４Ｈ），７．１１－７．１５（ｍ，２Ｈ），７．２６－７．３１（ｍ，２Ｈ），７．５２（ｓ，１Ｈ）７．６４（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），８．１５（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５１３（Ｍ＋Ｈ）＋． Example 25 (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (3-chloro-4-((4-fluorobenzyl) (propyl) amino) phenyl) piperidine Synthesis of -2-carboxamide:
Figure JPOXMLDOC01-appb-C000104
 Using the compound of Reference Example 62 instead of the compound of Reference Example 49, and using the same procedure as Example 16 except the above, the title compound (compound of Example 25 below) (0.140 g, 0.273 mmol, 69) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.3 Hz, 3 H), 1.37-1.51 (m, 2 H), 1.63-1.78 (m, 4H), 1.94 (d, J = 12.8 Hz, 1 H), 2.23 (d, J = 14.2 Hz, 1 H), 2.90 (t, J = 7.3 Hz, 2 H), 3. 33-3.43 (m, 1 H), 3.67 (d, J = 8.2 Hz, 1 H), 4.11 (s, 2 H), 4.81-4. 91 (m, 2 H), 5. 16 (d, J = 5.5 Hz, 1 H), 6.66-6.99 (m, 4 H), 7.11-7. 15 (m, 2 H), 7.26-7. 31 (m, 2 H) ), 7.52 (s, 1 H) 7.64 (d, J = 2.7 Hz, 1 H), 8. 15 (s, 1 H).
ESI-MS: m / z = 513 (M + H) <+> .
（実施例２６）（Ｒ）－１－（２－（１Ｈ－テトラゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（（４－フルオロベンジル）（プロピル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000105
 　参考例４９の化合物の代わりに参考例６２の化合物を、１－イミダゾール酢酸の代わりに２－（１Ｈ－テトラゾール－１－イル）酢酸を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例２６の化合物）（０．１００ｇ，０．１９５ｍｍｏｌ，８２％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８０（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３７－１．４６（ｍ，２Ｈ），１．５６－１．８７（ｍ，５Ｈ），２．２４（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），２．９０（ｔ，Ｊ＝７．１Ｈｚ，２Ｈ），３．５３（ｔ，Ｊ＝１１．９Ｈｚ，１Ｈ），３．６９（ｄ，Ｊ＝１２．８Ｈｚ，１Ｈ），４．１１（ｓ，２Ｈ），５．１４（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），５．３４－５．４４（ｍ，２Ｈ），６．９３－６．９７（ｍ，３Ｈ），７．１７（ｄｄ，Ｊ＝８．９，２．５Ｈｚ，１Ｈ），７．２９（ｄｄ，Ｊ＝８．７，５．５Ｈｚ，２Ｈ），７．６７（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．０３（ｓ，１Ｈ），８．８２（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５１４（Ｍ＋Ｈ）＋． Example 26 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4-((4-fluorobenzyl) (propyl) amino) phenyl) piperidine Synthesis of -2-carboxamide:
Figure JPOXMLDOC01-appb-C000105
 The procedure of Example 16 is repeated using the compound of Reference Example 62 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 26) (0.100 g, 0.195 mmol, 82%) was obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.80 (t, J = 7.3 Hz, 3 H), 1.37-1.46 (m, 2 H), 1.56-1.87 (m, 5H), 2.24 (d, J = 13.7 Hz, 1 H), 2.90 (t, J = 7.1 Hz, 2 H), 3.53 (t, J = 11.9 Hz, 1 H), 3. 69 (d, J = 12.8 Hz, 1 H), 4.11 (s, 2 H), 5. 14 (d, J = 5.0 Hz, 1 H), 5.34-5. 44 (m, 2 H), 6.93-6.97 (m, 3H), 7.17 (dd, J = 8.9, 2.5 Hz, 1 H), 7.29 (dd, J = 8.7, 5.5 Hz, 2 H) , 7.67 (d, J = 2.3 Hz, 1 H), 8.03 (s, 1 H), 8.82 (s, 1 H).
ESI-MS: m / z = 514 (M + H) + .
（参考例６３）Ｎ－（４－フルオロベンジル）－２－メチルプロパン－１－アミンの合成：
Figure JPOXMLDOC01-appb-C000106
 　ベンズアルデヒドの代わりに４－フルオロベンズアルデヒドを、プロピルアミンの代わりにイソブチルアミンを用いて、それ以外は参考例５５と同様の手順により、表題化合物（以下、参考例６３の化合物）（４．３４ｇ，２３．９ｍｍｏｌ，９９％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９３（ｄ，Ｊ＝６．９Ｈｚ，６Ｈ），１．７１－１．８１（ｍ，１Ｈ），２．４２（ｄ，Ｊ＝６．４Ｈｚ，２Ｈ），３．７４（ｓ，２Ｈ），６．９７－７．０４（ｍ，２Ｈ），７．２２－７．２８（ｍ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝１８２（Ｍ＋Ｈ）＋． Reference Example 63 Synthesis of N- (4-fluorobenzyl) -2-methylpropan-1-amine:
Figure JPOXMLDOC01-appb-C000106
 The title compound (the compound of Reference Example 63) (4.34 g, 23) was prepared by the same procedure as Reference Example 55 using 4-fluorobenzaldehyde instead of benzaldehyde and isobutylamine instead of propylamine. .9 mmol, 99%) were obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (d, J = 6.9 Hz, 6 H), 1.71-1.81 (m, 1 H), 2.42 (d, J = 6. 4 Hz, 2 H), 3.74 (s, 2 H), 6.97-7.04 (m, 2 H), 7.22-7.28 (m, 2 H).
ESI-MS: m / z = 182 (M + H) + .
（参考例６４）２－フルオロ－Ｎ－（４－フルオロベンジル）－Ｎ－イソブチル－４－ニトロアニリンの合成：
Figure JPOXMLDOC01-appb-C000107
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例６３の化合物を、３－クロロ－４－フルオロニトロベンゼンの代わりに３，４－ジフルオロニトロベンゼン用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例６４の化合物）（２．０３ｇ，６．３４ｍｍｏｌ，５７％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９１（ｄ，Ｊ＝６．９Ｈｚ，６Ｈ），２．００－２．０７（ｍ，１Ｈ），３．２３（ｄｄ，Ｊ＝７．３，０．９Ｈｚ，２Ｈ），４．５９（ｓ，２Ｈ），６．７５（ｔ，Ｊ＝９．１Ｈｚ，１Ｈ），６．９８－７．０４（ｍ，２Ｈ），７．１８（ｄｄ，Ｊ＝８．７，５．５Ｈｚ，２Ｈ），７．８６－７．９２（ｍ，２Ｈ）． Reference Example 64 Synthesis of 2-fluoro-N- (4-fluorobenzyl) -N-isobutyl-4-nitroaniline:
Figure JPOXMLDOC01-appb-C000107
 The compound of Reference Example 63 is used instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride, 3,4-difluoronitrobenzene is used instead of 3-chloro-4-fluoronitrobenzene, and the other conditions are the same as in Reference Example 47. The title compound (hereinafter, the compound of Reference Example 64) (2.03 g, 6.34 mmol, 57%) was obtained as a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (d, J = 6.9 Hz, 6 H), 2.00-2.07 (m, 1 H), 3.23 (dd, J = 7. 3, 0.9 Hz, 2 H), 4.59 (s, 2 H), 6. 75 (t, J = 9.1 Hz, 1 H), 6.98-7.04 (m, 2 H), 7.18 ( dd, J = 8.7, 5.5 Hz, 2 H), 7.86-7.92 (m, 2 H).
（参考例６５）２－フルオロ－Ｎ１－（４－フルオロベンジル）－Ｎ１－イソブチルベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000108
 　参考例７の化合物の代わりに参考例６４の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例６５の化合物）（１．５８ｇ，５．４４ｍｍｏｌ，７６％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｄ，Ｊ＝６．５Ｈｚ，６Ｈ），１．６３－１．７０（ｍ，１Ｈ），２．６８（ｄ，Ｊ＝６．９Ｈｚ，２Ｈ），３．５４（ｂｒｓ，２Ｈ），４．０５（ｓ，２Ｈ），６．３０－６．３３（ｍ，１Ｈ），６．３９（ｄｄ，Ｊ＝１３．３，２．７Ｈｚ，１Ｈ），６．７６－６．８０（ｍ，１Ｈ），６．９４－６．９７（ｍ，２Ｈ），７．２６－７．２９（ｍ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２９１（Ｍ＋Ｈ）＋． Reference Example 65 Synthesis of 2-fluoro-N 1- (4-fluorobenzyl) -N 1 -isobutylbenzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000108
 Using the compound of Reference Example 64 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 65) (1.58 g, 5.44 mmol, 76) %) As a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (d, J = 6.5 Hz, 6 H), 1.63-1.70 (m, 1 H), 2.68 (d, J = 6. 9 Hz, 2 H), 3.54 (brs, 2 H), 4.05 (s, 2 H), 6.30 to 6.33 (m, 1 H), 6.39 (dd, J = 13.3, 2. 7 Hz, 1 H), 6.76-6. 80 (m, 1 H), 6.94-6. 97 (m, 2 H), 7. 26-7. 29 (m, 2 H).
ESI-MS: m / z = 291 (M + H) + .
（参考例６６）（Ｒ）－２－（（３－フルオロ－４－（（４－フルオロベンジル）（イソブチル）アミノ）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000109
 　参考例８の化合物の代わりに参考例６５の化合物を、ジイソプロピルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例６６の化合物）（０．６７５ｇ，１．３５ｍｍｏｌ，９８％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８３（ｄ，Ｊ＝６．９Ｈｚ，６Ｈ），１．５１（ｓ，９Ｈ），１．５５－１．８１（ｍ，８Ｈ），２．３３（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），２．８１（ｔ，Ｊ＝９．８Ｈｚ，２Ｈ），４．１５－４．１８（ｍ，１Ｈ），４．１８（ｓ，２Ｈ），４．８３（ｓ，１Ｈ），６．８２－６．８５（ｍ，１Ｈ），６．９２－７．００（ｍ，４Ｈ），７．２１－７．２５（ｍ，１Ｈ），７．４５（ｄｄ，Ｊ＝１３．７，２．３Ｈｚ，１Ｈ）． Reference Example 66 Synthesis of tert-butyl (R) -2-((3-fluoro-4-((4-fluorobenzyl) (isobutyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000109
 The title compound (hereinafter, the compound of Reference Example 66) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 65 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. .675 g, 1.35 mmol, 98%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.83 (d, J = 6.9 Hz, 6 H), 1.51 (s, 9 H), 1.55-1. 81 (m, 8 H), 2 .33 (d, J = 13.3 Hz, 1 H), 2.81 (t, J = 9.8 Hz, 2 H), 4.15-4. 18 (m, 1 H), 4.18 (s, 2 H) , 4.83 (s, 1 H), 6.82-6. 85 (m, 1 H), 6.92-7.00 (m, 4 H), 7.21-7. 25 (m, 1 H), 7 .45 (dd, J = 13.7, 2.3 Hz, 1 H).
（実施例２７）（Ｒ）－１－アセチル－Ｎ－（３－フルオロ－４－（（４－フルオロベンジル）（イソブチル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000110
 　参考例９の化合物の代わりに参考例６６の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例２７の化合物）（０．０８５４ｇ，０．１９３ｍｍｏｌ，９７％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８２（ｄ，Ｊ＝６．９Ｈｚ，６Ｈ），１．４７－１．８０（ｍ，５Ｈ），１．９４（ｄ，Ｊ＝１２．３Ｈｚ，１Ｈ），２．１９（ｓ，３Ｈ），２．２６（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），２．８０（ｔ，Ｊ＝８．０Ｈｚ，２Ｈ），３．１７（ｔ，Ｊ＝１３．０Ｈｚ，１Ｈ），３．７５（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），４．１９（ｓ，２Ｈ），５．２５（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．８０－６．８３（ｍ，１Ｈ），６．９３－６．９７（ｍ，３Ｈ），７．２２－７．２５（ｍ，２Ｈ），７．４４（ｄｄ，Ｊ＝１４．０，２．５Ｈｚ，１Ｈ），８．３２（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４４４（Ｍ＋Ｈ）＋． Example 27 Synthesis of (R) -1-acetyl-N- (3-fluoro-4-((4-fluorobenzyl) (isobutyl) amino) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000110
 Using the compound of Reference Example 66 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 27 below) (0.0854 g, 0.193 mmol, 97) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.82 (d, J = 6.9 Hz, 6 H), 1.47-1.80 (m, 5 H), 1.94 (d, J = 12. 3 Hz, 1 H), 2. 19 (s, 3 H), 2. 26 (d, J = 13.3 Hz, 1 H), 2. 80 (t, J = 8.0 Hz, 2 H), 3. 17 (t, J = 13.0 Hz, 1 H), 3.75 (d, J = 13.3 Hz, 1 H), 4.19 (s, 2 H), 5.25 (d, J = 5.0 Hz, 1 H), 6. 80-6.83 (m, 1H), 6.93-6.97 (m, 3H), 7.22-7.25 (m, 2H), 7.44 (dd, J = 14.0, 2) .5 Hz, 1 H), 8.32 (s, 1 H).
ESI-MS: m / z = 444 (M + H) <+> .
（実施例２８）（Ｒ）－１－（２－（１Ｈ－テトラゾール－１－イル）アセチル）－Ｎ－（３－フルオロ－４－（（４－フルオロベンジル）（イソブチル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000111
 　参考例４９の化合物の代わりに参考例６６の化合物を、１－イミダゾール酢酸の代わりに２－（１Ｈ－テトラゾール－１－イル）酢酸を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例２８の化合物）（０．０８７０ｇ，０．１７０ｍｍｏｌ，４３％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８３（ｄ，Ｊ＝６．４Ｈｚ，６Ｈ），１．６０－１．８８（ｍ，５Ｈ），２．２５（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），２．８１（ｄ，Ｊ＝６．９Ｈｚ，２Ｈ），３．５２（ｔ，Ｊ＝１２．３Ｈｚ，１Ｈ），３．７０（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），４．１９（ｓ，２Ｈ），５．１４（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），５．３４－５．４４（ｍ，２Ｈ），６．７９－６．８２（ｍ，１Ｈ），６．９０－７．００（ｍ，３Ｈ），７．２３（ｄｄ，Ｊ＝８．２，５．５Ｈｚ，１Ｈ），７．４３（ｄ，Ｊ＝１４．２Ｈｚ，２Ｈ），７．８８（ｓ，１Ｈ），８．８３（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５１２（Ｍ＋Ｈ）＋． Example 28 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-fluoro-4-((4-fluorobenzyl) (isobutyl) amino) phenyl) piperidine Synthesis of -2-carboxamide:
Figure JPOXMLDOC01-appb-C000111
 The procedure of Example 16 is repeated using the compound of Reference Example 66 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 28) (0.0870 g, 0.170 mmol, 43%) was obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.83 (d, J = 6.4 Hz, 6 H), 1.60-1.88 (m, 5 H), 2.25 (d, J = 13. 7 Hz, 1 H), 2.81 (d, J = 6.9 Hz, 2 H), 3.52 (t, J = 12.3 Hz, 1 H), 3.70 (d, J = 13.7 Hz, 1 H), 4.19 (s, 2 H), 5. 14 (d, J = 5.0 Hz, 1 H), 5.34-5. 44 (m, 2 H), 6.79-6.82 (m, 1 H), 6.90-7.00 (m, 3H), 7.23 (dd, J = 8.2, 5.5 Hz, 1 H), 7.43 (d, J = 14.2 Hz, 2 H), 7.88 (S, 1 H), 8.83 (s, 1 H).
ESI-MS: m / z = 512 (M + H) + .
（参考例６７）Ｎ－（４－クロロベンジル）プロパン－１－アミンの合成：
Figure JPOXMLDOC01-appb-C000112
 　ベンズアルデヒドの代わりに４－クロロベンズアルデヒドを用いて、それ以外は参考例５５と同様の手順により、表題化合物（以下、参考例６７の化合物）（３．５８ｇ，１９．５ｍｍｏｌ，９１％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９２（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．５２（ｄｔ，Ｊ＝１４．５，７．２Ｈｚ，２Ｈ），２．５８（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．７５（ｓ，２Ｈ），７．２７（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．２９（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝１８４（Ｍ＋Ｈ）＋． Reference Example 67 Synthesis of N- (4-chlorobenzyl) propan-1-amine:
Figure JPOXMLDOC01-appb-C000112
 Using 4-chlorobenzaldehyde instead of benzaldehyde, and following the same procedure as in Reference Example 55 except that the title compound (the compound of Reference Example 67) (3.58 g, 19.5 mmol, 91%) was colorless oil I got it as a thing.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (t, J = 7.5 Hz, 3 H), 1.52 (dt, J = 14.5, 7.2 Hz, 2 H), 2.58 ( t, J = 7.2 Hz, 2 H), 3.75 (s, 2 H), 7. 27 (d, J = 8.0 Hz, 2 H), 7. 29 (d, J = 8.0 Hz, 2 H).
ESI-MS: m / z = 184 (M + H) + .
（参考例６８）２－クロロ－Ｎ－（４－クロロベンジル）－４－ニトロ－Ｎ－プロピルアニリンの合成：
Figure JPOXMLDOC01-appb-C000113
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例６７の化合物を用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例６８の化合物）（２．６０ｇ，７．６６ｍｍｏｌ，７０％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８６（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．５３－１．６２（ｍ，２Ｈ），３．１３－３．１７（ｍ，２Ｈ），４．４１（ｓ，２Ｈ），６．９６（ｄ，Ｊ＝９．１Ｈｚ，１Ｈ），７．２２（ｄｔ，Ｊ＝８．７，２．３Ｈｚ，２Ｈ），７．２８（ｄｔ，Ｊ＝８．５，１．９Ｈｚ，２Ｈ），８．０１（ｄｄ，Ｊ＝９．１，２．７Ｈｚ，１Ｈ），８．２７（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ）． Reference Example 68 Synthesis of 2-chloro-N- (4-chlorobenzyl) -4-nitro-N-propylaniline:
Figure JPOXMLDOC01-appb-C000113
 Using the compound of Reference Example 67 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 68) (2. 60 g, 7.66 mmol, 70%) were obtained as a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.86 (t, J = 7.3 Hz, 3 H), 1.53-1.62 (m, 2 H), 3.13-3.17 (m, 2H), 4.41 (s, 2H), 6.96 (d, J = 9.1 Hz, 1 H), 7.22 (dt, J = 8.7, 2.3 Hz, 2 H), 7.28 ( dt, J = 8.5, 1.9 Hz, 2 H), 8.01 (dd, J = 9.1, 2.7 Hz, 1 H), 8.27 (d, J = 2.7 Hz, 1 H).
（参考例６９）２－クロロ－Ｎ１－（４－クロロベンジル）－Ｎ１－プロピルベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000114
 　参考例７の化合物の代わりに参考例６８の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例６９の化合物）（２．０３ｇ，６．５６ｍｍｏｌ，８６％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．３９（ｔｄ，Ｊ＝１４．６，７．３Ｈｚ，２Ｈ），２．８２（ｄｄ，Ｊ＝８．０，６．６Ｈｚ，２Ｈ），３．５５（ｓ，２Ｈ），４．０２（ｓ，２Ｈ），６．４９（ｄｄ，Ｊ＝８．７，２．７Ｈｚ，１Ｈ），６．７４（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），６．８６（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．２３－７．３０（ｍ，４Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３１０（Ｍ＋Ｈ）＋． Reference Example 69 Synthesis of 2-chloro-N 1- (4-chlorobenzyl) -N 1 -propylbenzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000114
 Using the compound of Reference Example 68 instead of the compound of Reference Example 7, and using the same procedure as in Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 69) (2.03 g, 6.56 mmol, 86 %) As a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.5 Hz, 3 H), 1.39 (td, J = 14.6, 7.3 Hz, 2 H), 2.82 dd, J = 8.0, 6.6 Hz, 2 H), 3.55 (s, 2 H), 4.02 (s, 2 H), 6. 49 (dd, J = 8.7, 2.7 Hz, 1 H) ), 6.74 (d, J = 2.7 Hz, 1 H), 6.86 (d, J = 8.7 Hz, 1 H), 7.23-7.30 (m, 4 H).
ESI-MS: m / z = 310 (M + H) + .
（参考例７０）（Ｒ）－２－（（３－クロロ－４－（（４－クロロベンジル）（プロピル）アミノ）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000115
 　参考例８の化合物の代わりに参考例６９の化合物を、ジイソプロピルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例７０の化合物）（０．５９７ｇ，１．１５ｍｍｏｌ，８９％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．４２（ｔｄ，Ｊ＝１４．６，７．３Ｈｚ，２Ｈ），１．５１（ｓ，９Ｈ），１．５６－１．６９（ｍ，６Ｈ），２．３５－２．４２（ｍ，１Ｈ），２．７８－２．８２（ｍ，１Ｈ），２．９０（ｄｄ，Ｊ＝８．２，６．４Ｈｚ，２Ｈ），４．０９－４．１１（ｍ，１Ｈ），４．１１（ｓ，２Ｈ），４．８４（ｓ，１Ｈ），６．９７（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．２２－７．２９（ｍ，５Ｈ），７．６６（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ）． Reference Example 70 Synthesis of tert-butyl (R) -2-((3-chloro-4-((4-chlorobenzyl) (propyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000115
 The title compound (hereinafter, the compound of Reference Example 70) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 69 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. 597 g (1.15 mmol, 89%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.3 Hz, 3 H), 1.42 (td, J = 14.6, 7.3 Hz, 2 H), 1.51 ( s, 9H), 1.56-1.69 (m, 6H), 2.35-2.42 (m, 1 H), 2.78-2.82 (m, 1 H), 2.90 (dd,) J = 8.2, 6.4 Hz, 2 H), 4.09-4.11 (m, 1 H), 4.1 1 (s, 2 H), 4. 84 (s, 1 H), 6.97 (d, 5) J = 8.7 Hz, 1 H), 7.22-7.29 (m, 5 H), 7.66 (d, J = 2.7 Hz, 1 H).
（実施例２９）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（（４－クロロベンジル）（プロピル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000116
 　参考例９の化合物の代わりに参考例７０の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例２９の化合物）（０．０７００ｇ，０．１５１ｍｍｏｌ，７９％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．４５－１．５４（ｍ，２Ｈ），１．５９－１．７７（ｍ，４Ｈ），１．８９－１．９６（ｍ，１Ｈ），２．１９（ｓ，３Ｈ），２．２６（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），２．８９（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．１７（ｔ，Ｊ＝１３．３Ｈｚ，１Ｈ），３．７５（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），４．１２（ｓ，２Ｈ），５．２５（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．９４（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．２２－７．２９（ｍ，５Ｈ），７．６６（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．３８（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４６３（Ｍ＋Ｈ）＋． Example 29 Synthesis of (R) -1-acetyl-N- (3-chloro-4-((4-chlorobenzyl) (propyl) amino) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000116
 Using the compound of Reference Example 70 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 29 below) (0.0700 g, 0.151 mmol, 79) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.3 Hz, 3 H), 1.45-1.54 (m, 2 H), 1.59-1.77 (m, 4H), 1.89-1.96 (m, 1 H), 2.19 (s, 3 H), 2.26 (d, J = 13.7 Hz, 1 H), 2.89 (t, J = 7. 3Hz, 2H), 3.17 (t, J = 13.3Hz, 1H), 3.75 (d, J = 13.7Hz, 1H), 4.12 (s, 2H), 5.25 (d, J = 5.0 Hz, 1 H), 6.94 (d, J = 8.7 Hz, 1 H), 7.22-7.29 (m, 5 H), 7.66 (d, J = 2.3 Hz, 1 H) ), 8.38 (s, 1 H).
ESI-MS: m / z = 463 (M + H) + .
（実施例３０）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（（４－クロロベンジル）（プロピル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000117
 　参考例４９の化合物の代わりに参考例７０の化合物を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例３０の化合物）（０．１８５ｇ，０．３５０ｍｍｏｌ，９１％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３７－１．５１（ｍ，２Ｈ），１．５９－１．８４（ｍ，５Ｈ），２．２３（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），２．９０（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．３４－３．３７（ｍ，１Ｈ），３．６７（ｔ，Ｊ＝８．２Ｈｚ，１Ｈ），４．１１（ｓ，２Ｈ），４．８１－４．９１（ｍ，２Ｈ），５．１６（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．９４－６．９８（ｍ，２Ｈ），７．１２－７．１５（ｍ，１Ｈ），７．２５－７．２７（ｍ，５Ｈ），７．５２（ｓ，１Ｈ）７．６４（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．１６（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５２９（Ｍ＋Ｈ）＋． Example 30 (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (3-chloro-4-((4-chlorobenzyl) (propyl) amino) phenyl) piperidine Synthesis of -2-carboxamide:
Figure JPOXMLDOC01-appb-C000117
 Using the compound of Reference Example 70 instead of the compound of Reference Example 49, and using the same procedure as Example 16 except the above, the title compound (the compound of Example 30 below) (0.185 g, 0.350 mmol, 91) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.3 Hz, 3 H), 1.37-1.51 (m, 2 H), 1.59-1.84 (m, 5H), 2.23 (d, J = 13.7 Hz, 1 H), 2.90 (t, J = 7.3 Hz, 2 H), 3.34-3. 37 (m, 1 H), 3.67 ( t, J = 8.2 Hz, 1 H), 4.11 (s, 2 H), 4.81-4. 91 (m, 2 H), 5. 16 (d, J = 5.0 Hz, 1 H), 6. 94-6.98 (m, 2 H), 7.12-7.15 (m, 1 H), 7.25-7.27 (m, 5 H), 7.52 (s, 1 H) 7.64 (d , J = 2.3 Hz, 1 H), 8. 16 (s, 1 H).
ESI-MS: m / z = 529 (M + H) + .
（実施例３１）（Ｒ）－１－（２－（１Ｈ－テトラゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（（４－クロロベンジル）（プロピル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000118
 　参考例４９の化合物の代わりに参考例７０の化合物を、１－イミダゾール酢酸の代わりに２－（１Ｈ－テトラゾール－１－イル）酢酸を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例３１の化合物）（０．１００ｇ，０．１８９ｍｍｏｌ，８２％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．３７－１．４６（ｍ，２Ｈ），１．５５－１．８８（ｍ，３Ｈ），２．２４（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），２．８０（ｓ，２Ｈ），２．９０（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．５３（ｔｄ，Ｊ＝１２．９，２．４Ｈｚ，１Ｈ），３．６９（ｔ，Ｊ＝１１．９Ｈｚ，１Ｈ），４．１１（ｓ，２Ｈ），５．１３（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），５．３３－５．４４（ｍ，２Ｈ），６．９５（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．１６（ｄｄ，Ｊ＝８．７，２．５Ｈｚ，１Ｈ），７．２２－７．２８（ｍ，４Ｈ），７．６７（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．０３（ｓ，１Ｈ），８．８２（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５３０（Ｍ＋Ｈ）＋． Example 31 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4-((4-chlorobenzyl) (propyl) amino) phenyl) piperidine Synthesis of -2-carboxamide:
Figure JPOXMLDOC01-appb-C000118
 The procedure of Example 16 is repeated using the compound of Reference Example 70 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 31) (0.100 g, 0.189 mmol, 82%) was obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.5 Hz, 3 H), 1.37-1.46 (m, 2 H), 1.55-1. 88 (m, 3H), 2.24 (d, J = 13.7 Hz, 1 H), 2.80 (s, 2 H), 2.90 (t, J = 7.3 Hz, 2 H), 3.53 (td, J = 12.9, 2.4 Hz, 1H), 3.69 (t, J = 11.9 Hz, 1 H), 4.11 (s, 2 H), 5.13 (d, J = 5.0 Hz, 1 H), 5.33-5.44 (m, 2H), 6.95 (d, J = 8.7 Hz, 1 H), 7.16 (dd, J = 8.7, 2.5 Hz, 1 H), 7.22 -7.28 (m, 4H), 7.67 (d, J = 2.3 Hz, 1 H), 8.03 (s, 1 H), 8.82 (s, 1 H).
ESI-MS: m / z = 530 (M + H) + .
（参考例７１）Ｎ－（４－（トリフルオロメチル）ベンジル）プロパン－１－アミンの合成：
Figure JPOXMLDOC01-appb-C000119
 　ベンズアルデヒドの代わりに４－（トリフルオロメチル）ベンズアルデヒドを用いて、それ以外は参考例５５と同様の手順により、表題化合物（以下、参考例７１の化合物）（５．９０ｇ，２７．２ｍｍｏｌ，９５％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９３（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），１．５４（ｄｔ，Ｊ＝１４．６，７．３Ｈｚ，２Ｈ），２．５９（ｄｄ，Ｊ＝８．３，６．１Ｈｚ，２Ｈ），３．８５（ｓ，２Ｈ），７．４５（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５８（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２１８（Ｍ＋Ｈ）＋． Reference Example 71 Synthesis of N- (4- (trifluoromethyl) benzyl) propan-1-amine:
Figure JPOXMLDOC01-appb-C000119
 Using 4- (trifluoromethyl) benzaldehyde instead of benzaldehyde, and using the same procedure as Reference Example 55 except for the above, the title compound (the compound of Reference Example 71 below) (5.90 g, 27.2 mmol, 95%) ) Was obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (t, J = 7.4 Hz, 3 H), 1.54 (dt, J = 14.6, 7.3 Hz, 2 H), 2.59 dd, J = 8.3, 6.1 Hz, 2 H), 3.85 (s, 2 H), 7. 45 (d, J = 8.0 Hz, 2 H), 7.58 (d, J = 8.0 Hz) , 2H).
ESI-MS: m / z = 218 (M + H) + .
（参考例７２）２－クロロ－４－ニトロ－Ｎ－プロピル－Ｎ－（４－（トリフルオロメチル）ベンジル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000120
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例７１の化合物を用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例７２の化合物）（１．０５ｇ，２．８２ｍｍｏｌ，２４％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８４（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），１．５２－１．６４（ｍ，２Ｈ），３．１０（ｄｄ，Ｊ＝８．３，６．１Ｈｚ，２Ｈ），４．５０（ｓ，２Ｈ），７．００－７．０５（ｍ，１Ｈ），７．４３（ｄ，Ｊ＝７．８Ｈｚ，２Ｈ），７．５８（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），８．０３（ｔｄ，Ｊ＝８．９，６．２Ｈｚ，１Ｈ），８．２６（ｄｄ，Ｊ＝８．９，２．８Ｈｚ，１Ｈ）． Reference Example 72 Synthesis of 2-chloro-4-nitro-N-propyl-N- (4- (trifluoromethyl) benzyl) aniline:
Figure JPOXMLDOC01-appb-C000120
 Using the compound of Reference Example 71 in place of 1,2,3,4-tetrahydroisoquinoline hydrochloride and using the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 72) (1. 05 g, 2.82 mmol, 24%) were obtained as a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.84 (t, J = 7.4 Hz, 3 H), 1.52-1.64 (m, 2 H), 3.10 (dd, J = 8. 3, 6.1 Hz, 2 H), 4.50 (s, 2 H), 7.00-7.05 (m, 1 H), 7.43 (d, J = 7.8 Hz, 2 H), 7.58 ( d, J = 8.0 Hz, 2 H), 8.03 (td, J = 8.9, 6.2 Hz, 1 H), 8.26 (dd, J = 8.9, 2.8 Hz, 1 H).
（参考例７３）２－クロロ－Ｎ１－プロピル－Ｎ１－（４－（トリフルオロメチル）ベンジル）ベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000121
 　参考例７２の化合物（１．００ｇ，２．６８ｍｍｏｌ）をＴＨＦ（１３．４ｍＬ）に溶解し、エタノール（１３．４ｍＬ）、蒸留水（１３．４ｍＬ）、塩化アンモニウム（１．４４ｇ，２６．８ｍｍｏｌ）及び鉄（０．５９９ｇ，１０．７ｍｍｏｌ）を室温で加えた。７０℃で１６時間撹拌した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝８０／２０）で精製し、表題化合物（以下、参考例７３の化合物）（０．７１６ｇ，２．０９ｍｍｏｌ，７８％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８２（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．４０（ｔｄ，Ｊ＝１４．６，７．３Ｈｚ，２Ｈ），２．８４（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．５６（ｓ，２Ｈ），４．１２（ｓ，２Ｈ），６．５０（ｄｄ，Ｊ＝８．５，２．７Ｈｚ，１Ｈ），６．７４（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），６．８９（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），７．５０（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．５２（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３４３（Ｍ＋Ｈ）＋． Reference Example 73 Synthesis of 2-chloro-N 1 -propyl-N 1- (4- (trifluoromethyl) benzyl) benzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000121
 The compound of Reference Example 72 (1.00 g, 2.68 mmol) is dissolved in THF (13.4 mL), ethanol (13.4 mL), distilled water (13.4 mL), ammonium chloride (1.44 g, 26.8 mmol) ) And iron (0.599 g, 10.7 mmol) were added at room temperature. After stirring at 70 ° C. for 16 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 80/20) to give the title compound (the compound of Reference Example 73 below) (0.716 g, 2.09 mmol, 78%) as a yellow powder. Obtained as a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.82 (t, J = 7.3 Hz, 3 H), 1.40 (td, J = 14.6, 7.3 Hz, 2 H), 2.84 t, J = 7.3 Hz, 2 H), 3.56 (s, 2 H), 4.1 2 (s, 2 H), 6. 50 (dd, J = 8.5, 2.7 Hz, 1 H), 6. 74 (d, J = 2.4 Hz, 1 H), 6.89 (d, J = 8.5 Hz, 1 H), 7. 50 (d, J = 8.3 Hz, 2 H), 7.52 (d, J = 8.3 Hz, 2 H).
ESI-MS: m / z = 343 (M + H) + .
（参考例７４）（Ｒ）－２－（（３－クロロ－４－（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000122
 　参考例８の化合物の代わりに参考例７３の化合物を、ジイソプロピルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例７４の化合物）（０．５７５ｇ，１．０４ｍｍｏｌ，８９％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８３（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３９－１．４９（ｍ，４Ｈ），１．５３（ｓ，９Ｈ），１．６３－１．７２（ｍ，４Ｈ），２．３２（ｄ，Ｊ＝１１．０Ｈｚ，１Ｈ），２．８４（ｄｄ，Ｊ＝８．３，６．４Ｈｚ，１Ｈ），２．９２（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），４．０９（ｓ，１Ｈ），４．２０（ｓ，２Ｈ），４．８５（ｓ，１Ｈ），７．００（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），７．２５（ｄｄ，Ｊ＝８．５，２．７Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．５４（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．６８（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ）． Reference Example 74 Synthesis of tert-butyl (R) -2-((3-chloro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000122
 The title compound (hereinafter, the compound of Reference Example 74) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 73 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. .575 g, 1.04 mmol, 89%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.83 (t, J = 7.3 Hz, 3 H), 1.39-1.49 (m, 4 H), 1.53 (s, 9 H), 1 .63-1.72 (m, 4H), 2.32 (d, J = 11.0 Hz, 1 H), 2.84 (dd, J = 8.3, 6.4 Hz, 1 H), 2.92 (d t, J = 7.3 Hz, 2 H), 4.09 (s, 1 H), 4. 20 (s, 2 H), 4. 85 (s, 1 H), 7.00 (d, J = 8.5 Hz, 1H), 7.25 (dd, J = 8.5, 2.7 Hz, 1 H), 7.48 (d, J = 8.3 Hz, 2 H), 7.54 (d, J = 8.3 Hz, 2 H) ), 7.68 (d, J = 2.4 Hz, 1 H).
（参考例７５）（Ｒ）－Ｎ－（３－クロロ－４－（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000123
 　参考例７４の化合物（０．２００ｇ，０．３６１ｍｍｏｌ）をジクロロメタン（１．８１ｍＬ）に溶解し、トリフルオロ酢酸（０．４１７ｍＬ，５．４１ｍｍｏｌ）を０℃で加えた。室温で２時間撹拌した後、反応液を減圧濃縮し、１Ｍ水酸化ナトリウム水溶液を加え中和し、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をアミノシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝８０／２０）で精製し、表題化合物（以下、参考例７５の化合物）（０．１５２ｇ，０．３３５ｍｍｏｌ，９３％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８２（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），１．３８－１．５３（ｍ，４Ｈ），１．５６－１．６９（ｍ，２Ｈ），１．８１（ｓ，１Ｈ），２．０３（ｄ，Ｊ＝９．８Ｈｚ，１Ｈ），２．８４（ｂｒｓ，１Ｈ），２．９２（ｔ，Ｊ＝７．４Ｈｚ，２Ｈ），３．１０（ｄ，Ｊ＝１１．７Ｈｚ，１Ｈ），３．４８（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），４．２０（ｓ，２Ｈ），７．００（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．３５（ｄｄ，Ｊ＝８．７，２．３Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５４（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．７３（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４５４（Ｍ＋Ｈ）＋． Reference Example 75 Synthesis of (R) -N- (3-chloro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000123
 The compound of Reference Example 74 (0.200 g, 0.361 mmol) was dissolved in dichloromethane (1.81 mL), and trifluoroacetic acid (0.417 mL, 5.41 mmol) was added at 0 ° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated under reduced pressure, 1 M aqueous sodium hydroxide solution was added for neutralization, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by amino silica gel column chromatography (n-hexane / ethyl acetate = 80/20) to give the title compound (following, compound of Reference Example 75) (0.152 g, 0.335 mmol, 93%) Obtained as a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.82 (t, J = 7.4 Hz, 3 H), 1.38-1.53 (m, 4 H), 1.56-1.69 (m, 5) 2H), 1.81 (s, 1 H), 2.03 (d, J = 9.8 Hz, 1 H), 2.84 (brs, 1 H), 2.92 (t, J = 7.4 Hz, 2 H) , 3.10 (d, J = 11.7 Hz, 1 H), 3.48 (d, J = 6.8 Hz, 1 H), 4.20 (s, 2 H), 7.00 (d, J = 8. 8 Hz, 1 H), 7. 35 (dd, J = 8.7, 2.3 Hz, 1 H), 7.48 (d, J = 8.0 Hz, 2 H), 7.54 (d, J = 8.3 Hz , 2H), 7.73 (d, J = 2.2 Hz, 1 H).
ESI-MS: m / z = 454 (M + H) + .
（実施例３２）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000124
 　参考例７５の化合物（０．４４２ｇ，０．９７４ｍｍｏｌ）をジクロロメタン（９．７４ｍＬ）に溶解し、トリエチルアミン（０．６７９ｍＬ，４．８７ｍｍｏｌ）及び無水酢酸（０．１１０ｍＬ，１．１７ｍｍｏｌ）を０℃で加えた。室温で１６時間撹拌した後、反応液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝５０／５０～４０／６０）で精製し、表題化合物（以下、実施例３２の化合物）（０．４５０ｇ，０．９０７ｍｍｏｌ，９３％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８２（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３９－１．４７（ｍ，２Ｈ），１．４８－１．５５（ｍ，２Ｈ），１．７４（ｔ，Ｊ＝１３．４Ｈｚ，２Ｈ），１．８９－１．９９（ｍ，１Ｈ），２．１９（ｓ，３Ｈ），２．２６（ｄ，Ｊ＝１３．４Ｈｚ，１Ｈ），２．９１（ｔ，Ｊ＝７．４Ｈｚ，２Ｈ），３．１７（ｔｄ，Ｊ＝１３．２，２．６Ｈｚ，１Ｈ），３．７５（ｄ，Ｊ＝１３．９Ｈｚ，１Ｈ），４．１９（ｓ，２Ｈ），５．２５（ｄ，Ｊ＝４．９Ｈｚ，１Ｈ），６．９８（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），７．２６（ｄｄ，Ｊ＝８．４，２．６Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５４（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．６７（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．３８（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４９６（Ｍ＋Ｈ）＋． Example 32 Synthesis of (R) -1-Acetyl-N- (3-chloro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000124
 The compound of Reference Example 75 (0.442 g, 0.974 mmol) was dissolved in dichloromethane (9.74 mL), triethylamine (0.679 mL, 4.87 mmol) and acetic anhydride (0.110 mL, 1.17 mmol) were added at 0 ° C. Added. After stirring at room temperature for 16 hours, the reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 50/50 to 40/60) to give the title compound (compound of Example 32 below) (0.450 g, 0.907 mmol, 93) %) As a white solid.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.82 (t, J = 7.3 Hz, 3 H), 1.39-1.47 (m, 2 H), 1.48-1.55 (m, 2H), 1.74 (t, J = 13.4 Hz, 2H), 1.89-1.99 (m, 1H), 2.19 (s, 3H), 2.26 (d, J = 13. 4 Hz, 1 H), 2.91 (t, J = 7.4 Hz, 2 H), 3.17 (td, J = 13.2, 2.6 Hz, 1 H), 3.75 (d, J = 13.9 Hz , 1H), 4.19 (s, 2H), 5.25 (d, J = 4.9 Hz, 1 H), 6.98 (d, J = 8.5 Hz, 1 H), 7.26 (dd, J = 8.4, 2.6 Hz, 1 H), 7.48 (d, J = 8.0 Hz, 2 H), 7.54 (d, J = 8.0 Hz, 2 H), 7.67 (d, J = 2.4 Hz, 1 H , 8.38 (s, 1H).
ESI-MS: m / z = 496 (M + H) <+> .
（実施例３３）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000125
 　参考例７５の化合物（０．１００ｇ，０．２２０ｍｍｏｌ）をＤＭＦ（２．２０ｍＬ）に溶解し、１－イミダゾール酢酸（０．０３３３ｇ，０．２６４ｍｍｏｌ）、ＨＡＴＵ（０．１２６ｇ，０．３３０ｍｍｏｌ）及びトリエチルアミン（０．０６１４ｍＬ，０．４４１ｍｍｏｌ）を０℃で加えた。室温で１６時間撹拌した後、反応液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝９０／１０）で精製し、表題化合物（以下、実施例３３の化合物）（０．１１６ｇ，０．２０６ｍｍｏｌ，８８％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８３（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），１．４４－１．４７（ｍ，２Ｈ），１．７４－１．９８（ｍ，５Ｈ），２．２４（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），２．９１（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），３．４０（ｔ，Ｊ＝１２．０Ｈｚ，１Ｈ），３．６７（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），４．２０（ｓ，２Ｈ），４．８５（ｄ，Ｊ＝５．０Ｈｚ，２Ｈ），５．１４（ｄ，Ｊ＝５．４Ｈｚ，１Ｈ），６．９７（ｄｄ，Ｊ＝１３．６，５．０Ｈｚ，２Ｈ），７．１２（ｓ，１Ｈ），７．１６（ｄｄ，Ｊ＝８．６，２．３Ｈｚ，１Ｈ），７．４７－７．５５（ｍ，５Ｈ）７．６６（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），８．２１（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５６３（Ｍ＋Ｈ）＋． (Example 33) (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (3-chloro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000125
 The compound of Reference Example 75 (0.100 g, 0.220 mmol) is dissolved in DMF (2.20 mL), 1-imidazoleacetic acid (0.0333 g, 0.264 mmol), HATU (0.126 g, 0.330 mmol) and Triethylamine (0.0614 mL, 0.441 mmol) was added at 0 ° C. After stirring at room temperature for 16 hours, distilled water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 90/10) to give the title compound (hereinafter, the compound of Example 33) (0.116 g, 0.206 mmol, 88%) as a white amorphous. The
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.83 (t, J = 7.4 Hz, 3 H), 1.44-1.47 (m, 2 H), 1.74-1.98 (m, 5H), 2.24 (d, J = 13.6 Hz, 1H), 2.91 (t, J = 7.5 Hz, 2H), 3.40 (t, J = 12.0 Hz, 1 H), 3. 67 (d, J = 13.6 Hz, 1 H), 4. 20 (s, 2 H), 4. 85 (d, J = 5.0 Hz, 2 H), 5. 14 (d, J = 5.4 Hz, 1 H ), 6.97 (dd, J = 13.6, 5.0 Hz, 2 H), 7.12 (s, 1 H), 7.16 (dd, J = 8.6, 2.3 Hz, 1 H), 7 47-7.55 (m, 5H) 7.66 (d, J = 2.7 Hz, 1 H), 8.21 (s, 1 H).
ESI-MS: m / z = 563 (M + H) <+> .
（実施例３４）（Ｒ）－Ｎ－（３－クロロ－４－（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）－１－（２－シクロプロピルアセチル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000126
 　１－イミダゾール酢酸の代わりにシクロプロピル酢酸を、ＤＭＦの代わりにジクロロメタンを用いて、それ以外は実施例３３と同様の手順により、表題化合物（以下、実施例３４の化合物）（０．１０９ｇ，０．２０３ｍｍｏｌ，９２％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．２１－０．２４（ｍ，２Ｈ），０．５７－０．６１（ｍ，２Ｈ），０．８１（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．０２－１．１０（ｍ，１Ｈ），１．３８－１．６０（ｍ，４Ｈ），１．７０－１．７７（ｍ，２Ｈ），１．８８－１．９７（ｍ，１Ｈ），２．２６－２．３４（ｍ，２Ｈ），２．４６（ｄｄ，Ｊ＝１５．３，６．６Ｈｚ，１Ｈ），２．９０（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．１７（ｔ，Ｊ＝１３．３Ｈｚ，１Ｈ），３．７９（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），４．１９（ｓ，２Ｈ），５．２９（ｄ，Ｊ＝５．５Ｈｚ，１Ｈ），６．９７（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．２４（ｄｄ，Ｊ＝８．５，２．５Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５３（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．６８（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），８．５１（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５３６（Ｍ＋Ｈ）＋． Example 34 (R) -N- (3-chloro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) -1- (2-cyclopropylacetyl) piperidine-2-carboxamide Synthesis:
Figure JPOXMLDOC01-appb-C000126
 The title compound (hereinafter, the compound of Example 34) (0.109 g, 0%) by a procedure similar to Example 33 except for using cyclopropyl acetic acid instead of 1-imidazole acetic acid and dichloromethane instead of DMF 203 mmol, 92%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.21 to 0.24 (m, 2 H), 0.57 to 0.61 (m, 2 H), 0.81 (t, J = 7.3 Hz, 3H), 1.02-1.10 (m, 1H), 1.38-1.60 (m, 4H), 1.70-1. 77 (m, 2H), 1.88-1. m, 1 H), 2. 26-2. 34 (m, 2 H), 2. 46 (dd, J = 15.3, 6.6 Hz, 1 H), 2. 90 (t, J = 7.3 Hz, 2 H) ), 3.17 (t, J = 13.3 Hz, 1 H), 3.79 (d, J = 13.3 Hz, 1 H), 4.19 (s, 2 H), 5.29 (d, J = 5 .5 Hz, 1 H), 6.97 (d, J = 8.7 Hz, 1 H), 7.24 (dd, J = 8.5, 2.5 Hz, 1 H), 7.48 (d, J = 8). 2 Hz, 2 H), 7.5 (D, J = 8.2Hz, 2H), 7.68 (d, J = 2.7Hz, 1H), 8.51 (s, 1H).
ESI-MS: m / z = 536 (M + H) + .
（実施例３５）（Ｒ）－Ｎ－（３－クロロ－４－（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）－１－（２－シクロブチルアセチル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000127
 　１－イミダゾール酢酸の代わりにシクロブチル酢酸を、ＤＭＦの代わりにジクロロメタンを用いて、それ以外は実施例３３と同様の手順により、表題化合物（以下、実施例３５の化合物）（０．０５８５ｇ，０．１０６ｍｍｏｌ，９７％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３８－１．５８（ｍ，４Ｈ），１．６５－１．７９（ｍ，４Ｈ），１．８１－１．９６（ｍ，３Ｈ），２．１０－２．２１（ｍ，２Ｈ），２．２５（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），２．５６（ｄ，Ｊ＝７．３Ｈｚ，２Ｈ），２．６６－２．７８（ｍ，１Ｈ），２．９０（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．１２（ｔ，Ｊ＝１３．０Ｈｚ，１Ｈ），３．７９（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），４．１８（ｓ，２Ｈ），５．２４（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．９７（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．２０（ｄｄ，Ｊ＝８．７，２．３Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５３（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．６７（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），８．４５（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５５０（Ｍ＋Ｈ）＋． Example 35 (R) -N- (3-chloro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) -1- (2-cyclobutylacetyl) piperidine-2-carboxamide Synthesis:
Figure JPOXMLDOC01-appb-C000127
 The title compound (hereinafter, the compound of Example 35) (0.0585 g, 0. 1) was prepared by the same procedure as in Example 33 except for using cyclobutyl acetic acid instead of 1-imidazole acetic acid and dichloromethane instead of DMF. 106 mmol, 97%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.3 Hz, 3 H), 1.38-1.58 (m, 4 H), 1.65-1.79 (m, 4H), 1.81-1.96 (m, 3H), 2.10-2.21 (m, 2H), 2.25 (d, J = 13.7 Hz, 1H), 2.56 (d, J) J = 7.3 Hz, 2 H), 2.66-2.78 (m, 1 H), 2. 90 (t, J = 7.3 Hz, 2 H), 3. 12 (t, J = 13.0 Hz, 1 H) ), 3.79 (d, J = 13.3 Hz, 1 H), 4.18 (s, 2 H), 5.24 (d, J = 5.0 Hz, 1 H), 6.97 (d, J = 8) .7 Hz, 1 H), 7.20 (dd, J = 8.7, 2.3 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 2 H), 7.53 (d, J = 8). 2 Hz, 2 H), 7. 7 (d, J = 2.7Hz, 1H), 8.45 (s, 1H).
ESI-MS: m / z = 550 (M + H) + .
（実施例３６）（Ｒ）－Ｎ－（３－クロロ－４－（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）－１－（シクロプロパンカルボニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000128
 　参考例７５の化合物（０．１００ｇ，０．２２０ｍｍｏｌ）のジクロロメタン（２．２０ｍＬ）溶液に、シクロプロピルカルボニルクロリド（０．０２２０ｍＬ，０．２４２ｍｍｏｌ）及びトリエチルアミン（０．０３９９ｍＬ，０．２８６ｍｍｏｌ）を０℃で加えた。室温で２時間撹拌した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１００／０～７０／３０）で精製し、表題化合物（以下、実施例３６の化合物）（０．１１０ｇ，０．２１１ｍｍｏｌ，９６％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８０－０．９３（ｍ，６Ｈ），１．１８－１．２３（ｍ，１Ｈ），１．４０－１．４７（ｍ，２Ｈ），１．５５－１．５９（ｍ，２Ｈ），１．７２－１．８７（ｍ，３Ｈ），１．９２－２．０３（ｍ，１Ｈ），２．２８（ｄ，Ｊ＝１２．８Ｈｚ，１Ｈ），２．９０（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．１４（ｔｄ，Ｊ＝１３．０，２．０Ｈｚ，１Ｈ），４．１５－４．１７（ｍ，３Ｈ），５．１９（ｄ，Ｊ＝５．５Ｈｚ，１Ｈ），６．９７（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．２３（ｄｄ，Ｊ＝８．７，２．７Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ），７．５４（ｄ，Ｊ＝８．７Ｈｚ，２Ｈ），７．６４（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），８．４８（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５２２（Ｍ＋Ｈ）＋． Example 36 Synthesis of (R) -N- (3-chloro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) -1- (cyclopropanecarbonyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000128
 Cyclopropyl carbonyl chloride (0.0220 mL, 0.242 mmol) and triethylamine (0.0399 mL, 0.286 mmol) were added to a solution of the compound of Reference Example 75 (0. 100 g, 0.220 mmol) in dichloromethane (2.20 mL). Added at ° C. After stirring at room temperature for 2 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100/0 to 70/30) to give the title compound (compound of Example 36 below) (0.110 g, 0.211 mmol, 96) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.80-0.93 (m, 6 H), 1.18-1.23 (m, 1 H), 1.40-1. 47 (m, 2 H) , 1.55-1.59 (m, 2H), 1.72-1.87 (m, 3H), 1. 9-2.03 (m, 1 H), 2.28 (d, J = 12. 8 Hz, 1 H), 2. 90 (t, J = 7.3 Hz, 2 H), 3. 14 (td, J = 13.0, 2.0 Hz, 1 H), 4.15-4. 17 (m, 3 H) ), 5.19 (d, J = 5.5 Hz, 1 H), 6.97 (d, J = 8.7 Hz, 1 H), 7.23 (dd, J = 8.7, 2.7 Hz, 1 H) , 7.48 (d, J = 8.7 Hz, 2 H), 7.54 (d, J = 8.7 Hz, 2 H), 7.64 (d, J = 2.7 Hz, 1 H), 8.48 ( s, 1 H).
ESI-MS: m / z = 522 (M + H) + .
（実施例３７）（Ｒ）－Ｎ－（３－クロロ－４－（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）－１－（メチルスルホニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000129
 　シクロプロピルカルボニルクロリドの代わりにメタンスルホニルクロリドを用いて、それ以外は実施例３６と同様の手順により、表題化合物（以下、実施例３７の化合物）（０．０４７０ｇ，０．０８８３ｍｍｏｌ，９８％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８５（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），１．２０－１．２７（ｍ，２Ｈ），１．４２－１．７９（ｍ，５Ｈ），２．４３（ｄ，Ｊ＝１１．８Ｈｚ，１Ｈ），２．９３（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），３．０１（ｓ，３Ｈ），３．２１（ｄｄ，Ｊ＝１９．０，７．２Ｈｚ，１Ｈ），３．８９（ｄ，Ｊ＝１４．０Ｈｚ，１Ｈ），４．２１（ｓ，２Ｈ），４．５９（ｄ，Ｊ＝３．２Ｈｚ，１Ｈ），７．０１（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５４（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．７２（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．１１（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５３３（Ｍ＋Ｈ）＋． Example 37 Synthesis of (R) -N- (3-chloro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) -1- (methylsulfonyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000129
 The title compound (hereinafter, the compound of Example 37) (0.0470 g, 0.0883 mmol, 98%) was prepared by the same procedure as Example 36 except that methanesulfonyl chloride was used instead of cyclopropyl carbonyl chloride. Obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.85 (t, J = 7.4 Hz, 3 H), 1.20-1.27 (m, 2 H), 1.42-1. 79 (m, 5H), 2.43 (d, J = 11.8 Hz, 1 H), 2.93 (t, J = 7.5 Hz, 2 H), 3.01 (s, 3 H), 3.21 (dd, J =) 19.0, 7.2 Hz, 1 H), 3.89 (d, J = 14.0 Hz, 1 H), 4.21 (s, 2 H), 4.59 (d, J = 3.2 Hz, 1 H), 7.01 (d, J = 8.6 Hz, 1 H), 7.28 (d, J = 5.0 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 2 H), 7.54 (d , J = 8.2 Hz, 2 H), 7.72 (d, J = 2.3 Hz, 1 H), 8.11 (s, 1 H).
ESI-MS: m / z = 533 (M + H) + .
（参考例７６）Ｎ－メチル－１－（４－（トリフルオロメチル）フェニル）メタンアミンの合成：
Figure JPOXMLDOC01-appb-C000130
 　４－（トリフルオロメチル）ベンジルブロミド（１．００ｇ，４．１８ｍｍｏｌ）をエタノール（１３．３ｍＬ）に溶解し、４０重量％メチルアミン水溶液（１．５ｍＬ）を室温で加えた。同温度で１８時間撹拌した後、反応液に蒸留水を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝９０／１０）で精製し、表題化合物（以下、参考例７６の化合物）（０．５８１ｇ，３．０７ｍｍｏｌ，７７％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．４８（ｓ，３Ｈ），３．１８（ｓ，２Ｈ），７．４４（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５８（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝１９０（Ｍ＋Ｈ）＋． Reference Example 76 Synthesis of N-methyl-1- (4- (trifluoromethyl) phenyl) methanamine:
Figure JPOXMLDOC01-appb-C000130
 4- (Trifluoromethyl) benzyl bromide (1.00 g, 4.18 mmol) was dissolved in ethanol (13.3 mL) and 40 wt% methylamine aqueous solution (1.5 mL) was added at room temperature. After stirring at the same temperature for 18 hours, distilled water was added to the reaction solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 90/10) to give the title compound (hereinafter referred to as the compound of Reference Example 76) (0.581 g, 3.07 mmol, 77%) as a colorless oil Obtained.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.48 (s, 3 H), 3.18 (s, 2 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.58 (d , J = 8.0 Hz, 2 H).
ESI-MS: m / z = 190 (M + H) + .
（参考例７７）２－クロロ－Ｎ－メチル－４－ニトロ－Ｎ－（４－（トリフルオロメチル）ベンジル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000131
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例７６の化合物を用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例７７の化合物）（０．５５７ｇ，１．６２ｍｍｏｌ，８７％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．８８（ｓ，３Ｈ），４．４８（ｓ，２Ｈ），７．０７（ｄ，Ｊ＝８．９Ｈｚ，１Ｈ），７．５３（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ），７．６０（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ），８．０９（ｄｄ，Ｊ＝８．９，２．６Ｈｚ，１Ｈ），８．２９（ｄ，Ｊ＝２．６Ｈｚ，１Ｈ）． Reference Example 77 Synthesis of 2-chloro-N-methyl-4-nitro-N- (4- (trifluoromethyl) benzyl) aniline:
Figure JPOXMLDOC01-appb-C000131
 Using the compound of Reference Example 76 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 77) (0. 1). 557 g (1.62 mmol, 87%) were obtained as a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.88 (s, 3 H), 4.48 (s, 2 H), 7.07 (d, J = 8.9 Hz, 1 H), 7.53 (d , J = 8.8 Hz, 2 H), 7.60 (d, J = 8.8 Hz, 2 H), 8.09 (dd, J = 8.9, 2.6 Hz, 1 H), 8.29 (d, J = 2.6 Hz, 1 H).
（参考例７８）２－クロロ－Ｎ１－メチル－Ｎ１－（４－（トリフルオロメチル）ベンジル）ベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000132
 　参考例７２の化合物の代わりに参考例７７の化合物を用いて、それ以外は参考例７３と同様の手順により、表題化合物（以下、参考例７８の化合物）（０．４５１ｇ，１．４３ｍｍｏｌ，９９％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．６０（ｓ，３Ｈ），３．５５（ｓ，２Ｈ），４．１０（ｓ，２Ｈ），６．５２（ｄｄ，Ｊ＝８．５，２．７Ｈｚ，１Ｈ），６．７６（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），６．８９（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），７．５３（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５５（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３１５（Ｍ＋Ｈ）＋． (Reference Example 78) Synthesis of 2-chloro-N 1 -methyl-N 1- (4- (trifluoromethyl) benzyl) benzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000132
 The title compound (hereinafter, the compound of Reference Example 78) (0.451 g, 1.43 mmol, 99) was prepared by using the compound of Reference Example 77 instead of the compound of Reference Example 72 and using the same procedure as in Reference Example 73 except the above. %) As a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.60 (s, 3 H), 3.55 (s, 2 H), 4. 10 (s, 2 H), 6.52 (dd, J = 8.5) , 2.7 Hz, 1 H), 6.76 (d, J = 2.7 Hz, 1 H), 6.89 (d, J = 8.5 Hz, 1 H), 7.53 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H).
ESI-MS: m / z = 315 (M + H) + .
（実施例３８）１－アセチル－Ｎ－（３－クロロ－４－（メチル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000133
 　参考例７８の化合物（０．２００ｇ，０．６３５ｍｍｏｌ）をＤＭＦ（６．３６ｍＬ）に溶解し、Ｎ－アセチル－ピペコリン酸（０．１４１ｇ，０．８２６ｍｍｏｌ）、ＨＡＴＵ（０．３６２ｇ，０．９３５ｍｍｏｌ）及びトリエチルアミン（０．１７７ｍＬ，１．２７ｍｍｏｌ）を室温で加えた。同温度で１４時間撹拌した後、反応液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル）で精製し、表題化合物（以下、実施例３８の化合物）（０．２１７ｇ，０．４６４ｍｍｏｌ，７３％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４９－１．６１（ｍ，３Ｈ），１．７１－１．７８（ｍ，１Ｈ），１．９２－１．９９（ｍ，１Ｈ），２．２２（ｓ，３Ｈ），２．２８（ｄ，Ｊ＝１３．２Ｈｚ，１Ｈ），２．６６（ｓ，３Ｈ），３．１７（ｔｄ，Ｊ＝１３．２，２．６Ｈｚ，１Ｈ），３．７６（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），４．２０（ｓ，２Ｈ），５．２６（ｄ，Ｊ＝４．９Ｈｚ，１Ｈ），６．９９（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．２８（ｄｄ，Ｊ＝８．６，２．４Ｈｚ，１Ｈ），７．５２（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５７（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．６８（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．３６（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４６８（Ｍ＋Ｈ）＋． Example 38 Synthesis of 1-acetyl-N- (3-chloro-4- (methyl (4- (trifluoromethyl) benzyl) amino) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000133
 The compound of Reference Example 78 (0.200 g, 0.635 mmol) was dissolved in DMF (6.36 mL), N-acetyl-pipecolic acid (0.141 g, 0.826 mmol), HATU (0.362 g, 0.935 mmol) ) And triethylamine (0.177 mL, 1.27 mmol) were added at room temperature. After stirring at the same temperature for 14 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate) to give the title compound (hereinafter, the compound of Example 38) (0.217 g, 0.464 mmol, 73%) as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.49-1.61 (m, 3 H), 1.71-1. 78 (m, 1 H), 1.9 2-1.99 (m, 1 H) , 2.22 (s, 3H), 2.28 (d, J = 13.2 Hz, 1 H), 2.66 (s, 3 H), 3.17 (td, J = 13.2, 2.6 Hz, 1H), 3.76 (d, J = 13.7 Hz, 1 H), 4.20 (s, 2 H), 5.26 (d, J = 4.9 Hz, 1 H), 6.99 (d, J = 8.8 Hz, 1 H), 7.28 (dd, J = 8.6, 2.4 Hz, 1 H), 7.52 (d, J = 8.2 Hz, 2 H), 7.57 (d, J = 8 2 Hz, 2 H), 7.68 (d, J = 2.4 Hz, 1 H), 8. 36 (s, 1 H).
ESI-MS: m / z = 468 (M + H) <+> .
（参考例７９）２－メチル－Ｎ－（４－（トリフルオロメチル）ベンジル）プロパン－１－アミンの合成：
Figure JPOXMLDOC01-appb-C000134
 　ベンズアルデヒドの代わりに４－（トリフルオロメチル）ベンズアルデヒドを、プロピルアミンの代わりにイソブチルアミンを用いて、それ以外は参考例５５と同様の手順により、表題化合物（以下、参考例７９の化合物）（０．９５０ｇ，４．１１ｍｍｏｌ，７２％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９１（ｄ，Ｊ＝６．６Ｈｚ，６Ｈ），１．７３－１．８０（ｍ，１Ｈ），２．４１（ｄ，Ｊ＝６．８Ｈｚ，２Ｈ），３．８３（ｓ，２Ｈ），７．４５（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５７（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２３２（Ｍ＋Ｈ）＋． Reference Example 79 Synthesis of 2-Methyl-N- (4- (trifluoromethyl) benzyl) propan-1-amine:
Figure JPOXMLDOC01-appb-C000134
 The title compound (hereinafter, the compound of Reference Example 79) was prepared by the same procedure as Reference Example 55 using 4- (trifluoromethyl) benzaldehyde instead of benzaldehyde and isobutylamine instead of propylamine. .950 g (4.11 mmol, 72%) were obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (d, J = 6.6 Hz, 6 H), 1.73-1.80 (m, 1 H), 2.41 (d, J = 6. 8 Hz, 2 H), 3.83 (s, 2 H), 7. 45 (d, J = 8.0 Hz, 2 H), 7.57 (d, J = 8.0 Hz, 2 H).
ESI-MS: m / z = 232 (M + H) + .
（参考例８０）２－クロロ－Ｎ－イソブチル－４－ニトロ－Ｎ－（４－（トリフルオロメチル）ベンジル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000135
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例７９の化合物を用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例８０の化合物）（０．８１２ｇ，２．１０ｍｍｏｌ，４９％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．３２（ｄ，Ｊ＝６．９Ｈｚ，６Ｈ），１．５６－１．５９（ｍ，１Ｈ），２．４１（ｄ，Ｊ＝７．２Ｈｚ，２Ｈ），４．４８（ｓ，２Ｈ），７．０３（ｔ，Ｊ＝９．０Ｈｚ，１Ｈ），７．４３（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５７（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），８．０２（ｄｄ，Ｊ＝９．０，２．７Ｈｚ，１Ｈ），８．２２（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ）． Reference Example 80 Synthesis of 2-chloro-N-isobutyl-4-nitro-N- (4- (trifluoromethyl) benzyl) aniline:
Figure JPOXMLDOC01-appb-C000135
 Using the compound of Reference Example 79 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 80) (0. 1). 812 g (2.10 mmol, 49%) were obtained as a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.32 (d, J = 6.9 Hz, 6 H), 1.56-1.59 (m, 1 H), 2.41 (d, J = 7. 2 Hz, 2 H), 4.48 (s, 2 H), 7.03 (t, J = 9.0 Hz, 1 H), 7.43 (d, J = 8.2 Hz, 2 H), 7.57 (d, J = 8.2 Hz, 2 H), 8.02 (dd, J = 9.0, 2.7 Hz, 1 H), 8.22 (d, J = 2.7 Hz, 1 H).
（参考例８１）２－クロロ－Ｎ１－イソブチル－Ｎ１－（４－（トリフルオロメチル）ベンジル）ベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000136
 　参考例７２の化合物の代わりに参考例８０の化合物を用いて、それ以外は参考例７３と同様の手順により、表題化合物（以下、参考例８１の化合物）（０．１５９ｇ，０．４４６ｍｍｏｌ，２１％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８４（ｄ，Ｊ＝６．８Ｈｚ，６Ｈ），１．５９－１．６６（ｍ，１Ｈ），２．６３（ｄ，Ｊ＝７．２Ｈｚ，２Ｈ），３．５７（ｂｒｓ，２Ｈ），４．０４（ｓ，２Ｈ），６．５２（ｄｄ，Ｊ＝８．２，２．７Ｈｚ，１Ｈ），６．７６（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），６．８９（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．５１（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５３（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３５７（Ｍ＋Ｈ）＋． Reference Example 81 Synthesis of 2-chloro-N 1 -isobutyl-N 1- (4- (trifluoromethyl) benzyl) benzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000136
 Using the compound of Reference Example 80 instead of the compound of Reference Example 72, and using the same procedure as Reference Example 73 except for this, the title compound (hereinafter, the compound of Reference Example 81) (0.159 g, 0.446 mmol, 21) %) As a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.84 (d, J = 6.8 Hz, 6 H), 1.59-1.66 (m, 1 H), 2.63 (d, J = 7. 2 Hz, 2 H), 3.57 (brs, 2 H), 4.04 (s, 2 H), 6.52 (dd, J = 8.2, 2.7 Hz, 1 H), 6.76 (d, J = 2.7 Hz, 1 H), 6.89 (d, J = 8.2 Hz, 1 H), 7.51 (d, J = 8.0 Hz, 2 H), 7.53 (d, J = 8.0 Hz, 2 H ).
ESI-MS: m / z = 357 (M + H) + .
（参考例８２）（Ｒ）－２－（（３－クロロ－４－（イソブチル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000137
 　参考例８の化合物の代わりに参考例８１の化合物を、ジイソプロピルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例８２の化合物）（０．２３３ｇ，０．４１０ｍｍｏｌ，９８％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｄ，Ｊ＝６．６Ｈｚ，６Ｈ），１．５１（ｓ，９Ｈ），１．５２－１．６４（ｍ，７Ｈ），２．３３（ｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），２．７０（ｄ，Ｊ＝７．２Ｈｚ，２Ｈ），２．８２（ｔ，Ｊ＝１２．０Ｈｚ，１Ｈ），４．１３－４．１４（ｍ，１Ｈ），４．１４（ｓ，２Ｈ），４．８５（ｓ，１Ｈ），７．０１（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．２５－７．２８（ｍ，１Ｈ），７．４９（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５５（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．７０（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）． Reference Example 82 Synthesis of tert-butyl (R) -2-((3-chloro-4- (isobutyl (4- (trifluoromethyl) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000137
 Using the compound of Reference Example 81 in place of the compound of Reference Example 8 and triethylamine in place of diisopropylamine, and using the same procedure as in Reference Example 9 except for this, the title compound (hereinafter referred to as compound of Reference Example 82) (0) .233 g, 0.410 mmol, 98%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (d, J = 6.6 Hz, 6 H), 1.51 (s, 9 H), 1.52-1.64 (m, 7 H), 2 .33 (d, J = 10.0 Hz, 1 H), 2.70 (d, J = 7.2 Hz, 2 H), 2.82 (t, J = 1 2.0 Hz, 1 H), 4.13-4. 14 (m, 1 H), 4. 14 (s, 2 H), 4. 85 (s, 1 H), 7.01 (d, J = 8.6 Hz, 1 H), 7.25-7.28 (m, 1H), 7.49 (d, J = 8.2 Hz, 2 H), 7.55 (d, J = 8.2 Hz, 2 H), 7.70 (d, J = 2.3 Hz, 1 H).
（実施例３９）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（イソブチル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000138
 　参考例９の化合物の代わりに参考例８２の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例３９の化合物）（０．０８６５ｇ，０．１７０ｍｍｏｌ，６４％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８４（ｄ，Ｊ＝６．６Ｈｚ，６Ｈ），１．４９－１．７８（ｍ，５Ｈ），１．９３（ｄｄ，Ｊ＝１４．７，１１．１Ｈｚ，１Ｈ），２．１９（ｓ，３Ｈ），２．２７（ｄ，Ｊ＝１３．１Ｈｚ，１Ｈ），２．６９（ｄ，Ｊ＝７．２Ｈｚ，２Ｈ），３．１７（ｄｄ，Ｊ＝１８．６，７．７Ｈｚ，１Ｈ），３．７６（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），４．１４（ｓ，２Ｈ），５．２６（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），６．９９（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．２４－７．２８（ｍ，１Ｈ），７．４８（ｄｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５５（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．６９（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．３９（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５１０（Ｍ＋Ｈ）＋． Example 39 Synthesis of (R) -1-Acetyl-N- (3-chloro-4- (isobutyl (4- (trifluoromethyl) benzyl) amino) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000138
 Using the compound of Reference Example 82 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 39 below) (0.0865 g, 0.170 mmol, 64) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.84 (d, J = 6.6 Hz, 6 H), 1.49-1 to 78 (m, 5 H), 1.93 (dd, J = 14. 7, 11. 1 Hz, 1 H), 2. 19 (s, 3 H), 2. 27 (d, J = 13.1 Hz, 1 H), 2.69 (d, J = 7.2 Hz, 2 H); 17 (dd, J = 18.6, 7.7 Hz, 1 H), 3.76 (d, J = 13.6 Hz, 1 H), 4.14 (s, 2 H), 5.26 (d, J = 8 .2 Hz, 1 H), 6.99 (d, J = 8.6 Hz, 1 H), 7.24-7. 28 (m, 1 H), 7.48 (dd, J = 8.2 Hz, 2 H), 7 .55 (d, J = 8.2 Hz, 2 H), 7.69 (d, J = 2.3 Hz, 1 H), 8.39 (s, 1 H).
ESI-MS: m / z = 510 (M + H) + .
（実施例４０）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（イソブチル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000139
 　参考例４９の化合物の代わりに参考例８２の化合物を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例４０の化合物）（０．１２６ｇ，０．２１９ｍｍｏｌ，５４％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８２（ｄ，Ｊ＝６．８Ｈｚ，６Ｈ），１．４３－１．５３（ｍ，１Ｈ），１．６６－１．８８（ｍ，５Ｈ），２．２２（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），２．６９（ｄ，Ｊ＝７．２Ｈｚ，２Ｈ），３．４７（ｄｄ，Ｊ＝１６．９，９．３Ｈｚ，１Ｈ），３．６６（ｄ，Ｊ＝１４．５Ｈｚ，１Ｈ），４．１２（ｓ，２Ｈ），４．８２（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），４．８８（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），５．１７（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．９５（ｓ，１Ｈ），６．９７（ｄ，Ｊ＝９．１Ｈｚ，１Ｈ），７．１０（ｓ，１Ｈ），７．１７（ｄｄ，Ｊ＝８．６，２．７Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５０（ｓ，１Ｈ），７．５５（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．６６（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．４９（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５７７（Ｍ＋Ｈ）＋． (Example 40) (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (3-chloro-4- (isobutyl (4- (trifluoromethyl) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000139
 Using the compound of Reference Example 82 instead of the compound of Reference Example 49, and using the same procedure as Example 16 except the above, the title compound (the compound of Example 40) (0.126 g, 0.219 mmol, 54) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.82 (d, J = 6.8 Hz, 6 H), 1.43-1.53 (m, 1 H), 1.66-1.88 (m, 5H), 2.22 (d, J = 13.6 Hz, 1 H), 2.69 (d, J = 7.2 Hz, 2 H), 3.47 (dd, J = 16.9, 9.3 Hz, 1 H) ), 3.66 (d, J = 14.5 Hz, 1 H), 4.12 (s, 2 H), 4.82 (d, J = 16.8 Hz, 1 H), 4.88 (d, J = 16) .8 Hz, 1 H), 5.17 (d, J = 5.0 Hz, 1 H), 6.95 (s, 1 H), 6.97 (d, J = 9.1 Hz, 1 H), 7. 10 (s , 1 H), 7.17 (dd, J = 8.6, 2.7 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 2 H), 7. 50 (s, 1 H), 7.55 (D, J = 8 2Hz, 2H), 7.66 (d, J = 2.3Hz, 1H), 8.49 (s, 1H).
ESI-MS: m / z = 577 (M + H) <+> .
（実施例４１）（Ｒ）－１－（２－（１Ｈ－テトラゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（イソブチル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000140
 　参考例４９の化合物の代わりに参考例８２の化合物を、１－イミダゾール酢酸の代わりに２－（１Ｈ－テトラゾール－１－イル）酢酸を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例４１の化合物）（０．１５０ｇ，０．２６０ｍｍｏｌ，７８％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８３（ｄ，Ｊ＝６．８Ｈｚ，６Ｈ），１．６４－１．８８（ｍ，６Ｈ），２．２５（ｄ，Ｊ＝１４．０Ｈｚ，１Ｈ），２．７０（ｄ，Ｊ＝７．２Ｈｚ，２Ｈ），３．５６（ｔ，Ｊ＝６．８Ｈｚ，１Ｈ），３．７１（ｄ，Ｊ＝１２．２Ｈｚ，１Ｈ），４．１３（ｓ，２Ｈ），５．１４（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），５．３７（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），５．４４（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），６．９９（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．２０（ｄｄ，Ｊ＝８．８，２．７Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５５（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．７０（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），８．１０（ｓ，１Ｈ），８．８３（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５７９（Ｍ＋Ｈ）＋． Example 41 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4- (isobutyl (4- (trifluoromethyl) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000140
 The procedure of Example 16 is repeated using the compound of Reference Example 82 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 41) (0.150 g, 0.260 mmol, 78%) was obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.83 (d, J = 6.8 Hz, 6 H), 1.64-1.88 (m, 6 H), 2.25 (d, J = 14. 0 Hz, 1 H), 2.70 (d, J = 7.2 Hz, 2 H), 3.56 (t, J = 6.8 Hz, 1 H), 3.71 (d, J = 12.2 Hz, 1 H), 4.13 (s, 2 H), 5. 14 (d, J = 5.0 Hz, 1 H), 5. 37 (d, J = 16.8 Hz, 1 H), 5. 44 (d, J = 16.8 Hz) , 1 H), 6.99 (d, J = 8.6 Hz, 1 H), 7. 20 (dd, J = 8.8, 2.7 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2 H), 7.70 (d, J = 2.7 Hz, 1 H), 8.10 (s, 1 H), 8.83 (s, 1 H) .
ESI-MS: m / z = 579 (M + H) <+> .
（参考例８３）Ｎ－（４－（トリフルオロメチル）ベンジル）ブタン－１－アミンの合成：
Figure JPOXMLDOC01-appb-C000141
 　ベンズアルデヒドの代わりに４－（トリフルオロメチル）ベンズアルデヒドを、プロピルアミンの代わりにブチルアミンを用いて、それ以外は参考例５５と同様の手順により、表題化合物（以下、参考例８３の化合物）（１．１５ｇ，４．９７ｍｍｏｌ，８７％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９２（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．３６（ｔｄ，Ｊ＝１４．８，７．２Ｈｚ，３Ｈ），１．５０（ｄｔ，Ｊ＝１４．８，７．２Ｈｚ，２Ｈ），２．６２（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．８５（ｓ，２Ｈ），７．４４（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５８（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２３２（Ｍ＋Ｈ）＋． Reference Example 83 Synthesis of N- (4- (trifluoromethyl) benzyl) butane-1-amine:
Figure JPOXMLDOC01-appb-C000141
 Using 4- (trifluoromethyl) benzaldehyde in place of benzaldehyde and butylamine in place of propylamine, the procedure is the same as in Reference Example 55 except for using the title compound (hereinafter, the compound of Reference Example 83) (1. 15 g, 4.97 mmol, 87%) were obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (t, J = 7.2 Hz, 3 H), 1.36 (td, J = 14.8, 7.2 Hz, 3 H), 1.50 dt, J = 14.8, 7.2 Hz, 2 H), 2.62 (t, J = 7.2 Hz, 2 H), 3.85 (s, 2 H), 7.44 (d, J = 8.0 Hz , 2H), 7.58 (d, J = 8.0 Hz, 2 H).
ESI-MS: m / z = 232 (M + H) + .
（参考例８４）Ｎ－ブチル－２－クロロ－４－ニトロ－Ｎ－（４－（トリフルオロメチル）ベンジル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000142
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例８３の化合物を用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例８４の化合物）（１．００ｇ，２．５６ｍｍｏｌ，６０％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８７（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．２８（ｔｔ，Ｊ＝１３．６，４．８Ｈｚ，２Ｈ），１．５４（ｄｔ，Ｊ＝１７．８，６．３Ｈｚ，２Ｈ），３．２０（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），４．４９（ｓ，２Ｈ），７．０３（ｔ，Ｊ＝９．１Ｈｚ，１Ｈ），７．４３（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５８（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），８．０２（ｄｄ，Ｊ＝９．１，２．７Ｈｚ，１Ｈ），８．２９（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ）． Reference Example 84 Synthesis of N-butyl-2-chloro-4-nitro-N- (4- (trifluoromethyl) benzyl) aniline:
Figure JPOXMLDOC01-appb-C000142
 Using the compound of Reference Example 83 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 84) (1. 00 g, 2.56 mmol, 60%) were obtained as a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.87 (t, J = 7.2 Hz, 3 H), 1.28 (tt, J = 13.6, 4.8 Hz, 2 H), 1.54 ( dt, J = 17.8, 6.3 Hz, 2H), 3.20 (t, J = 7.5 Hz, 2 H), 4.49 (s, 2 H), 7.03 (t, J = 9.1 Hz) , 1 H), 7.43 (d, J = 8.2 Hz, 2 H), 7.58 (d, J = 8.2 Hz, 2 H), 8.02 (dd, J = 9.1, 2.7 Hz, 1H), 8.29 (d, J = 2.7 Hz, 1 H).
（参考例８５）Ｎ１－ブチル－２－クロロ－Ｎ１－（４－（トリフルオロメチル）ベンジル）ベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000143
 　参考例７２の化合物の代わりに参考例８４の化合物を用いて、それ以外は参考例７３と同様の手順により、表題化合物（以下、参考例８５の化合物）（０．５６５ｇ，１．５８ｍｍｏｌ，６１％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．２５（ｔｄ，Ｊ＝１４．５，７．２Ｈｚ，２Ｈ），１．３６（ｄｑ，Ｊ＝１４．２，４．５Ｈｚ，２Ｈ），２．８７（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．５６（ｂｒｓ，２Ｈ），４．１０（ｓ，２Ｈ），６．５１（ｄｄ，Ｊ＝８．２，２．７Ｈｚ，１Ｈ），６．７５（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），６．８９（ｄ，Ｊ＝７．２Ｈｚ，１Ｈ），７．５１（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．５２（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３５７（Ｍ＋Ｈ）＋． Reference Example 85 Synthesis of N 1 -butyl-2-chloro-N 1- (4- (trifluoromethyl) benzyl) benzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000143
 The title compound (following, compound of Reference Example 85) (0.565 g, 1.58 mmol, 61) was prepared by using the compound of Reference Example 84 instead of the compound of Reference Example 72 and using the same procedure as in Reference Example 73 except the above. %) As a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.2 Hz, 3 H), 1.25 (td, J = 14.5, 7.2 Hz, 2 H), 1.36 ( dq, J = 14.2, 4.5 Hz, 2 H), 2.87 (t, J = 7.2 Hz, 2 H), 3.56 (brs, 2 H), 4. 10 (s, 2 H), 6. 51 (dd, J = 8.2, 2.7 Hz, 1 H), 6. 75 (d, J = 2.7 Hz, 1 H), 6.89 (d, J = 7.2 Hz, 1 H), 7.51 (D, J = 8.3 Hz, 2 H), 7.52 (d, J = 8.3 Hz, 2 H).
ESI-MS: m / z = 357 (M + H) + .
（参考例８６）（Ｒ）－２－（（４－（ブチル（４－（トリフルオロメチル）ベンジル）アミノ）－３－クロロフェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000144
 　参考例８の化合物の代わりに参考例８５の化合物を、ジイソプロピルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例８６の化合物）（０．４００ｇ，０．７０４ｍｍｏｌ，８４％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８２（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．２５（ｄｄ，Ｊ＝１４．７，７．５Ｈｚ，２Ｈ），１．３６－１．４７（ｍ，２Ｈ），１．５１（ｓ，９Ｈ），１．５７－１．６５（ｍ，６Ｈ），２．３３（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），２．８１（ｔ，Ｊ＝１２．０Ｈｚ，１Ｈ），２．９５（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），４．０２－４．０７（ｍ，１Ｈ），４．２０（ｓ，２Ｈ），４．８４（ｓ，１Ｈ），７．００（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．２５－７．２８（ｍ，１Ｈ），７．４８（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ），７．５４（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ），７．６７（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ）． Reference Example 86 Synthesis of tert-butyl (R) -2-((4- (butyl (4- (trifluoromethyl) benzyl) amino) -3-chlorophenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000144
 The title compound (hereinafter, the compound of Reference Example 86) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 85 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. .400 g, 0.704 mmol, 84%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.82 (t, J = 7.2 Hz, 3 H), 1.25 (dd, J = 14.7, 7.5 Hz, 2 H), 1.36- 1.47 (m, 2 H), 1.51 (s, 9 H), 1.57-1. 65 (m, 6 H), 2. 33 (d, J = 1 3.6 Hz, 1 H), 2.81 (m t, J = 1 2.0 Hz, 1 H), 2.95 (t, J = 7.2 Hz, 2 H), 4.02-4.07 (m, 1 H), 4. 20 (s, 2 H), 4. 84 (s, 1 H), 7.00 (d, J = 8.6 Hz, 1 H), 7.25-7. 28 (m, 1 H), 7.48 (d, J = 8.6 Hz, 2 H), 7.54 (d, J = 8.6 Hz, 2 H), 7.67 (d, J = 2.7 Hz, 1 H).
（実施例４２）（Ｒ）－１－アセチル－Ｎ－（４－（ブチル（４－（トリフルオロメチル）ベンジル）アミノ）－３－クロロフェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000145
 　参考例９の化合物の代わりに参考例８６の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例４２の化合物）（０．１６４ｇ，０．３２２ｍｍｏｌ，９１％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．２４（ｔｔ，Ｊ＝１２．２，４．８Ｈｚ，２Ｈ）１．３５－１．４３（ｍ，２Ｈ），１．４５－１．６１（ｍ，２Ｈ），１．７３（ｔ，Ｊ＝１５．０Ｈｚ，２Ｈ），１．９０（ｔ，Ｊ＝１３．０Ｈｚ，１Ｈ），２．２０（ｓ，３Ｈ），２．２６（ｄ，Ｊ＝１３．０Ｈｚ，１Ｈ），２．９４（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．２４（ｄｄ，Ｊ＝１８．６，８．２Ｈｚ，１Ｈ），３．７５（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），４．２０（ｓ，２Ｈ），５．２６（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．９８（ｄ，Ｊ＝９．０Ｈｚ，１Ｈ），７．２８（ｄｄ，Ｊ＝９．０，２．３Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５３（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．６８（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．５０（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５１０（Ｍ＋Ｈ）＋． Example 42 Synthesis of (R) -1-Acetyl-N- (4- (butyl (4- (trifluoromethyl) benzyl) amino) -3-chlorophenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000145
 Using the compound of Reference Example 86 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 42 below) (0.164 g, 0.322 mmol, 91) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.2 Hz, 3 H), 1.24 (tt, J = 12.2, 4.8 Hz, 2 H) 1.35-1 .43 (m, 2 H), 1.45-1. 61 (m, 2 H), 1. 73 (t, J = 15.0 Hz, 2 H), 1. 90 (t, J = 1 3.0 Hz, 1 H) , 2.20 (s, 3H), 2.26 (d, J = 13.0 Hz, 1 H), 2.94 (t, J = 7.2 Hz, 2 H), 3.24 (dd, J = 18. 6, 8.2 Hz, 1 H), 3. 75 (d, J = 13.6 Hz, 1 H), 4. 20 (s, 2 H), 5. 26 (d, J = 5.0 Hz, 1 H), 6. 98 (d, J = 9.0 Hz, 1 H), 7.28 (dd, J = 9.0, 2.3 Hz, 1 H), 7.48 (d, J = 8.2 Hz, 2 H), 7.53 (D, J 8.2Hz, 2H), 7.68 (d, J = 2.3Hz, 1H), 8.50 (s, 1H).
ESI-MS: m / z = 510 (M + H) + .
（実施例４３）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（４－（ブチル（４－（トリフルオロメチル）ベンジル）アミノ）－３－クロロフェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000146
 　参考例４９の化合物の代わりに参考例８６の化合物を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例４３の化合物）（０．２６２ｇ，０．４５５ｍｍｏｌ，６５％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８０（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．２１－１．２８（ｍ，２Ｈ），１．３４－１．５１（ｍ，２Ｈ），１．５８－１．７２（ｍ，２Ｈ），１．７８－１．９５（ｍ，３Ｈ），２．２０（ｄ，Ｊ＝１３．１Ｈｚ，１Ｈ），２．９３（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．４９（ｔ，Ｊ＝１３．１Ｈｚ，１Ｈ），３．６４（ｄ，Ｊ＝１１．８Ｈｚ，１Ｈ），４．１７（ｓ，２Ｈ），４．７９（ｄ，Ｊ＝１８．１Ｈｚ，１Ｈ），４．８５（ｄ，Ｊ＝１６．３Ｈｚ，１Ｈ），５．１５（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．９３（ｓ，１Ｈ），６．９５（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．０７（ｓ，１Ｈ），７．１６（ｄｄ，Ｊ＝８．８，２．５Ｈｚ，１Ｈ），７．４７（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．４８（ｓ，１Ｈ），７．５３（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．６３（ｓ，１Ｈ），８．６４（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５７７（Ｍ＋Ｈ）＋． Example 43 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (4- (butyl (4- (trifluoromethyl) benzyl) amino) -3-chlorophenyl) Synthesis of piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000146
 Using the compound of Reference Example 86 instead of the compound of Reference Example 49, and using the same procedure as Example 16 except the above, the title compound (the compound of Example 43 below) (0.262 g, 0.455 mmol, 65) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.80 (t, J = 7.5 Hz, 3 H), 1.21-1.28 (m, 2 H), 1.34-1.51 (m, 2H), 1.58-1.72 (m, 2H), 1.78-1.95 (m, 3H), 2.20 (d, J = 13.1 Hz, 1H), 2.93 (t, J = 7.2 Hz, 2H), 3.49 (t, J = 13.1 Hz, 1 H), 3.64 (d, J = 11.8 Hz, 1 H), 4.17 (s, 2 H), 4. 79 (d, J = 18.1 Hz, 1 H), 4. 85 (d, J = 16.3 Hz, 1 H), 5. 15 (d, J = 5.0 Hz, 1 H), 6.93 (s, 1 H) ), 6.95 (d, J = 8.6 Hz, 1 H), 7.07 (s, 1 H), 7.16 (dd, J = 8.8, 2.5 Hz, 1 H), 7.47 (d , J = 8.2 H , 2H), 7.48 (s, 1H), 7.53 (d, J = 8.2Hz, 2H), 7.63 (s, 1H), 8.64 (s, 1H).
ESI-MS: m / z = 577 (M + H) <+> .
（実施例４４）（Ｒ）－１－（２－（１Ｈ－テトラゾール－１－イル）アセチル）－Ｎ－（４－（ブチル（４－（トリフルオロメチル）ベンジル）アミノ）－３－クロロフェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000147
 　参考例４９の化合物の代わりに参考例８６の化合物を、１－イミダゾール酢酸の代わりに２－（１Ｈ－テトラゾール－１－イル）酢酸を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例４４の化合物）（０．２１３ｇ，０．３６８ｍｍｏｌ，定量的）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．２０－１．２９（ｍ，２Ｈ），１．３５－１．４３（ｍ，２Ｈ），１．５６－１．８９（ｍ，３Ｈ），２．２４（ｄ，Ｊ＝１３．１Ｈｚ，１Ｈ），２．８０（ｓ，２Ｈ），２．９５（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．５４（ｔ，Ｊ＝１２．０Ｈｚ，１Ｈ），３．７０（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），４．１９（ｓ，２Ｈ），５．１４（ｄ，Ｊ＝４．５Ｈｚ，１Ｈ），５．３７（ｄ，Ｊ＝１６．３Ｈｚ，１Ｈ），５．４３（ｄ，Ｊ＝１６．３Ｈｚ，１Ｈ），６．９８（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．１９（ｄｄ，Ｊ＝８．６，２．３Ｈｚ，１Ｈ），７．４７（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５４（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．６８（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．０４（ｓ，１Ｈ），８．８３（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５７８（Ｍ＋Ｈ）＋． Example 44 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (4- (butyl (4- (trifluoromethyl) benzyl) amino) -3-chlorophenyl) Synthesis of piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000147
 The procedure of Example 16 is repeated using the compound of Reference Example 86 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 44) (0.213 g, 0.368 mmol, quantitative) was obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.5 Hz, 3 H), 1.20-1.29 (m, 2 H), 1.35-1. 43 (m, 2H), 1.56-1.89 (m, 3H), 2.24 (d, J = 13.1 Hz, 1H), 2.80 (s, 2H), 2.95 (t, J = 7. 2 Hz, 2 H), 3.54 (t, J = 12.0 Hz, 1 H), 3.70 (d, J = 13.6 Hz, 1 H), 4.19 (s, 2 H), 5.14 (d, 5) J = 4.5 Hz, 1 H), 5.37 (d, J = 16.3 Hz, 1 H), 5.43 (d, J = 16.3 Hz, 1 H), 6.98 (d, J = 8.6 Hz) , 1 H), 7.19 (dd, J = 8.6, 2.3 Hz, 1 H), 7.47 (d, J = 8.2 Hz, 2 H), 7.54 (d, J = 8.2 Hz, 2H), 7. 8 (d, J = 2.3Hz, 1H), 8.04 (s, 1H), 8.83 (s, 1H).
ESI-MS: m / z = 578 (M + H) <+> .
（参考例８７）２－（（４－（トリフルオロメチル）ベンジル）アミノ）エタン－１－オールの合成：
Figure JPOXMLDOC01-appb-C000148
 　ベンズアルデヒドの代わりに４－（トリフルオロメチル）ベンズアルデヒドを、プロピルアミンの代わりにエタノールアミンを用いて、それ以外は参考例５５と同様の手順により、表題化合物（以下、参考例８７の化合物）（０．３５９ｇ，１．６４ｍｍｏｌ，５７％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．０３（ｓ，２Ｈ），２．８１（ｄｄ，Ｊ＝６．４，４．０Ｈｚ，２Ｈ），３．６８（ｄｄ，Ｊ＝６．２，４．０Ｈｚ，２Ｈ），３．８８（ｓ，１Ｈ），７．４４（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５９（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２２０（Ｍ＋Ｈ）＋． Reference Example 87 Synthesis of 2-((4- (trifluoromethyl) benzyl) amino) ethan-1-ol:
Figure JPOXMLDOC01-appb-C000148
 The title compound (hereinafter, the compound of Reference Example 87) was prepared according to the same procedure as in Reference Example 55 except for using 4- (trifluoromethyl) benzaldehyde instead of benzaldehyde and ethanolamine instead of propylamine. .359 g, 1.64 mmol, 57%) were obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.03 (s, 2 H), 2.81 (dd, J = 6.4, 4.0 Hz, 2 H), 3.68 (dd, J = 6. 2, 4.0 Hz, 2 H), 3.88 (s, 1 H), 7.44 (d, J = 8.0 Hz, 2 H), 7.59 (d, J = 8.0 Hz, 2 H).
ESI-MS: m / z = 220 (M + H) + .
（参考例８８）２－（（２－クロロ－４－ニトロフェニル）（４－（トリフルオロメチル）ベンジル）アミノ）エタン－１－オールの合成：
Figure JPOXMLDOC01-appb-C000149
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例８７の化合物を用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例８８の化合物）（０．３５８ｇ，０．９５５ｍｍｏｌ，６０％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．４３（ｔ，Ｊ＝５．５Ｈｚ，２Ｈ），３．７６（ｔ，Ｊ＝５．５Ｈｚ，２Ｈ），４．５８（ｓ，２Ｈ），７．１３（ｄ，Ｊ＝９．０Ｈｚ，１Ｈ），７．４０（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５８（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），８．０４（ｄｄ，Ｊ＝９．０，２．７Ｈｚ，１Ｈ），８．２９（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ）． Reference Example 88 Synthesis of 2-((2-chloro-4-nitrophenyl) (4- (trifluoromethyl) benzyl) amino) ethan-1-ol:
Figure JPOXMLDOC01-appb-C000149
 Using the compound of Reference Example 87 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride, and using the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 88) (0. 1). 358 g (0.955 mmol, 60%) were obtained as a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.43 (t, J = 5.5 Hz, 2 H), 3.76 (t, J = 5.5 Hz, 2 H), 4.58 (s, 2 H) , 7.13 (d, J = 9.0 Hz, 1 H), 7.40 (d, J = 8.0 Hz, 2 H), 7.58 (d, J = 8.0 Hz, 2 H), 8.04 (d dd, J = 9.0, 2.7 Hz, 1 H), 8. 29 (d, J = 2.7 Hz, 1 H).
（参考例８９）２－（（４－アミノ－２－クロロフェニル）（４－（トリフルオロメチル）ベンジル）アミノ）エタン－１－オールの合成：
Figure JPOXMLDOC01-appb-C000150
 　参考例７２の化合物の代わりに参考例８８の化合物を用いて、それ以外は参考例７３と同様の手順により、表題化合物（以下、参考例８９の化合物）（０．１１７ｇ，０．３３９ｍｍｏｌ，６４％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．６０（ｂｒｓ，１Ｈ），３．０８（ｔ，Ｊ＝５．１Ｈｚ，２Ｈ），３．４８（ｔ，Ｊ＝５．１Ｈｚ，２Ｈ），３．６７（ｓ，２Ｈ），４．１５（ｓ，２Ｈ），６．５２（ｄｄ，Ｊ＝８．５，２．７Ｈｚ，１Ｈ），６．７４（ｔ，Ｊ＝３．０Ｈｚ，１Ｈ），６．９１（ｄ，Ｊ＝４．３Ｈｚ，１Ｈ），７．４１（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５４（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３４５（Ｍ＋Ｈ）＋． Reference Example 89 Synthesis of 2-((4-amino-2-chlorophenyl) (4- (trifluoromethyl) benzyl) amino) ethan-1-ol:
Figure JPOXMLDOC01-appb-C000150
 The title compound (hereinafter, the compound of Reference Example 89) (0.117 g, 0.339 mmol, 64) was prepared by using the compound of Reference Example 88 in place of the compound of Reference Example 72 and using the same procedure as in Reference Example 73 %) As a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.60 (brs, 1 H), 3.08 (t, J = 5.1 Hz, 2 H), 3.48 (t, J = 5.1 Hz, 2 H) , 3.67 (s, 2 H), 4. 15 (s, 2 H), 6.52 (dd, J = 8.5, 2.7 Hz, 1 H), 6.74 (t, J = 3.0 Hz, 1H), 6.91 (d, J = 4.3 Hz, 1 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.54 (d, J = 8.0 Hz, 2 H).
ESI-MS: m / z = 345 (M + H) + .
（実施例４５）１－アセチル－Ｎ－（３－クロロ－４－（（２－ヒドロキシエチル）（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000151
 　参考例７８の化合物の代わりに参考例８９の化合物を用いて、それ以外は実施例３８と同様の手順により、表題化合物（以下、実施例４５の化合物）（０．１０７ｇ，０．２１５ｍｍｏｌ，７４％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．４７－１．６５（ｍ，２Ｈ），１．７２－１．７９（ｍ，１Ｈ），１．８９－１．９８（ｍ，１Ｈ），２．２２（ｓ，３Ｈ），２．２６（ｄ，Ｊ＝１３．２Ｈｚ，１Ｈ），２．３５－２．４０（ｍ，１Ｈ），３．１５－３．２５（ｍ，３Ｈ），３．５３（ｑ，Ｊ＝５．４Ｈｚ，３Ｈ），３．７６（ｄ，Ｊ＝１３．４Ｈｚ，１Ｈ），４．２３（ｓ，２Ｈ），５．２４（ｄ，Ｊ＝５．１Ｈｚ，１Ｈ），７．０２（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．２６－７．３０（ｍ，１Ｈ），７．３９（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５３（ｄ，Ｊ＝９．４Ｈｚ，２Ｈ），７．７２（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．４９（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４９８（Ｍ＋Ｈ）＋． EXAMPLE 45 Synthesis of 1-Acetyl-N- (3-chloro-4-((2-hydroxyethyl) (4- (trifluoromethyl) benzyl) amino) phenyl) piperidine-2-carboxamide
Figure JPOXMLDOC01-appb-C000151
 Using the compound of Reference Example 89 instead of the compound of Reference Example 78, and using the procedure of Example 38 except for the above, the title compound (the compound of Example 45 below) (0.107 g, 0.215 mmol, 74) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.47-1.65 (m, 2 H), 1.72-1. 79 (m, 1 H), 1.89-1. 98 (m, 1 H) , 2.22 (s, 3 H), 2. 26 (d, J = 13.2 Hz, 1 H), 2.35-2.40 (m, 1 H), 3.15-3. 25 (m, 3 H) , 3.53 (q, J = 5.4 Hz, 3 H), 3.76 (d, J = 13.4 Hz, 1 H), 4.23 (s, 2 H), 5.24 (d, J = 5. 1 Hz, 1 H), 7.02 (d, J = 8.8 Hz, 1 H), 7.26-7.30 (m, 1 H), 7.39 (d, J = 8.0 Hz, 2 H), 7. 53 (d, J = 9.4 Hz, 2 H), 7.72 (d, J = 2.4 Hz, 1 H), 8.49 (s, 1 H).
ESI-MS: m / z = 498 (M + H) + .
（参考例９０）２－メトキシ－Ｎ－（４－（トリフルオロメチル）ベンジル）エタン－１－アミンの合成：
Figure JPOXMLDOC01-appb-C000152
 　ベンズアルデヒドの代わりに４－（トリフルオロメチル）ベンズアルデヒドを、プロピルアミンの代わりにメトキシエチルアミンを用いて、それ以外は参考例５５と同様の手順により、表題化合物（以下、参考例９０の化合物）（０．５９１ｇ，２．５３ｍｍｏｌ，８８％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：２．７９（ｔ，Ｊ＝５．０Ｈｚ，２Ｈ），３．３６（ｓ，３Ｈ），３．５２（ｔ，Ｊ＝５．０Ｈｚ，２Ｈ），３．８７（ｓ，２Ｈ），７．４５（ｄ，Ｊ＝７．７Ｈｚ，２Ｈ），７．５７（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２３４（Ｍ＋Ｈ）＋． Reference Example 90 Synthesis of 2-methoxy-N- (4- (trifluoromethyl) benzyl) ethan-1-amine:
Figure JPOXMLDOC01-appb-C000152
 The title compound (hereinafter, the compound of Reference Example 90) was prepared by the same procedure as Reference Example 55 using 4- (trifluoromethyl) benzaldehyde instead of benzaldehyde and methoxyethylamine instead of propylamine. .591 g (2.53 mmol, 88%) were obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 2.79 (t, J = 5.0 Hz, 2 H), 3.36 (s, 3 H), 3.52 (t, J = 5.0 Hz, 2 H) , 3.87 (s, 2 H), 7. 45 (d, J = 7.7 Hz, 2 H), 7.57 (d, J = 8.2 Hz, 2 H).
ESI-MS: m / z = 234 (M + H) + .
（参考例９１）２－クロロ－Ｎ－（２－メトキシエチル）－４－ニトロ－Ｎ－（４－（トリフルオロメチル）ベンジル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000153
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例９０の化合物を用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例９１の化合物）（０．４５３ｇ，１．１７ｍｍｏｌ，５１％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．２７（ｓ，２Ｈ），３．５１－３．５２（ｍ，４Ｈ），４．６３（ｓ，２Ｈ），７．１２（ｄ，Ｊ＝９．１Ｈｚ，１Ｈ），７．４４（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５７（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），８．０２（ｄｄ，Ｊ＝９．１，２．７Ｈｚ，１Ｈ），８．２６（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ）． Reference Example 91 Synthesis of 2-chloro-N- (2-methoxyethyl) -4-nitro-N- (4- (trifluoromethyl) benzyl) aniline:
Figure JPOXMLDOC01-appb-C000153
 Using the compound of Reference Example 90 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 91) (0. 1). 453 g (1.17 mmol, 51%) were obtained as a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.27 (s, 2 H), 3.51-3. 52 (m, 4 H), 4.63 (s, 2 H), 7.12 (d, J = 9.1 Hz, 1 H), 7.44 (d, J = 8.2 Hz, 2 H), 7.57 (d, J = 8.2 Hz, 2 H), 8.02 (dd, J = 9.1, 2.7 Hz, 1 H), 8. 26 (d, J = 2.7 Hz, 1 H).
（参考例９２）２－クロロ－Ｎ１－（２－メトキシエチル）－Ｎ１－（４－（トリフルオロメチル）ベンジル）ベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000154
 　参考例７２の化合物の代わりに参考例９１の化合物を用いて、それ以外は参考例７３と同様の手順により、表題化合物（以下、参考例９２の化合物）（０．０７３０ｇ，０．２０３ｍｍｏｌ，７９％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：３．１６（ｔ，Ｊ＝６．０Ｈｚ，２Ｈ），３．２６（ｓ，３Ｈ），３．４０（ｔ，Ｊ＝６．０Ｈｚ，２Ｈ），３．５６（ｂｒｓ，２Ｈ），４．２６（ｓ，２Ｈ），６．４８（ｄｄ，Ｊ＝８．５，１．３Ｈｚ，１Ｈ），６．７２（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），６．９５（ｄ，Ｊ＝４．３Ｈｚ，１Ｈ），７．５０（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．５２（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３５９（Ｍ＋Ｈ）＋． Reference Example 92 Synthesis of 2-Chloro-N 1- (2-methoxyethyl) -N 1- (4- (trifluoromethyl) benzyl) benzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000154
 The title compound (hereinafter, the compound of Reference Example 92) (0.0730 g, 0.203 mmol, 79) was prepared by using the compound of Reference Example 91 instead of the compound of Reference Example 72 and using the same procedure as in Reference Example 73 except the above. %) As a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 3.16 (t, J = 6.0 Hz, 2 H), 3.26 (s, 3 H), 3. 40 (t, J = 6.0 Hz, 2 H) , 3.56 (brs, 2H), 4.26 (s, 2H), 6.48 (dd, J = 8.5, 1.3 Hz, 1 H), 6.72 (d, J = 2.3 Hz, 1 H), 6.95 (d, J = 4.3 Hz, 1 H), 7. 50 (d, J = 8.3 Hz, 2 H), 7.52 (d, J = 8.3 Hz, 2 H).
ESI-MS: m / z = 359 (M + H) + .
（参考例９３）（Ｒ）－２－（（３－クロロ－４－（（２－メトキシエチル）（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000155
 　参考例８の化合物の代わりに参考例９２の化合物を、ジイソプロピルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例９３の化合物）（０．０６６０ｇ，０．１１６ｍｍｏｌ，５７％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．５１（ｓ，９Ｈ），１．５３－１．７２（ｍ，６Ｈ），２．３０－２．３５（ｍ，１Ｈ），２．６７－２．７５（ｍ，１Ｈ），３．１５－３．２１（ｍ，２Ｈ），３．２５（ｓ，３Ｈ），３．４１－３．４５（ｍ，２Ｈ），４．１３－４．１４（ｍ，１Ｈ），４．１４（ｓ，２Ｈ），４．８３（ｓ，１Ｈ），７．００（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．２５（ｄｄ，Ｊ＝８．８，２．３Ｈｚ，１Ｈ），７．４９（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．５３（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．６５（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）． (Reference Example 93) (R) -2-((3-Chloro-4-((2-methoxyethyl) (4- (trifluoromethyl) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylic acid tert- Synthesis of butyl:
Figure JPOXMLDOC01-appb-C000155
 The title compound (hereinafter, the compound of Reference Example 93) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 92 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. .0660 g, 0.116 mmol, 57%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.51 (s, 9 H), 1.53-1.72 (m, 6 H), 2.30-2.35 (m, 1 H), 2.67 -2.75 (m, 1 H), 3.15-3. 21 (m, 2 H), 3. 25 (s, 3 H), 3.41-3. 45 (m, 2 H), 4.13-4 .14 (m, 1 H), 4.14 (s, 2 H), 4.83 (s, 1 H), 7.00 (d, J = 8.8 Hz, 1 H), 7.25 (dd, J = 8) .8, 2.3 Hz, 1 H), 7.49 (d, J = 8.3 Hz, 2 H), 7.53 (d, J = 8.3 Hz, 2 H), 7.65 (d, J = 2. 3 Hz, 1 H).
（実施例４６）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（（２－メトキシエチル）（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000156
 　参考例４９の化合物の代わりに参考例９３の化合物を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例４６の化合物）（０．０６１７ｇ，０．１０７ｍｍｏｌ，９２％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：１．５３－１．７２（ｍ，６Ｈ），２．６７－２．７５（ｍ，２Ｈ），３．２１－３．２６（ｍ，２Ｈ），３．３４（ｓ，３Ｈ），３．５１－３．５５（ｍ，２Ｈ），４．３６（ｓ，２Ｈ），５．１５（ｄ，Ｊ＝１６．８Ｈｚ，２Ｈ），５．３２（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．９８－７．０９（ｍ，３Ｈ），７．２５（ｍ，１Ｈ），７．４７（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．４９（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．７６（ｓ，１Ｈ），７．７７（ｓ，１Ｈ），８．０９（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５７８（Ｍ＋Ｈ）＋． Example 46 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (3-chloro-4-((2-methoxyethyl) (4- (trifluoromethyl)) Synthesis of benzyl) amino) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000156
 Using the compound of Reference Example 93 instead of the compound of Reference Example 49, and using the same procedure as Example 16 except the above, the title compound (the compound of Example 46 below) (0.0617 g, 0.107 mmol, 92) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 1.53-1.72 (m, 6 H), 2.67-2.75 (m, 2 H), 3.21-3. 26 (m, 2 H) , 3.34 (s, 3 H), 3.51-3. 55 (m, 2 H), 4. 36 (s, 2 H), 5. 15 (d, J = 16.8 Hz, 2 H), 5.32 (D, J = 5.0 Hz, 1 H), 6.98-7.09 (m, 3 H), 7. 25 (m, 1 H), 7.47 (d, J = 8.2 Hz, 2 H), 7 .49 (d, J = 8.2 Hz, 2 H), 7.76 (s, 1 H), 7.77 (s, 1 H), 8.09 (s, 1 H).
ESI-MS: m / z = 578 (M + H) <+> .
（参考例９４）１－シクロプロピル－Ｎ－（４－（トリフルオロメチル）ベンジル）メタンアミンの合成：
Figure JPOXMLDOC01-appb-C000157
 　ベンズアルデヒドの代わりに４－（トリフルオロメチル）ベンズアルデヒドを、プロピルアミンの代わりにシクロプロピルメチルアミンを用いて、それ以外は参考例５５と同様の手順により、表題化合物（以下、参考例９４の化合物）（０．６６０ｇ，２．８８ｍｍｏｌ，９９％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．０９－０．１３（ｍ，２Ｈ），０．４７－０．５２（ｍ，２Ｈ），０．９５－１．０３（ｍ，１Ｈ），２．４９（ｄ，Ｊ＝６．８Ｈｚ，２Ｈ），３．８８（ｓ，２Ｈ），７．４５（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．５８（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２３０（Ｍ＋Ｈ）＋． Reference Example 94 Synthesis of 1-Cyclopropyl-N- (4- (trifluoromethyl) benzyl) methanamine:
Figure JPOXMLDOC01-appb-C000157
 The title compound (the compound of Reference Example 94) was prepared by the same procedure as Reference Example 55 except for using 4- (trifluoromethyl) benzaldehyde instead of benzaldehyde and cyclopropylmethylamine instead of propylamine. (0.660 g, 2.88 mmol, 99%) was obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.09 to 0.13 (m, 2 H), 0.47 to 0.52 (m, 2 H), 0.95 to 1.03 (m, 1 H) , 2.49 (d, J = 6.8 Hz, 2 H), 3.88 (s, 2 H), 7. 45 (d, J = 8.4 Hz, 2 H), 7.58 (d, J = 8). 4 Hz, 2 H).
ESI-MS: m / z = 230 (M + H) + .
（参考例９５）２－クロロ－Ｎ－（シクロプロピルメチル）－４－ニトロ－Ｎ－（４－（トリフルオロメチル）ベンジル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000158
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例９４の化合物を用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例９５の化合物）（０．３５０ｇ，０．９１０ｍｍｏｌ，５２％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．０３－０．０７（ｍ，２Ｈ），０．４６－０．５２（ｍ，２Ｈ），０．９５－１．０１（ｍ，１Ｈ），３．１４（ｄ，Ｊ＝６．８Ｈｚ，２Ｈ），４．６３（ｓ，２Ｈ），７．１３（ｄ，Ｊ＝９．１Ｈｚ，１Ｈ），７．４７（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５８（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），８．０３（ｄｄ，Ｊ＝９．１，２．７Ｈｚ，１Ｈ），８．２７（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ）． Reference Example 95 Synthesis of 2-chloro-N- (cyclopropylmethyl) -4-nitro-N- (4- (trifluoromethyl) benzyl) aniline:
Figure JPOXMLDOC01-appb-C000158
 Using the compound of Reference Example 94 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride and following the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 95) (0. 1). 350 g, 0.910 mmol, 52%) were obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.03 to 0.07 (m, 2 H), 0.46 to 0.52 (m, 2 H), 0.95 to 1.01 (m, 1 H) , 3.14 (d, J = 6.8 Hz, 2H), 4.63 (s, 2H), 7.13 (d, J = 9.1 Hz, 1H), 7.47 (d, J = 8. 0 Hz, 2 H), 7.58 (d, J = 8.2 Hz, 2 H), 8.03 (dd, J = 9.1, 2.7 Hz, 1 H), 8. 27 (d, J = 2.7 Hz) , 1 H).
（参考例９６）２－クロロ－Ｎ１－（シクロプロピルメチル）－Ｎ１－（４－（トリフルオロメチル）ベンジル）ベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000159
 　参考例７２の化合物の代わりに参考例９５の化合物を用いて、それ以外は参考例７３と同様の手順により、表題化合物（以下、参考例９６の化合物）（０．１８９ｇ，０．５３３ｍｍｏｌ，５９％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．００－０．０２（ｍ，２Ｈ），０．３７－０．３９（ｍ，２Ｈ），０．８５－０．９０（ｍ，１Ｈ），２．８０（ｄ，Ｊ＝６．８Ｈｚ，２Ｈ），３．５５（ｂｒｓ，２Ｈ），４．２８（ｓ，２Ｈ），６．４９（ｄｄ，Ｊ＝８．２，２．７Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），６．９７（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．５２－７．５３（ｍ，４Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３５５（Ｍ＋Ｈ）＋． Reference Example 96 Synthesis of 2-chloro-N 1- (cyclopropylmethyl) -N 1- (4- (trifluoromethyl) benzyl) benzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000159
 The title compound (hereinafter, the compound of Reference Example 96) (0.189 g, 0.533 mmol, 59) was prepared by using the compound of Reference Example 95 in place of the compound of Reference Example 72 and using the same procedure as Reference Example 73 except the above. %) As a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.00-0.02 (m, 2 H), 0.37-0.39 (m, 2 H), 0.85-0.90 (m, 1 H) , 2.80 (d, J = 6.8 Hz, 2 H), 3.55 (brs, 2 H), 4. 28 (s, 2 H), 6. 49 (dd, J = 8.2, 2.7 Hz, 1 H), 6.73 (d, J = 2.7 Hz, 1 H), 6.97 (d, J = 8.2 Hz, 1 H), 7.52-7.53 (m, 4 H).
ESI-MS: m / z = 355 (M + H) + .
（参考例９７）（Ｒ）－２－（（３－クロロ－４－（（シクロプロピルメチル）（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000160
 　参考例８の化合物の代わりに参考例９６の化合物を、ジイソプロピルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例９７の化合物）（０．１７０ｇ，０．３００ｍｍｏｌ，９７％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．０１－０．０３（ｍ，２Ｈ），０．３９（ｄｔ，Ｊ＝８．２，２．９Ｈｚ，２Ｈ），０．８８（ｔ，Ｊ＝６．９Ｈｚ，１Ｈ），１．５１（ｓ，９Ｈ），１．６２－１．７２（ｍ，６Ｈ），２．３２（ｄ，Ｊ＝１２．２Ｈｚ，１Ｈ），２．８１（ｔ，Ｊ＝１２．２Ｈｚ，１Ｈ），２．８９（ｄ，Ｊ＝６．８Ｈｚ，２Ｈ），４．００－４．０９（ｍ，１Ｈ），４．３７（ｓ，２Ｈ），４．８３（ｓ，１Ｈ），７．０８（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．２４（ｄｄ，Ｊ＝８．６，２．３Ｈｚ，１Ｈ），７．５２（ｄ，Ｊ＝９．５Ｈｚ，２Ｈ），７．５３（ｄ，Ｊ＝９．５Ｈｚ，２Ｈ），７．６５（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）． (Reference Example 97) (R) -2-((3-Chloro-4-((cyclopropylmethyl) (4- (trifluoromethyl) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Composition of:
Figure JPOXMLDOC01-appb-C000160
 The title compound (hereinafter, the compound of Reference Example 97) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 96 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. 170 g (0.300 mmol, 97%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.01-0.03 (m, 2 H), 0.39 (dt, J = 8.2, 2.9 Hz, 2 H), 0.88 (t, t) J = 6.9 Hz, 1 H), 1.51 (s, 9 H), 1.62-1. 72 (m, 6 H), 2. 32 (d, J = 12.2 Hz, 1 H), 2.81 ( t, J = 12.2 Hz, 1 H), 2.89 (d, J = 6.8 Hz, 2 H), 4.00-0.09 (m, 1 H), 4. 37 (s, 2 H), 4. 83 (s, 1 H), 7.08 (d, J = 8.6 Hz, 1 H), 7.24 (dd, J = 8.6, 2.3 Hz, 1 H), 7.52 (d, J = 9 .5 Hz, 2 H), 7.53 (d, J = 9.5 Hz, 2 H), 7. 65 (d, J = 2.3 Hz, 1 H).
（実施例４７）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（（シクロプロピルメチル）（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000161
 　参考例４９の化合物の代わりに参考例９７の化合物を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例４７の化合物）（０．１５５ｇ，０．２７０ｍｍｏｌ，９３％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．０１－０．０３（ｍ，２Ｈ），０．３８（ｄｄ，Ｊ＝１２．９，５．２Ｈｚ，２Ｈ），０．８３－０．９０（ｍ，１Ｈ），１．６２－１．６６（ｍ，１Ｈ），１．７９（ｄ，Ｊ＝１２．２Ｈｚ，２Ｈ），１．９５－２．０１（ｍ，２Ｈ），２．１９（ｄ，Ｊ＝１３．１Ｈｚ，１Ｈ），２．８７（ｄ，Ｊ＝６．３Ｈｚ，２Ｈ），３．４９（ｔ，Ｊ＝１２．５Ｈｚ，１Ｈ），３．６３（ｄ，Ｊ＝１０．４Ｈｚ，１Ｈ），４．３５（ｓ，２Ｈ），４．８１（ｄ，Ｊ＝３．２Ｈｚ，２Ｈ），５．１５（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．９１（ｓ，１Ｈ），７．０５（ｄｄ，Ｊ＝１１．６，８．４Ｈｚ，２Ｈ），７．１５（ｄｄ，Ｊ＝８．６，２．３Ｈｚ，１Ｈ），７．４８－７．５２（ｍ，５Ｈ），７．６１（ｓ，１Ｈ），８．７１（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５７５（Ｍ＋Ｈ）＋． (Example 47) (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (3-chloro-4-((cyclopropylmethyl) (4- (trifluoromethyl) benzyl) Synthesis of)) amino) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000161
 Using the compound of Reference Example 97 instead of the compound of Reference Example 49, and using the same procedure as Example 16 except the above, the title compound (the compound of Example 47 below) (0.155 g, 0.270 mmol, 93 %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.01-0.03 (m, 2 H), 0.38 (dd, J = 12.9, 5.2 Hz, 2 H), 0.83-0. 90 (m, 1H), 1.62-1.66 (m, 1H), 1.79 (d, J = 12.2 Hz, 2H), 1.95-2.01 (m, 2H), 19 (d, J = 13.1 Hz, 1 H), 2.87 (d, J = 6.3 Hz, 2 H), 3.49 (t, J = 12.5 Hz, 1 H), 3.63 (d, J = 10.4 Hz, 1 H), 4. 35 (s, 2 H), 4.8 1 (d, J = 3.2 Hz, 2 H), 5. 15 (d, J = 5.0 Hz, 1 H), 6. 91 (S, 1 H), 7.05 (dd, J = 11.6, 8.4 Hz, 2 H), 7.15 (dd, J = 8.6, 2.3 Hz, 1 H), 7.48-7. 52 (m, 5 ), 7.61 (s, 1H), 8.71 (s, 1H).
ESI-MS: m / z = 575 (M + H) <+> .
（参考例９８）２－フルオロ－４－ニトロ－Ｎ－プロピル－Ｎ－（４－（トリフルオロメチル）ベンジル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000162
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例７１の化合物を、３－クロロ－４－フルオロニトロベンゼンの代わりに３，４－ジフルオロニトロベンゼン用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例９８の化合物）（２．４０ｇ，６．７４ｍｍｏｌ，７３％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９３（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．６７－１．７７（ｍ，２Ｈ），３．３７（ｔｄ，Ｊ＝７．８，１．４Ｈｚ，２Ｈ），４．６７（ｓ，２Ｈ），６．６９－６．７３（ｍ，１Ｈ），７．３５（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．６０（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．８７－７．９２（ｍ，２Ｈ）． (Reference Example 98) Synthesis of 2-fluoro-4-nitro-N-propyl-N- (4- (trifluoromethyl) benzyl) aniline:
Figure JPOXMLDOC01-appb-C000162
 The compound of Reference Example 71 is used instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride, 3,4-difluoronitrobenzene is used instead of 3-chloro-4-fluoronitrobenzene, and the other conditions are the same as in Reference Example 47. The title compound (hereinafter, the compound of Reference Example 98) (2.40 g, 6.74 mmol, 73%) was obtained as a yellow-brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (t, J = 7.5 Hz, 3 H), 1.67-1.77 (m, 2 H), 3.37 (td, J = 7. 8, 1.4 Hz, 2 H), 4. 67 (s, 2 H), 6. 69-6. 73 (m, 1 H), 7. 35 (d, J = 8.2 Hz, 2 H), 7. 60 ( d, J = 8.2 Hz, 2 H), 7.87-7.92 (m, 2 H).
（参考例９９）２－フルオロ－Ｎ１－プロピル－Ｎ１－（４－（トリフルオロメチル）ベンジル）ベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000163
 　参考例７の化合物の代わりに参考例９８の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例９９の化合物）（１．６０ｇ，４．９０ｍｍｏｌ，７６％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８３（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．４３（ｄｄ，Ｊ＝１４．６，７．３Ｈｚ，２Ｈ），２．８９（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．５５（ｓ，２Ｈ），４．１８（ｓ，２Ｈ），６．３２（ｄｑ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），６．４０（ｄｄ，Ｊ＝１３．３，２．３Ｈｚ，１Ｈ），６．７６－６．８０（ｍ，１Ｈ），７．４３（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５２（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３２７（Ｍ＋Ｈ）＋． Reference Example 99 Synthesis of 2-fluoro-N 1 -propyl-N 1- (4- (trifluoromethyl) benzyl) benzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000163
 The title compound (hereinafter, the compound of Reference Example 99) (1.60 g, 4.90 mmol, 76) was prepared by using the compound of Reference Example 98 in place of the compound of Reference Example 7 and using the same procedure as in Reference Example 8 %) As a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.83 (t, J = 7.3 Hz, 3 H), 1.43 (dd, J = 14.6, 7.3 Hz, 2 H), 2.89 ( t, J = 7.3 Hz, 2 H), 3.55 (s, 2 H), 4. 18 (s, 2 H), 6.32 (dq, J = 8.2, 2.3 Hz, 1 H), 6. 40 (dd, J = 13.3, 2.3 Hz, 1 H), 6.76-6.80 (m, 1 H), 7.43 (d, J = 8.2 Hz, 2 H), 7.52 (d , J = 8.2 Hz, 2 H).
ESI-MS: m / z = 327 (M + H) + .
（参考例１００）（Ｒ）－２－（（３－フルオロ－４－（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000164
 　参考例８の化合物の代わりに参考例９９の化合物を、ジイソプロピルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例１００の化合物）（０．５２９ｇ，０．９８４ｍｍｏｌ，８０％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８４（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．２６（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），１．５２（ｓ，９Ｈ），１．５５－１．７２（ｍ，６Ｈ），２．３３（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），２．８０（ｔ，Ｊ＝１１．９Ｈｚ，１Ｈ），３．０２（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），４．１０（ｓ，１Ｈ），４．３１（ｓ，２Ｈ），４．８３（ｓ，１Ｈ），６．８３（ｔ，Ｊ＝８．９Ｈｚ，１Ｈ），６．９６－６．９８（ｍ，１Ｈ），７．４２－７．４９（ｍ，３Ｈ），７．５４（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ）． Reference Example 100 Synthesis of tert-butyl (R) -2-((3-fluoro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000164
 The title compound (hereinafter, the compound of Reference Example 100) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 99 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. (5.29 g, 0.984 mmol, 80%) was obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.84 (t, J = 7.3 Hz, 3 H), 1.26 (t, J = 7.3 Hz, 2 H), 1.52 (s, 9 H) , 1.55-1.72 (m, 6 H), 2. 33 (d, J = 13.3 Hz, 1 H), 2.80 (t, J = 11.9 Hz, 1 H), 3.02 (t, J = 7.3 Hz, 2 H), 4. 10 (s, 1 H), 4.31 (s, 2 H), 4. 83 (s, 1 H), 6. 83 (t, J = 8.9 Hz, 1 H) , 6.96-6.98 (m, 1 H), 7.42-7.49 (m, 3 H), 7.54 (d, J = 8.2 Hz, 2 H).
（実施例４８）（Ｒ）－１－アセチル－Ｎ－（３－フルオロ－４－（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000165
 　参考例９の化合物の代わりに参考例１００の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例４８の化合物）（０．０７０９ｇ，０．１４８ｍｍｏｌ，７９％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８３（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．４１－１．５９（ｍ，４Ｈ），１．６６－１．７７（ｍ，２Ｈ），１．８８－１．９８（ｍ，１Ｈ），２．１９（ｓ，３Ｈ），２．２６（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），３．０１（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．１８（ｔ，Ｊ＝１３．３Ｈｚ，１Ｈ），３．７４（ｄ，Ｊ＝１３．３Ｈｚ，１Ｈ），４．２９（ｓ，２Ｈ），５．２５（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．８１（ｔ，Ｊ＝８．９Ｈｚ，１Ｈ），６．９６（ｄｄ，Ｊ＝８．５，２．５Ｈｚ，１Ｈ），７．４１－７．４７（ｍ，３Ｈ），７．５３（ｄ，Ｊ＝７．８Ｈｚ，２Ｈ），８．３４（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４８０（Ｍ＋Ｈ）＋． EXAMPLE 48 Synthesis of (R) -1-acetyl-N- (3-fluoro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000165
 Using the compound of Reference Example 100 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 48 below) (0.0709 g, 0.148 mmol, 79) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.83 (t, J = 7.3 Hz, 3 H), 1.41-1.59 (m, 4 H), 1.66-1.77 (m, 2H), 1.88-1 to 1.98 (m, 1H), 2.19 (s, 3H), 2.26 (d, J = 13.7 Hz, 1H), 3.01 (t, J = 7. 3 Hz, 2 H), 3. 18 (t, J = 13.3 Hz, 1 H), 3. 74 (d, J = 13.3 Hz, 1 H), 4. 29 (s, 2 H), 5.25 (d, J = 5.0 Hz, 1 H), 6.81 (t, J = 8.9 Hz, 1 H), 6.96 (dd, J = 8.5, 2.5 Hz, 1 H), 7.41-7.47 (M, 3 H), 7.53 (d, J = 7.8 Hz, 2 H), 8.34 (s, 1 H).
ESI-MS: m / z = 480 (M + H) + .
（実施例４９）（Ｒ）－１－（２－（１Ｈ－テトラゾール－１－イル）アセチル）－Ｎ－（３－フルオロ－４－（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000166
 　参考例４９の化合物の代わりに参考例１００の化合物を、１－イミダゾール酢酸の代わりに２－（１Ｈ－テトラゾール－１－イル）酢酸を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例４９の化合物）（０．０９５１ｇ，０．１７３ｍｍｏｌ，４７％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８４（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．４５－１．７８（ｍ，５Ｈ），１．８４－１．９０（ｍ，２Ｈ），２．２４（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），３．０２（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．４９－３．５４（ｍ，１Ｈ），３．６９（ｄ，Ｊ＝１２．３Ｈｚ，１Ｈ），４．３１（ｓ，２Ｈ），５．１３（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），５．３６（ｄ，Ｊ＝１６．５Ｈｚ，１Ｈ），５．４３（ｄ，Ｊ＝１６．９Ｈｚ，１Ｈ），６．８１（ｔ，Ｊ＝８．９Ｈｚ，１Ｈ），６．９１（ｄｄ，Ｊ＝８．７，１．８Ｈｚ，１Ｈ），７．４０－７．４５（ｍ，３Ｈ），７．５３（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．９１（ｓ，１Ｈ），８．８２（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５４８（Ｍ＋Ｈ）＋． Example 49 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-fluoro-4- (propyl (4- (trifluoromethyl) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000166
 The procedure of Example 16 is repeated using the compound of Reference Example 100 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 49) (0.0951 g, 0.173 mmol, 47%) was obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.84 (t, J = 7.3 Hz, 3 H), 1.45-1.78 (m, 5 H), 1.84-1.90 (m, 2H), 2.24 (d, J = 13.7 Hz, 1 H), 3.02 (t, J = 7.3 Hz, 2 H), 3.49-3. 54 (m, 1 H), 3.69 ( d, J = 12.3 Hz, 1 H), 4.31 (s, 2 H), 5.13 (d, J = 5.0 Hz, 1 H), 5. 36 (d, J = 16.5 Hz, 1 H), 5.43 (d, J = 16.9 Hz, 1 H), 6.81 (t, J = 8.9 Hz, 1 H), 6.91 (dd, J = 8.7, 1.8 Hz, 1 H), 7 40-7.45 (m, 3 H), 7.53 (d, J = 8.2 Hz, 2 H), 7.91 (s, 1 H), 8.82 (s, 1 H).
ESI-MS: m / z = 548 (M + H) <+> .
（参考例１０１）２－クロロ－４－ニトロ－Ｎ－プロピル－Ｎ－（３－（トリフルオロメチル）ベンジル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000167
 　３－（トリフルオロメチル）ベンズアルデヒド（０．５００ｇ，２．８７ｍｍｏｌ）をジクロロメタン（５．７４ｍＬ）に溶解し、プロピルアミン（０．１７０ｇ，２．８７ｍｍｏｌ）及び硫酸ナトリウム（０．８１６ｇ，５．７４ｍｍｏｌ）を室温で加えた。同温度で３０分間撹拌した後、水素化ホウ素ナトリウム（０．２１７ｇ，５．７４ｍｍｏｌ）を０℃で加え、ゆっくりとメタノールを加えた。室温で１時間撹拌した後、反応液に蒸留水を加え、クロロホルムで抽出した。有機層を無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物をＤＭＳＯ（７．９８ｍＬ）に溶解し、３－クロロ－４－フルオロニトロベンゼン（０．５０１ｇ，２．８５ｍｍｏｌ）及びＮ－メチルモルホリン（０．５７７ｇ，５．７１ｍｍｏｌ）を室温で加えた。１００℃で１４時間撹拌した後、反応液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝９７／３）で精製し、表題化合物（以下、参考例１０１の化合物）（０．４０４ｇ，１．０８ｍｍｏｌ，３８％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８７（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），１．５３－１．６３（ｍ，２Ｈ），３．１６（ｔ，Ｊ＝７．４Ｈｚ，２Ｈ），４．４９（ｓ，２Ｈ），７．０４（ｄ，Ｊ＝７．６Ｈｚ，１Ｈ），７．５１－７．５３（ｍ，２Ｈ），７．５９（ｓ，１Ｈ），８．２８（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），８．３６（ｄｄ，Ｊ＝６．２，２．８Ｈｚ，１Ｈ）． (Reference Example 101) Synthesis of 2-chloro-4-nitro-N-propyl-N- (3- (trifluoromethyl) benzyl) aniline:
Figure JPOXMLDOC01-appb-C000167
 Dissolve 3- (trifluoromethyl) benzaldehyde (0.500 g, 2.87 mmol) in dichloromethane (5.74 mL), propylamine (0.170 g, 2.87 mmol) and sodium sulfate (0.816 g, 5.74 mmol) ) Was added at room temperature. After stirring for 30 minutes at the same temperature, sodium borohydride (0.217 g, 5.74 mmol) was added at 0 ° C., and methanol was slowly added. After stirring at room temperature for 1 hour, distilled water was added to the reaction solution, and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product is dissolved in DMSO (7.98 mL) and 3-chloro-4-fluoronitrobenzene (0.501 g, 2.85 mmol) and N-methylmorpholine (0.577 g, 5.71 mmol) at room temperature added. After stirring at 100 ° C. for 14 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 97/3), and the title compound (hereinafter, the compound of Reference Example 101) (0.404 g, 1.08 mmol, 38%) was yellowed. Obtained as a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.87 (t, J = 7.4 Hz, 3 H), 1.53-1.63 (m, 2 H), 3.16 (t, J = 7. 4 Hz, 2 H), 4. 49 (s, 2 H), 7.0 4 (d, J = 7.6 Hz, 1 H), 7.51-7.53 (m, 2 H), 7.59 (s, 1 H) , 8.28 (d, J = 2.7 Hz, 1 H), 8. 36 (dd, J = 6.2, 2.8 Hz, 1 H).
（参考例１０２）２－クロロ－Ｎ１－プロピル－Ｎ１－（３－（トリフルオロメチル）ベンジル）ベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000168
 　参考例７２の化合物の代わりに参考例１０１の化合物を用いて、それ以外は参考例７３と同様の手順により表題化合物（以下、参考例１０２の化合物）（０．２０７ｇ，０．６０４ｍｍｏｌ，７５％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８２（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），１．３９（ｔｄ，Ｊ＝１４．６，７．３Ｈｚ，２Ｈ），２．８４（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．５６（ｂｒｓ，２Ｈ），４．１２（ｓ，２Ｈ），６．５０（ｄｄ，Ｊ＝５．０，３．３Ｈｚ，１Ｈ），６．７４（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），６．９０（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．３８（ｔ，Ｊ＝７．７Ｈｚ，１Ｈ），７．４７（ｄ，Ｊ＝７．６Ｈｚ，１Ｈ）７．５８（ｄ，Ｊ＝７．６Ｈｚ，１Ｈ），７．６５（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３４２（Ｍ＋Ｈ）＋． Reference Example 102 Synthesis of 2-chloro-N 1 -propyl-N 1- (3- (trifluoromethyl) benzyl) benzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000168
 Using the compound of Reference Example 101 instead of the compound of Reference Example 72, and using the same procedure as Reference Example 73 except for the above, the title compound (hereinafter, the compound of Reference Example 102) (0.207 g, 0.604 mmol, 75% ) Was obtained as a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.82 (t, J = 7.4 Hz, 3 H), 1.39 (td, J = 14.6, 7.3 Hz, 2 H), 2.84 t, J = 7.2 Hz, 2 H), 3.56 (brs, 2 H), 4.12 (s, 2 H), 6. 50 (dd, J = 5.0, 3.3 Hz, 1 H), 6. 74 (d, J = 2.7 Hz, 1 H), 6. 90 (d, J = 8.8 Hz, 1 H), 7.38 (t, J = 7.7 Hz, 1 H), 7.47 (d, J = 7.6 Hz, 1 H) 7.58 (d, J = 7.6 Hz, 1 H), 7.65 (s, 1 H).
ESI-MS: m / z = 342 (M + H) + .
（参考例１０３）（Ｒ）－２－（（３－クロロ－４－（プロピル（３－（トリフルオロメチル）ベンジル）アミノ）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000169
 　参考例８の化合物の代わりに参考例１０２の化合物を、ジイソプロピルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例１０３の化合物）（０．１９０ｇ，０．３４３ｍｍｏｌ，４５％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８４（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３５－１．４７（ｍ，４Ｈ），１．５３（ｓ，９Ｈ），１．６１－１．７８（ｍ，４Ｈ），２．３２（ｄ，Ｊ＝１１．２Ｈｚ，１Ｈ），２．８３（ｔ，Ｊ＝１２．４Ｈｚ，１Ｈ），２．９１（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），４．０５－４．０９（ｍ，１Ｈ），４．１９（ｓ，２Ｈ），４．８４（ｓ，１Ｈ），７．０１（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），７．２６（ｄｄ，Ｊ＝８．４，２．８Ｈｚ，１Ｈ），７．４０（ｔ，Ｊ＝７．７Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝７．６Ｈｚ，１Ｈ），７．５７（ｄ，Ｊ＝７．６Ｈｚ，１Ｈ），７．６４（ｓ，１Ｈ），７．６６（ｓ，１Ｈ）． Reference Example 103 Synthesis of tert-butyl (R) -2-((3-chloro-4- (propyl (3- (trifluoromethyl) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000169
 The title compound (hereinafter, the compound of Reference Example 103) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 102 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. 190 g (0.343 mmol, 45%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.84 (t, J = 7.3 Hz, 3 H), 1.35-1. 47 (m, 4 H), 1.53 (s, 9 H), 1 .61-1.78 (m, 4H), 2.32 (d, J = 11.2 Hz, 1 H), 2.83 (t, J = 12.4 Hz, 1 H), 2.91 (t, J =) 7.2 Hz, 2 H), 4.05-4. 09 (m, 1 H), 4. 19 (s, 2 H), 4. 84 (s, 1 H), 7.01 (d, J = 8.5 Hz, 1H), 7.26 (dd, J = 8.4, 2.8 Hz, 1 H), 7.40 (t, J = 7.7 Hz, 1 H), 7.48 (d, J = 7.6 Hz, 1 H) ), 7.57 (d, J = 7.6 Hz, 1 H), 7.64 (s, 1 H), 7.66 (s, 1 H).
（実施例５０）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（プロピル（３－（トリフルオロメチル）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000170
 　参考例４９の化合物の代わりに参考例１０３の化合物を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例５０の化合物）（０．１０６ｇ，０．１８９ｍｍｏｌ，５５％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８０（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３６－１．４６（ｍ，３Ｈ），１．６０－１．８０（ｍ，３Ｈ），２．０１－２．２０（ｍ，２Ｈ），２．８９（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．５２（ｔ，Ｊ＝１２．９Ｈｚ，１Ｈ），３．６３－３．６７（ｍ，１Ｈ），４．１３（ｓ，２Ｈ），４．８１（ｄ，Ｊ＝５．９Ｈｚ，２Ｈ），５．１６（ｄ，Ｊ＝４．９Ｈｚ，１Ｈ），６．９２（ｓ，１Ｈ），６．９６（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．０２（ｓ，１Ｈ），７．１６（ｄｄ，Ｊ＝１６．７，６．６Ｈｚ，１Ｈ），７．３８（ｔ，Ｊ＝７．８Ｈｚ，１Ｈ），７．４６－７．４７（ｍ，２Ｈ），７．５５（ｄ，Ｊ＝７．６Ｈｚ，１Ｈ），７．６２（ｓ，１Ｈ），７．６４（ｓ，１Ｈ），８．８１－８．９４（ｍ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５６３（Ｍ＋Ｈ）＋． Example 50 (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (3-chloro-4- (propyl (3- (trifluoromethyl) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000170
 Using the compound of Reference Example 103 instead of the compound of Reference Example 49, and using the same procedure as Example 16 except the above, the title compound (the compound of Example 50 below) (0.106 g, 0.189 mmol, 55) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.80 (t, J = 7.3 Hz, 3 H), 1.36 to 1.46 (m, 3 H), 1.60 to 1.80 (m, 3H), 2.01-2.20 (m, 2H), 2.89 (t, J = 7.2 Hz, 2 H), 3.52 (t, J = 12.9 Hz, 1 H), 3.63- 3.67 (m, 1 H), 4. 13 (s, 2 H), 4.8 1 (d, J = 5.9 Hz, 2 H), 5. 16 (d, J = 4.9 Hz, 1 H), 6. 92 (s, 1 H), 6.96 (d, J = 8.8 Hz, 1 H), 7.02 (s, 1 H), 7.16 (dd, J = 16.7, 6.6 Hz, 1 H), 7.38 (t, J = 7.8 Hz, 1 H), 7.46-7.47 (m, 2 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.62 (s, 1 H) ), 7.64 (s, 1) ), 8.81-8.94 (m, 1H).
ESI-MS: m / z = 563 (M + H) <+> .
（参考例１０４）２－クロロ－４－ニトロ－Ｎ－プロピル－Ｎ－（４－（トリフルオロメトキシ）ベンジル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000171
 　３－（トリフルオロメチル）ベンズアルデヒドの代わりに４－（トリフルオロメトキシ）ベンズアルデヒドを用いて、それ以外は参考例１０１と同様の手順により、表題化合物（以下、参考例１０４の化合物）（０．４７８ｇ，１．２３ｍｍｏｌ，４７％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８６（ｔ，Ｊ＝７．４Ｈｚ，３Ｈ），１．５８（ｄｄ，Ｊ＝１４．９，７．３Ｈｚ，２Ｈ），３．１７（ｔ，Ｊ＝７．４Ｈｚ，２Ｈ），４．４５（ｓ，２Ｈ），７．０２（ｄ，Ｊ＝９．０Ｈｚ，１Ｈ），７．１７（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．３３（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），８．２６（ｄ，Ｊ＝２．６Ｈｚ，１Ｈ），８．３５（ｄｄ，Ｊ＝６．２，２．８Ｈｚ，１Ｈ）． Reference Example 104 Synthesis of 2-chloro-4-nitro-N-propyl-N- (4- (trifluoromethoxy) benzyl) aniline:
Figure JPOXMLDOC01-appb-C000171
 The title compound (hereinafter, the compound of Reference Example 104) (0.478 g) was prepared according to the same procedure as in Reference Example 101 except that 4- (trifluoromethoxy) benzaldehyde was used instead of 3- (trifluoromethyl) benzaldehyde , 1.23 mmol, 47%) were obtained as a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.86 (t, J = 7.4 Hz, 3 H), 1.58 (dd, J = 14.9, 7.3 Hz, 2 H), 3.17 ( t, J = 7.4 Hz, 2 H), 4. 45 (s, 2 H), 7.02 (d, J = 9.0 Hz, 1 H), 7.17 (d, J = 8.0 Hz, 2 H), 7.33 (d, J = 8.0 Hz, 2 H), 8.26 (d, J = 2.6 Hz, 1 H), 8. 35 (dd, J = 6.2, 2.8 Hz, 1 H).
（参考例１０５）２－クロロ－Ｎ１－プロピル－Ｎ１－（４－（トリフルオロメトキシ）ベンジル）ベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000172
 　参考例７２の化合物の代わりに参考例１０４の化合物を用いて、それ以外は参考例７３と同様の手順により表題化合物（以下、参考例１０５の化合物）（０．２４４ｇ，０．６８０ｍｍｏｌ，８８％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３９（ｄｄ，Ｊ＝１４．６，７．３Ｈｚ，２Ｈ），２．８３（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．５５（ｂｒｓ，２Ｈ），４．０５（ｓ，２Ｈ），６．５０（ｄｄ，Ｊ＝８．５，２．７Ｈｚ，１Ｈ），６．７４（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），６．８９（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），７．１２（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．３９（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３５９（Ｍ＋Ｈ）＋． Reference Example 105 Synthesis of 2-chloro-N 1 -propyl-N 1- (4- (trifluoromethoxy) benzyl) benzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000172
 The title compound (hereinafter, the compound of Reference Example 105) (0.244 g, 0.680 mmol, 88%) was prepared by using the compound of Reference Example 104 instead of the compound of Reference Example 72 and using the same procedure as in Reference Example 73 except the above. ) Was obtained as a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.3 Hz, 3 H), 1.39 (dd, J = 14.6, 7.3 Hz, 2 H), 2.83 t, J = 7.3 Hz, 2 H), 3.55 (brs, 2 H), 4.05 (s, 2 H), 6. 50 (dd, J = 8.5, 2.7 Hz, 1 H), 6. 74 (d, J = 2.7 Hz, 1 H), 6.89 (d, J = 8.5 Hz, 1 H), 7.12 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 8.0 Hz, 2 H).
ESI-MS: m / z = 359 (M + H) + .
（参考例１０６）（Ｒ）－２－（（３－クロロ－４－（プロピル（４－（トリフルオロメトキシ）ベンジル）アミノ）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000173
 　参考例８の化合物の代わりに参考例１０５の化合物を、ジイソプロピルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例１０６の化合物）（０．３８１ｇ，０．６６８ｍｍｏｌ，９２％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３８－１．４９（ｍ，４Ｈ），１．５３（ｓ，９Ｈ），１．５７－１．７８（ｍ，４Ｈ），２．３２（ｄ，Ｊ＝１２．２Ｈｚ，１Ｈ），２．８３（ｔ，Ｊ＝１２．４Ｈｚ，１Ｈ），２．９０（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），４．０５－４．０８（ｍ，１Ｈ），４．１３（ｓ，２Ｈ），４．８４（ｓ，１Ｈ），６．９８（ｄ，Ｊ＝８．５Ｈｚ，１Ｈ），７．１２（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．２５（ｄｄ，Ｊ＝８．７，２．６Ｈｚ，１Ｈ），７．３８（ｄ，Ｊ＝８．５Ｈｚ，２Ｈ），７．６７（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ）． Reference Example 106 Synthesis of tert-butyl (R) -2-((3-chloro-4- (propyl (4- (trifluoromethoxy) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000173
 The title compound (hereinafter, the compound of Reference Example 106) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 105 was used instead of the compound of Reference Example 8, and triethylamine was used instead of diisopropylamine. .381 g, 0.668 mmol, 92%) were obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.3 Hz, 3 H), 1.38-1.49 (m, 4 H), 1.53 (s, 9 H), 1 .57-1.78 (m, 4H), 2.32 (d, J = 12.2 Hz, 1 H), 2.83 (t, J = 12.4 Hz, 1 H), 2.90 (t, J = 7.3 Hz, 2 H), 4.05-4. 08 (m, 1 H), 4. 13 (s, 2 H), 4. 84 (s, 1 H), 6.98 (d, J = 8.5 Hz, 1H), 7.12 (d, J = 8.5 Hz, 2 H), 7. 25 (dd, J = 8.7, 2.6 Hz, 1 H), 7.38 (d, J = 8.5 Hz, 2 H) ), 7.67 (d, J = 2.4 Hz, 1 H).
（実施例５１）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（プロピル（４－（トリフルオロメトキシ）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000174
 　参考例４９の化合物の代わりに参考例１０６の化合物を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例５１の化合物）（０．０４７５ｇ，０．０８２２ｍｍｏｌ，１２％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８０（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３６－１．４７（ｍ，３Ｈ），１．５６－１．８１（ｍ，３Ｈ），２．０４（ｄ，Ｊ＝４．９Ｈｚ，１Ｈ），２．１９（ｄ，Ｊ＝１３．４Ｈｚ，１Ｈ），２．８８（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．５１（ｄｄ，Ｊ＝１２．９，１０．５Ｈｚ，１Ｈ），３．６４（ｔ，Ｊ＝５．６Ｈｚ，１Ｈ），４．１２（ｓ，２Ｈ），４．８１（ｄ，Ｊ＝４．９Ｈｚ，２Ｈ），５．１５（ｄ，Ｊ＝４．９Ｈｚ，１Ｈ），６．９２－６．９８（ｍ，２Ｈ），７．０３（ｓ，１Ｈ），７．１０－７．２０（ｍ，３Ｈ），７．４０（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．４８（ｓ，１Ｈ），７．６３（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．８０（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５７８（Ｍ＋Ｈ）＋． Example 51 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (3-chloro-4- (propyl (4- (trifluoromethoxy) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000174
 The title compound (the compound of Example 51 below) (0.0475 g, 0.0822 mmol, 12) was prepared by the same procedure as in Example 16 except for using the compound of Reference Example 106 in place of the compound of Reference Example 49. %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.80 (t, J = 7.3 Hz, 3 H), 1.36-1.47 (m, 3 H), 1.56-1.81 (m, 3H), 2.04 (d, J = 4.9 Hz, 1 H), 2.19 (d, J = 13.4 Hz, 1 H), 2.88 (t, J = 7.3 Hz, 2 H), 3. 51 (dd, J = 12.9, 10.5 Hz, 1 H), 3.64 (t, J = 5.6 Hz, 1 H), 4.12 (s, 2 H), 4.81 (d, J = 4 .9 Hz, 2 H), 5. 15 (d, J = 4.9 Hz, 1 H), 6.96-6. 98 (m, 2 H), 7.03 (s, 1 H), 7.10-7.20 (M, 3 H), 7.40 (d, J = 8.4 Hz, 2 H), 7.48 (s, 1 H), 7.63 (d, J = 2.4 Hz, 1 H), 8. 80 (s , 1 H).
ESI-MS: m / z = 578 (M + H) <+> .
（参考例１０７）Ｎ－（３－（トリフルオロメトキシ）ベンジル）プロパン－１－アミンの合成：
Figure JPOXMLDOC01-appb-C000175
 　ベンズアルデヒドの代わりに３－（トリフルオロメトキシ）ベンズアルデヒドをを用いて、それ以外は参考例５５と同様の手順により、表題化合物（以下、参考例１０７の化合物）（３．２０ｇ，１３．７ｍｍｏｌ，６５％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９３（ｔ，Ｊ＝６．９Ｈｚ，３Ｈ），１．５０－１．５７（ｍ，２Ｈ），２．６０（ｔ，Ｊ＝６．８Ｈｚ，２Ｈ），３．８１（ｓ，２Ｈ），７．０９（ｄ，Ｊ＝６．８Ｈｚ，１Ｈ），７．２１－７．２７（ｍ，２Ｈ），７．３１－７．３５（ｍ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２３４（Ｍ＋Ｈ）＋． Reference Example 107 Synthesis of N- (3- (trifluoromethoxy) benzyl) propan-1-amine:
Figure JPOXMLDOC01-appb-C000175
 Using 3- (trifluoromethoxy) benzaldehyde instead of benzaldehyde, and using the same procedure as Reference Example 55 except for the above, the title compound (the compound of Reference Example 107 below) (3.20 g, 13.7 mmol, 65) %) As a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.93 (t, J = 6.9 Hz, 3 H), 1.50-1.57 (m, 2 H), 2.60 (t, J = 6. 8 Hz, 2 H), 3.81 (s, 2 H), 7.09 (d, J = 6.8 Hz, 1 H), 7.21-7. 27 (m, 2 H), 7.31-7. 35 ( m, 1 H).
ESI-MS: m / z = 234 (M + H) + .
（参考例１０８）２－クロロ－４－ニトロ－Ｎ－プロピル－Ｎ－（３－（トリフルオロメトキシ）ベンジル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000176
 　１，２，３，４－テトラヒドロイソキノリン塩酸塩の代わりに参考例１０７の化合物を用いて、それ以外は参考例４７と同様の手順により、表題化合物（以下、参考例１０８の化合物）（０．７９８ｇ，２．０５ｍｍｏｌ，２４％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８７（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．４９－１．６２（ｍ，２Ｈ），３．１６（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），４．４６（ｓ，２Ｈ），７．０２（ｄ，Ｊ＝９．１Ｈｚ，１Ｈ），７．１１－７．３４（ｍ，４Ｈ），８．０３（ｄｄ，Ｊ＝９．１，２．７Ｈｚ，１Ｈ），８．２８（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ）． Reference Example 108 Synthesis of 2-chloro-4-nitro-N-propyl-N- (3- (trifluoromethoxy) benzyl) aniline:
Figure JPOXMLDOC01-appb-C000176
 Using the compound of Reference Example 107 instead of 1,2,3,4-tetrahydroisoquinoline hydrochloride, and using the same procedure as Reference Example 47 except for the above, the title compound (hereinafter, the compound of Reference Example 108) (0. 1). 798 g (2.05 mmol, 24%) were obtained as a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.87 (t, J = 7.2 Hz, 3 H), 1.49-1.62 (m, 2 H), 3.16 (t, J = 7. 5 Hz, 2 H), 4.46 (s, 2 H), 7.02 (d, J = 9.1 Hz, 1 H), 7.1 1-7. 34 (m, 4 H), 8.03 (dd, J = 9.1, 2.7 Hz, 1 H), 8. 28 (d, J = 2.7 Hz, 1 H).
（参考例１０９）２－クロロ－Ｎ１－プロピル－Ｎ１－（３－（トリフルオロメトキシ）ベンジル）ベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000177
 　参考例７の化合物の代わりに参考例１０８の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例１０９の化合物）（０．７０７ｇ，１．９７ｍｍｏｌ，９６％）を黄褐色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８２（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．３９（ｔｄ，Ｊ＝１４．３，６．８Ｈｚ，２Ｈ），２．８４（ｔ，Ｊ＝７．０Ｈｚ，２Ｈ），３．５５（ｓ，２Ｈ），４．０７（ｓ，２Ｈ），６．５０（ｄｄ，Ｊ＝８．６，２．７Ｈｚ，１Ｈ），６．７４（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），６．８９（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．０３－７．０８（ｍ，１Ｈ），７．２５－７．３１（ｍ，３Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３５９（Ｍ＋Ｈ）＋． Reference Example 109 Synthesis of 2-chloro-N 1 -propyl-N 1- (3- (trifluoromethoxy) benzyl) benzene-1,4-diamine:
Figure JPOXMLDOC01-appb-C000177
 Using the compound of Reference Example 108 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except the above, the title compound (the compound of Reference Example 109) (0.707 g, 1.97 mmol, 96) %) As a tan oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.82 (t, J = 7.2 Hz, 3 H), 1.39 (td, J = 14.3, 6.8 Hz, 2 H), 2.84 t, J = 7.0 Hz, 2 H), 3.55 (s, 2 H), 4.07 (s, 2 H), 6. 50 (dd, J = 8.6, 2.7 Hz, 1 H), 6. 74 (d, J = 2.7 Hz, 1 H), 6.89 (d, J = 8.6 Hz, 1 H), 7.03-7.08 (m, 1 H), 7.25-7.31 (m , 3H).
ESI-MS: m / z = 359 (M + H) + .
（参考例１１０）（Ｒ）－２－（（３－クロロ－４－（プロピル（３－（トリフルオロメトキシ）ベンジル）アミノ）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000178
 　参考例８の化合物の代わりに参考例１０９の化合物を、ジイソプロピルアミンの代わりにトリエチルアミンを用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例１１０の化合物）（０．４６７ｇ，０．８１９ｍｍｏｌ，９８％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ｄ－ＤＭＳＯ）δ：０．８１－０．８８（ｍ，３Ｈ），１．２４－１．３２（ｍ，４Ｈ），１．５４（ｓ，９Ｈ），１．４４－１．６５（ｍ，４Ｈ），１．９９－２．０７（ｍ，１Ｈ），２．２８－２．３２（ｍ，１Ｈ），２．８８－２．９５（ｍ，２Ｈ），４．１０－４．１３（ｍ，１Ｈ），４．１３（ｓ，２Ｈ），４．８６（ｓ，１Ｈ），６．９２－７．１０（ｍ，２Ｈ），７．１７－７．３２（ｍ，４Ｈ），７．６９（ｓ，１Ｈ）． Reference Example 110 Synthesis of tert-butyl (R) -2-((3-chloro-4- (propyl (3- (trifluoromethoxy) benzyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000178
 The title compound (hereinafter, the compound of Reference Example 110) was prepared by the same procedure as Reference Example 9 except that the compound of Reference Example 109 was used instead of the compound of Reference Example 8, and triethylamine instead of diisopropylamine. 467 g, 0.819 mmol, 98%) were obtained as a white amorphous.
1 H-NMR (400 MHz, d-DMSO) δ: 0.81-0.88 (m, 3 H), 1.24-1. 32 (m, 4 H), 1.54 (s, 9 H), 1. 44-1.65 (m, 4 H), 1.99-2.07 (m, 1 H), 2.28-2.32 (m, 1 H), 2.88-2.95 (m, 2 H), 4.10-4.13 (m, 1 H), 4.13 (s, 2 H), 4.86 (s, 1 H), 6.92-7. 10 (m, 2 H), 7.17-7. 32 (m, 4 H), 7.69 (s, 1 H).
（実施例５２）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（プロピル（３－（トリフルオロメトキシ）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000179
 　参考例９の化合物の代わりに参考例１１０の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例５２の化合物）（０．１２２ｇ，０．２３８ｍｍｏｌ，９１％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．５ｚ，３Ｈ），１．４２－１．３７（ｍ，２Ｈ），１．４５－１．６０（ｍ，２Ｈ），１．６２－１．７４（ｍ，２Ｈ），１．９１（ｔ，Ｊ＝１２．５Ｈｚ，１Ｈ），２．１９（ｓ，３Ｈ），２．２６（ｄ，Ｊ＝１３．１Ｈｚ，１Ｈ），２．９２（ｄｄ，Ｊ＝１５．６，８．４Ｈｚ，２Ｈ），３．２０（ｔ，Ｊ＝１３．１Ｈｚ，１Ｈ），３．７５（ｄ，Ｊ＝１３．１Ｈｚ，１Ｈ），４．１４（ｄｄ，Ｊ＝１３．８，９．７Ｈｚ，２Ｈ），５．２５（ｄ，Ｊ＝５．０Ｈｚ，１Ｈ），６．９８（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．０３－７．０７（ｍ，１Ｈ），７．２２－７．２８（ｍ，４Ｈ），７．６７（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．４４（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５１２（Ｍ＋Ｈ）＋． Example 52 Synthesis of (R) -1-acetyl-N- (3-chloro-4- (propyl (3- (trifluoromethoxy) benzyl) amino) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000179
 Using the compound of Reference Example 110 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 52 below) (0.122 g, 0.238 mmol, 91) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.5 z, 3 H), 1.42-1. 37 (m, 2 H), 1.45-1. 60 (m, 2H), 1.62-1.74 (m, 2H), 1.91 (t, J = 12.5 Hz, 1H), 2.19 (s, 3H), 2.26 (d, J = 13. 1 Hz, 1 H), 2.92 (dd, J = 15.6, 8.4 Hz, 2 H), 3.20 (t, J = 13.1 Hz, 1 H), 3.75 (d, J = 13.1 Hz) , 1H), 4.14 (dd, J = 13.8, 9.7 Hz, 2H), 5.25 (d, J = 5.0 Hz, 1 H), 6.98 (d, J = 8.6 Hz, 1H), 7.03-7.07 (m, 1 H), 7.22-7. 28 (m, 4 H), 7.67 (d, J = 2.3 Hz, 1 H), 8.44 (s, 1H).
ESI-MS: m / z = 512 (M + H) + .
（実施例５３）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（プロピル（３－（トリフルオロメトキシ）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000180
 　参考例４９の化合物の代わりに参考例１１０の化合物を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例５３の化合物）（０．０３６５ｇ，０．０６３１ｍｍｏｌ，２４％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８０（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．４２（ｔｄ，Ｊ＝１４．５，７．４Ｈｚ，２Ｈ），１．６６（ｔｔ，Ｊ＝１９．０，５．９Ｈｚ，１Ｈ），１．７９（ｄ，Ｊ＝１２．２Ｈｚ，２Ｈ），２．０５（ｄ，Ｊ＝８．６Ｈｚ，２Ｈ），２．２０（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），２．８９（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．５０（ｔ，Ｊ＝１１．８Ｈｚ，１Ｈ），３．６４（ｔ，Ｊ＝５．９Ｈｚ，１Ｈ），４．１３（ｓ，２Ｈ），４．７９（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），４．８５（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），５．１６（ｄ，Ｊ＝４．５Ｈｚ，１Ｈ），６．９２（ｓ，１Ｈ），６．９５（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．０６（ｄ，Ｊ＝７．２Ｈｚ，２Ｈ），７．１７（ｄｄ，Ｊ＝８．６，２．７Ｈｚ，１Ｈ），７．２４－７．２９（ｍ，３Ｈ），７．４９（ｓ，１Ｈ），７．６２（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．７８（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５７９（Ｍ＋Ｈ）＋． Example 53 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (3-chloro-4- (propyl (3- (trifluoromethoxy) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000180
 Using the compound of Reference Example 110 instead of the compound of Reference Example 49, and using the procedure of Example 16 except the above, the title compound (the compound of Example 53 below) (0.0365 g, 0.0631 mmol, 24) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.80 (t, J = 7.5 Hz, 3 H), 1.42 (td, J = 14.5, 7.4 Hz, 2 H), 1.66 ( tt, J = 19.0, 5.9 Hz, 1H), 1.79 (d, J = 12.2 Hz, 2 H), 2.05 (d, J = 8.6 Hz, 2 H), 2.20 (d , J = 13.6 Hz, 1 H), 2.89 (t, J = 7.2 Hz, 2 H), 3.50 (t, J = 11.8 Hz, 1 H), 3.64 (t, J = 5. 9 Hz, 1H), 4.13 (s, 2 H), 4.79 (d, J = 16.8 Hz, 1 H), 4.85 (d, J = 16.8 Hz, 1 H), 5.16 (d, J) J = 4.5 Hz, 1 H), 6.92 (s, 1 H), 6. 95 (d, J = 8.6 Hz, 1 H), 7.06 (d, J = 7.2 Hz, 2 H), 7. 17 ( d, J = 8.6, 2.7 Hz, 1 H, 7.24-7. 29 (m, 3 H), 7. 49 (s, 1 H), 7.62 (d, J = 2.3 Hz, 1 H ), 8.78 (s, 1 H).
ESI-MS: m / z = 579 (M + H) <+> .
（実施例５４）（Ｒ）－１－（２－（１Ｈ－テトラゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（プロピル（３－（トリフルオロメトキシ）ベンジル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000181
 　参考例４９の化合物の代わりに参考例１１０の化合物を、１－イミダゾール酢酸の代わりに２－（１Ｈ－テトラゾール－１－イル）酢酸を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例５４の化合物）（０．１２２ｇ，０．２１０ｍｍｏｌ，８０％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８１（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．３７－１．４６（ｍ，２Ｈ），１．５２－１．８６（ｍ，５Ｈ），２．２３（ｄ，Ｊ＝１３．７Ｈｚ，１Ｈ），２．９１（ｔ，Ｊ＝７．３Ｈｚ，２Ｈ），３．５４（ｔｄ，Ｊ＝１３．２，２．９Ｈｚ，１Ｈ），３．６９（ｄ，Ｊ＝１２．８Ｈｚ，１Ｈ），４．１４（ｓ，２Ｈ），５．１２（ｄ，Ｊ＝４．６Ｈｚ，１Ｈ），５．３５（ｄ，Ｊ＝１６．９Ｈｚ，１Ｈ），５．４３（ｄ，Ｊ＝１６．５Ｈｚ，１Ｈ），６．９８（ｄ，Ｊ＝８．７Ｈｚ，１Ｈ），７．０７（ｄ，Ｊ＝７．８Ｈｚ，１Ｈ），７．１８（ｄｄ，Ｊ＝８．７，２．７Ｈｚ，１Ｈ），７．２４－７．３１（ｍ，３Ｈ），７．６８（ｄ，Ｊ＝２．７Ｈｚ，１Ｈ），８．１３（ｓ，１Ｈ），８．８２（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５８１（Ｍ＋Ｈ）＋． Example 54 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4- (propyl (3- (trifluoromethoxy) benzyl) amino) phenyl ) Synthesis of piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000181
 The procedure of Example 16 is repeated using the compound of Reference Example 110 in place of the compound of Reference Example 49 and 2- (1H-tetrazol-1-yl) acetic acid instead of 1-imidazoleacetic acid The title compound (hereinafter, the compound of Example 54) (0.122 g, 0.210 mmol, 80%) was obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.81 (t, J = 7.3 Hz, 3 H), 1.37-1.46 (m, 2 H), 1.52-1.86 (m, 5H), 2.23 (d, J = 13.7 Hz, 1 H), 2.91 (t, J = 7.3 Hz, 2 H), 3.54 (td, J = 13.2, 2.9 Hz, 1 H ), 3.69 (d, J = 12.8 Hz, 1 H), 4.14 (s, 2 H), 5.12 (d, J = 4.6 Hz, 1 H), 5. 35 (d, J = 16) .9 Hz, 1 H), 5.43 (d, J = 16.5 Hz, 1 H), 6.98 (d, J = 8.7 Hz, 1 H), 7.07 (d, J = 7.8 Hz, 1 H) , 7.18 (dd, J = 8.7, 2.7 Hz, 1 H), 7.24-7. 31 (m, 3 H), 7.68 (d, J = 2.7 Hz, 1 H), 8. 13 (s, 1 ), 8.82 (s, 1H).
ESI-MS: m / z = 581 (M + H) + .
（参考例１１１）Ｎ－（２－クロロ－４－ニトロベンジル）－Ｎ－（４－（トリフルオロメチル）ベンジル）プロパン－１－アミンの合成：
Figure JPOXMLDOC01-appb-C000182
 　参考例６の化合物の代わりに参考例７１の化合物を用いて、それ以外は参考例７と同様の手順により、表題化合物（以下、参考例１１１の化合物）（８．５４ｇ，２２．１ｍｍｏｌ，９６％）を淡黄色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８９（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．５２－１．６２（ｍ，２Ｈ），２．４３－２．４７（ｍ，２Ｈ），３．６９（ｓ，２Ｈ），３．７４（ｓ，２Ｈ），７．４８（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５７（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．８５（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），８．１１（ｄｄ，Ｊ＝８．６，２．３Ｈｚ，１Ｈ），８．２１（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３８７（Ｍ＋Ｈ）＋． Reference Example 111 Synthesis of N- (2-chloro-4-nitrobenzyl) -N- (4- (trifluoromethyl) benzyl) propan-1-amine:
Figure JPOXMLDOC01-appb-C000182
 Using the compound of Reference Example 71 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 7 except for this, the title compound (hereinafter, the compound of Reference Example 111) (8.54 g, 22.1 mmol, 96 %) As a pale yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.89 (t, J = 7.2 Hz, 3 H), 1.52-1.62 (m, 2 H), 2.43-2.47 (m, 2H), 3.69 (s, 2H), 3.74 (s, 2H), 7.48 (d, J = 8.2 Hz, 2 H), 7.57 (d, J = 8.2 Hz, 2 H) , 7.85 (d, J = 8.6 Hz, 1 H), 8.11 (dd, J = 8.6, 2.3 Hz, 1 H), 8.21 (d, J = 2.3 Hz, 1 H).
ESI-MS: m / z = 387 (M + H) + .
（参考例１１２）３－クロロ－４－（（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）メチル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000183
 　参考例７の化合物の代わりに参考例１１１の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例１１２の化合物）（９．５７ｇ，２６．８ｍｍｏｌ，９４％）を淡黄色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８４（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．４８－１．５７（ｍ，２Ｈ），２．３６－２．４０（ｍ，２Ｈ），３．５７（ｓ，２Ｈ），３．５９（ｓ，２Ｈ），３．６５（ｂｒｓ，２Ｈ），６．５５（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），６．６７（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．４６（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５３（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３５７（Ｍ＋Ｈ）＋． Reference Example 112 Synthesis of 3-chloro-4-((propyl (4- (trifluoromethyl) benzyl) amino) methyl) aniline:
Figure JPOXMLDOC01-appb-C000183
 Using the compound of Reference Example 111 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 112) (9.57 g, 26.8 mmol, 94 %) As a pale yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.84 (t, J = 7.5 Hz, 3 H), 1.48-1.57 (m, 2 H), 2.36-2.40 (m, 2H), 3.57 (s, 2H), 3.59 (s, 2H), 3.65 (brs, 2H), 6.55 (dd, J = 8.2, 2.3 Hz, 1H), 6 .67 (d, J = 2.3 Hz, 1 H), 7.28 (d, J = 8.2 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 2 H), 7.53 (d, J J = 8.2 Hz, 2 H).
ESI-MS: m / z = 357 (M + H) + .
（参考例１１３）（Ｒ）－２－（（３－クロロ－４－（（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）メチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000184
 　参考例８の化合物の代わりに参考例１１２の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例１１３の化合物）（８．０１ｇ，１４．１ｍｍｏｌ，７７％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８５（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．４４－１．６９（ｍ，７Ｈ），１．５２（ｓ，９Ｈ），２．３１－２．３４（ｍ，１Ｈ），２．３８－２．４２（ｍ，２Ｈ），２．７７－２．８４（ｍ，１Ｈ），３．６２（ｓ，２Ｈ），３．６３（ｓ，２Ｈ），４．０６（ｂｒｓ，１Ｈ），４．８４（ｓ，１Ｈ），７．２７（ｄｄ，Ｊ＝８．６，２．３Ｈｚ，１Ｈ），７．４６（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５０（ｄ，Ｊ＝８．６Ｈｚ，１Ｈ），７．５３（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．６７（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５６８（Ｍ＋Ｈ）＋． (Reference Example 113) (R) -2-((3-chloro-4-((propyl (4- (trifluoromethyl) benzyl) amino) methyl) phenyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Synthesis:
Figure JPOXMLDOC01-appb-C000184
 The title compound (hereinafter, the compound of Reference Example 113) (8.01 g, 14.1 mmol, 77) was prepared by using the compound of Reference Example 112 in place of the compound of Reference Example 8 and using the same procedure as in Reference Example 9 %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.85 (t, J = 7.2 Hz, 3 H), 1.44-1.69 (m, 7 H), 1.52 (s, 9 H), 2 .31-2.34 (m, 1 H), 2.38-2.42 (m, 2 H), 2.77-2.84 (m, 1 H), 3.62 (s, 2 H), 3.63. (S, 2 H), 4.06 (brs, 1 H), 4. 84 (s, 1 H), 7. 27 (dd, J = 8.6, 2.3 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 2 H), 7. 50 (d, J = 8.6 Hz, 1 H), 7.53 (d, J = 8.2 Hz, 2 H), 7.67 (d, J = 2.3 Hz, 1H).
ESI-MS: m / z = 568 (M + H) + .
（実施例５５）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）メチル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000185
 　参考例９の化合物の代わりに参考例１１３の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例５５の化合物）（０．０４００ｇ，０．０７８４ｍｍｏｌ，７３％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８５（ｔ，Ｊ＝７．３Ｈｚ，３Ｈ），１．４８－１．５７（ｍ，４Ｈ），１．７４（ｂｒｓ，２Ｈ），１．８９－２．００（ｍ，１Ｈ），２．２０（ｓ，３Ｈ），２．２７（ｄ，Ｊ＝１３．２Ｈｚ，１Ｈ），２．４１（ｄ，Ｊ＝７．３Ｈｚ，２Ｈ），３．１５（ｔｄ，Ｊ＝１３．２，２．７Ｈｚ，１Ｈ），３．６１（ｓ，２Ｈ），３．６２（ｓ，２Ｈ），３．７５（ｄ，Ｊ＝１３．９Ｈｚ，１Ｈ），５．２５（ｄ，Ｊ＝５．１Ｈｚ，１Ｈ），７．２８（ｄｄ，Ｊ＝８．４，２．１Ｈｚ，１Ｈ），７．４６（ｔ，Ｊ＝７．８Ｈｚ，３Ｈ），７．５３（ｄ，Ｊ＝８．３Ｈｚ，２Ｈ），７．６４（ｄ，Ｊ＝２．２Ｈｚ，１Ｈ），８．４２（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５１０（Ｍ＋Ｈ）＋． Example 55 Synthesis of (R) -1-acetyl-N- (3-chloro-4-((propyl (4- (trifluoromethyl) benzyl) amino) methyl) phenyl) piperidine-2-carboxamide
Figure JPOXMLDOC01-appb-C000185
 Using the compound of Reference Example 113 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 55 below) (0.0400 g, 0.0784 mmol, 73) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.85 (t, J = 7.3 Hz, 3 H), 1.48-1.57 (m, 4 H), 1.74 (brs, 2 H), 1 .89-2.00 (m, 1 H), 2.20 (s, 3 H), 2.27 (d, J = 13.2 Hz, 1 H), 2.41 (d, J = 7.3 Hz, 2 H) , 3.15 (td, J = 13.2, 2.7 Hz, 1 H), 3.61 (s, 2 H), 3.62 (s, 2 H), 3.75 (d, J = 13.9 Hz, 1H), 5.25 (d, J = 5.1 Hz, 1H), 7.28 (dd, J = 8.4, 2.1 Hz, 1H), 7.46 (t, J = 7.8 Hz, 3H ), 7.53 (d, J = 8.3 Hz, 2 H), 7.64 (d, J = 2.2 Hz, 1 H), 8.42 (s, 1 H).
ESI-MS: m / z = 510 (M + H) + .
（実施例５６）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）メチル）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000186
 　参考例４９の化合物の代わりに参考例１１３の化合物を用いて、それ以外は実施例１６と同様の手順により、表題化合物（以下、実施例５６の化合物）（０．０３７５ｇ，０．０６５０ｍｍｏｌ，３１％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８５（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．４６－１．７０（ｍ，４Ｈ），１．７４－１．８２（ｍ，２Ｈ），１．８９－２．０１（ｍ，１Ｈ），２．２２－２．２５（ｍ，１Ｈ），２．３９（ｔ，Ｊ＝７．５Ｈｚ，２Ｈ），３．３４－３．４３（ｍ，１Ｈ），３．６１（ｓ，２Ｈ），３．６２（ｓ，２Ｈ），３．６６－３．６９（ｍ，１Ｈ），４．８４（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），４．８９（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），５．１６（ｄ，Ｊ＝５．４Ｈｚ，１Ｈ），６．９６（ｓ，１Ｈ），７．１２（ｂｒｓ，１Ｈ），７．１９（ｄｄ，Ｊ＝８．２，１．８Ｈｚ，１Ｈ），７．４５－７．４６（ｍ，３Ｈ），７．５２－７．５４（ｍ，３Ｈ），７．６２（ｂｒｓ，１Ｈ），８．１７（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５７６（Ｍ＋Ｈ）＋． Example 56 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (3-chloro-4-((propyl (4- (trifluoromethyl) benzyl) amino) Synthesis of methyl) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000186
 Using the compound of Reference Example 113 instead of the compound of Reference Example 49, and using the procedure of Example 16 except the above, the title compound (the compound of Example 56) (0.0375 g, 0.0650 mmol, 31) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.85 (t, J = 7.2 Hz, 3 H), 1.46-1.70 (m, 4 H), 1.74-1.82 (m, 2H), 1.89-2.01 (m, 1 H), 2.22-22. 25 (m, 1 H), 2.39 (t, J = 7.5 Hz, 2 H), 3.34-3. 43 (m, 1 H), 3.61 (s, 2 H), 3.62 (s, 2 H), 3.66-3. 69 (m, 1 H), 4. 84 (d, J = 16.8 Hz, 1H), 4.89 (d, J = 16.8 Hz, 1 H), 5.16 (d, J = 5.4 Hz, 1 H), 6.96 (s, 1 H), 7.12 (brs, 1 H) , 7.19 (dd, J = 8.2, 1.8 Hz, 1 H), 7.45 to 7.46 (m, 3 H), 7.52 to 7.54 (m, 3 H), 7.62 (m. brs, 1 H), 8. 7 (brs, 1H).
ESI-MS: m / z = 576 (M + H) + .
（実施例５７）（Ｒ）－１－（２－（１Ｈ－テトラゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）メチル）フェニル）ピペリジン－２－カルボキサミド　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000187
 　参考例１１３の化合物（０．７４０ｇ，１．３０３ｍｍｏｌ）をジクロロメタン（１３．０ｍＬ）に溶解し、トリフルオロ酢酸（３．２６ｍＬ，４２．３ｍｍｏｌ）を０℃で加えた。室温で１．５時間撹拌した後、反応液を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物（０．１００ｇ）をＤＭＦ（１．７６ｍＬ）に溶解し、２－（１Ｈ－テトラゾール－１－イル）酢酸（０．０２２６ｇ，０．１７６ｍｍｏｌ）、ＨＡＴＵ（０．０６６９ｇ，０．１７６ｍｍｏｌ）及びジイソプロピルエチルアミン（０．０３１０ｍＬ，０．１８ｍｍｏｌ）を０℃で加えた。室温で６７時間撹拌した後、減圧濃縮し、蒸留水を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（クロロホルム／メタノール＝１００／０～９０／１０）で精製した。得られた精製物をジエチルエーテル（１．２９ｍＬ）及びｎ－ヘキサン（１．２９ｍＬ）に溶解し、１Ｍ塩化水素－ジエチルエーテル溶液（１．２９ｍＬ）を室温で加えた。反応液を濾過し、濾取した固体を乾燥し、表題化合物（以下、実施例５７の化合物）（０．０４３９ｇ，０．０７１４ｍｍｏｌ，３３％）を白色固体として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ３ＯＤ）δ：０．９１（ｔ，Ｊ＝６．３Ｈｚ，３Ｈ），１．５６－１．８７（ｍ，７Ｈ），２．２５（ｄ，Ｊ＝１５．０Ｈｚ，１Ｈ），３．３０－３．３１（ｍ，２Ｈ），３．６６（ｔｄ，Ｊ＝１２．８，３．０Ｈｚ，１Ｈ），３．８９（ｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），４．８６（ｓ，４Ｈ），５．１３（ｄ，Ｊ＝４．５Ｈｚ，１Ｈ），５．６４（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），５．７６（ｄ，Ｊ＝１７．２Ｈｚ，１Ｈ），７．４７－７．５１（ｍ，２Ｈ），７．５９－７．６７（ｍ，４Ｈ），７．７６－７．８１（ｍ，１Ｈ），９．１３（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５８１（Ｍ＋Ｈ）＋． Example 57 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4-((propyl (4- (trifluoromethyl) benzyl) amino) Synthesis of methyl) phenyl) piperidine-2-carboxamide hydrochloride:
Figure JPOXMLDOC01-appb-C000187
 The compound of Reference Example 113 (0.740 g, 1.303 mmol) was dissolved in dichloromethane (13.0 mL), and trifluoroacetic acid (3.26 mL, 42.3 mmol) was added at 0 ° C. After stirring at room temperature for 1.5 hours, the reaction solution was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product (0.100 g) is dissolved in DMF (1.76 mL) and 2- (1H-tetrazol-1-yl) acetic acid (0.0226 g, 0.176 mmol), HATU (0.0669 g, 0) .176 mmol) and diisopropylethylamine (0.0310 mL, 0.18 mmol) were added at 0.degree. After stirring at room temperature for 67 hours, the mixture was concentrated under reduced pressure, distilled water was added, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform / methanol = 100/0 to 90/10). The purified product obtained was dissolved in diethyl ether (1.29 mL) and n-hexane (1.29 mL), and 1 M hydrogen chloride-diethyl ether solution (1.29 mL) was added at room temperature. The reaction solution was filtered, and the collected solid was dried to give the title compound (hereinafter, the compound of Example 57) (0.0439 g, 0.0714 mmol, 33%) as a white solid.
1 H-NMR (400 MHz, CD 3 OD) δ: 0.91 (t, J = 6.3 Hz, 3 H), 1.56-1.87 (m, 7 H), 2.25 (d, J = 15) .0 Hz, 1 H), 3.30-3.31 (m, 2 H), 3.66 (td, J = 12.8, 3.0 Hz, 1 H), 3.89 (d, J = 13.6 Hz, 1H), 4.86 (s, 4 H), 5. 13 (d, J = 4.5 Hz, 1 H), 5.64 (d, J = 16.8 Hz, 1 H), 5.76 (d, J = 17.2 Hz, 1 H), 7.47-7.51 (m, 2 H), 7.59-7.67 (m, 4 H), 7. 76-7.81 (m, 1 H), 9. 13 ( s, 1 H).
ESI-MS: m / z = 581 (M + H) + .
（実施例５８）（Ｒ）－Ｎ－（３－クロロ－４－（（プロピル（４－（トリフルオロメチル）ベンジル）アミノ）メチル）フェニル）－１－（メチルスルホニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000188
 　参考例１１３の化合物（８．００ｇ，１４．１ｍｍｏｌ）をジクロロメタン（３４．１ｍＬ）に溶解し、トリフルオロ酢酸（８．５４ｍＬ，１１１ｍｍｏｌ）を０℃で加えた。室温で１２時間撹拌した後、反応液を飽和炭酸ナトリウム水溶液に加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、ろ過し、ろ液を減圧濃縮した。得られた残渣を精製すること無く、続く反応に用いた。
　上記の粗生成物をジクロロメタン（４２．７ｍＬ）に溶解し、トリエチルアミン（２．３６ｍＬ，１６．９ｍｍｏｌ）及びメタンスルホニルクロリド（１．２１ｍＬ，１５．５ｍｍｏｌ）を０℃で加えた。同温度で１時間撹拌した後、反応液を飽和炭酸ナトリウム水溶液に加え、クロロホルムで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝８５／１５～７０／３０）で精製し、表題化合物（以下、実施例５８の化合物）（６．００ｇ，１１．０ｍｍｏｌ，７８％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８５（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．４９－１．８０（ｍ，７Ｈ），２．３８－２．４６（ｍ，３Ｈ），３．０１（ｓ，３Ｈ），３．１４－３．２１（ｍ，１Ｈ），３．６２（ｓ，２Ｈ），３．６４（ｓ，２Ｈ），３．８９－３．９２（ｍ，１Ｈ），４．５８－４．５９（ｍ，１Ｈ），７．３２（ｄｄ，Ｊ＝８．２，２．３Ｈｚ，１Ｈ），７．４６（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．５２（ｄ，Ｊ＝８．２Ｈｚ，１Ｈ），７．５４（ｄ，Ｊ＝８．２Ｈｚ，２Ｈ），７．６８（ｄ，Ｊ＝２．３Ｈｚ，１Ｈ），８．１４（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５４６（Ｍ＋Ｈ）＋． Example 58 (R) -N- (3-Chloro-4-((propyl (4- (trifluoromethyl) benzyl) amino) methyl) phenyl) -1- (methylsulfonyl) piperidine-2-carboxamide Synthesis:
Figure JPOXMLDOC01-appb-C000188
 The compound of Reference Example 113 (8.00 g, 14.1 mmol) was dissolved in dichloromethane (34.1 mL), and trifluoroacetic acid (8.54 mL, 111 mmol) was added at 0 ° C. After stirring at room temperature for 12 hours, the reaction solution was added to a saturated aqueous solution of sodium carbonate and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was used for the subsequent reaction without purification.
The above crude product was dissolved in dichloromethane (42.7 mL) and triethylamine (2.36 mL, 16.9 mmol) and methanesulfonyl chloride (1.21 mL, 15.5 mmol) were added at 0 ° C. After stirring for 1 hour at the same temperature, the reaction solution was added to a saturated aqueous solution of sodium carbonate and extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 85/15 to 70/30) to give the title compound (compound of Example 58 below) (6.00 g, 11.0 mmol, 78) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.85 (t, J = 7.5 Hz, 3 H), 1.49-1 to 80 (m, 7 H), 2.38 to 2.46 (m, 3H), 3.01 (s, 3 H), 3.14-3. 21 (m, 1 H), 3.62 (s, 2 H), 3.64 (s, 2 H), 3.89-3. 92 (M, 1 H), 4.58-4.59 (m, 1 H), 7.32 (dd, J = 8.2, 2.3 Hz, 1 H), 7.46 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 1 H), 7.54 (d, J = 8.2 Hz, 2 H), 7.68 (d, J = 2.3 Hz, 1 H), 8. 14 (s, 1 H).
ESI-MS: m / z = 546 (M + H) <+> .
（参考例１１４）Ｎ－（２－クロロ－４－ニトロベンジル）－２－メチル－Ｎ－（４－（トリフルオロメチル）ベンジル）プロパン－１－アミンの合成：
Figure JPOXMLDOC01-appb-C000189
 　参考例６の化合物の代わりに参考例７９の化合物を用いて、それ以外は参考例７と同様の手順により、表題化合物（以下、参考例１１４の化合物）（０．２１９ｇ，０．５４６ｍｍｏｌ，８４％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９１（ｄ，Ｊ＝６．４Ｈｚ，６Ｈ），１．８３－１．９４（ｍ，１Ｈ），２．２３（ｄ，Ｊ＝７．２Ｈｚ，２Ｈ），３．６５（ｓ，２Ｈ），３．７１（ｓ，２Ｈ），７．４８（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．５７（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．８６（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），８．１１（ｄｄ，Ｊ＝８．８，２．４Ｈｚ，１Ｈ），８．２１（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４０１（Ｍ＋Ｈ）＋． Reference Example 114 Synthesis of N- (2-chloro-4-nitrobenzyl) -2-methyl-N- (4- (trifluoromethyl) benzyl) propan-1-amine:
Figure JPOXMLDOC01-appb-C000189
 Using the compound of Reference Example 79 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 7 except for this, the title compound (hereinafter, the compound of Reference Example 114) (0.219 g, 0.546 mmol, 84 %) As a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (d, J = 6.4 Hz, 6 H), 1.83-1.94 (m, 1 H), 2.23 (d, J = 7. 2 Hz, 2 H), 3. 65 (s, 2 H), 3.7 1 (s, 2 H), 7. 48 (d, J = 8.4 Hz, 2 H), 7.57 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.8 Hz, 1 H), 8.11 (dd, J = 8.8, 2.4 Hz, 1 H), 8.21 (d, J = 2.4 Hz, 1 H) ).
ESI-MS: m / z = 401 (M + H) + .
（参考例１１５）３－クロロ－４－（（イソブチル（４－（トリフルオロメチル）ベンジル）アミノ）メチル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000190
 　参考例７の化合物の代わりに参考例１１４の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例１１５の化合物）（０．１６７ｇ，０．４５０ｍｍｏｌ，８２％）を黄色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８５（ｄ，Ｊ＝６．４Ｈｚ，６Ｈ），１．８０－１．９０（ｍ，１Ｈ），２．１５（ｄ，Ｊ＝７．２Ｈｚ，２Ｈ），３．５４（ｓ，２Ｈ），３．５５（ｓ，２Ｈ），３．６５（ｂｒｓ，２Ｈ），６．５６（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），６．６６（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），７．３０（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．４５（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．５３（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３７１（Ｍ＋Ｈ）＋． Reference Example 115 Synthesis of 3-chloro-4-((isobutyl (4- (trifluoromethyl) benzyl) amino) methyl) aniline:
Figure JPOXMLDOC01-appb-C000190
 Using the compound of Reference Example 114 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 115) (0.167 g, 0.450 mmol, 82) %) As a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.85 (d, J = 6.4 Hz, 6 H), 1.80-1.90 (m, 1 H), 2.15 (d, J = 7. 2 Hz, 2 H), 3.5 4 (s, 2 H), 3.5 5 (s, 2 H), 3. 65 (brs, 2 H), 6.56 (dd, J = 8.4, 2.4 Hz, 1 H) , 6.66 (d, J = 2.4 Hz, 1 H), 7. 30 (d, J = 8.4 Hz, 1 H), 7. 45 (d, J = 8.4 Hz, 2 H), 7.53 (d d, J = 8.4 Hz, 2 H).
ESI-MS: m / z = 371 (M + H) + .
（参考例１１６）（Ｒ）－２－（（３－クロロ－４－（（イソブチル（４－（トリフルオロメチル）ベンジル）アミノ）メチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000191
 　参考例８の化合物の代わりに参考例１１５の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例１１６の化合物）（０．２２２ｇ，０．３８１ｍｍｏｌ，８５％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８７（ｄ，Ｊ＝６．８Ｈｚ，６Ｈ），１．５１（ｓ，９Ｈ），１．４２－１．７０（ｍ，５Ｈ），１．８１－１．９１（ｍ，１Ｈ），２．１８（ｄ，Ｊ＝７．２Ｈｚ，２Ｈ），２．２９－２．３５（ｍ，１Ｈ），２．８１（ｄｄｄ，Ｊ＝１３．２，１３．２，２．８Ｈｚ，１Ｈ），３．５８（ｓ，２Ｈ），３．６０（ｓ，２Ｈ），４．０２－４．０９（ｍ，１Ｈ），４．８４－４．８５（ｍ，１Ｈ），７．２６－７．２９（ｍ，１Ｈ），７．４６（ｄ，Ｊ＝７．６Ｈｚ，２Ｈ），７．５１（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．５３（ｄ，Ｊ＝７．６Ｈｚ，２Ｈ），７．６７（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．１８（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５８２（Ｍ＋Ｈ）＋． (Reference Example 116) (R) -2-((3-chloro-4-((isobutyl (4- (trifluoromethyl) benzyl) amino) methyl) phenyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Synthesis:
Figure JPOXMLDOC01-appb-C000191
 The title compound (hereinafter, the compound of Reference Example 116) (0.222 g, 0.381 mmol, 85) was prepared by using the compound of Reference Example 115 instead of the compound of Reference Example 8 and using the same procedure as in Reference Example 9 except the above. %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.87 (d, J = 6.8 Hz, 6 H), 1.51 (s, 9 H), 1.42-1.70 (m, 5 H), 1 .81-1.91 (m, 1 H), 2.18 (d, J = 7.2 Hz, 2 H), 2.29-2.35 (m, 1 H), 2.81 (ddd, J = 13. 2, 13.2, 2.8 Hz, 1 H), 3.58 (s, 2 H), 3. 60 (s, 2 H), 4.02-4.09 (m, 1 H), 4.84-4. 85 (m, 1 H), 7. 26-7. 29 (m, 1 H), 7.46 (d, J = 7.6 Hz, 2 H), 7.51 (d, J = 8.8 Hz, 1 H), 7.53 (d, J = 7.6 Hz, 2 H), 7.67 (d, J = 2.4 Hz, 1 H), 8.18 (brs, 1 H).
ESI-MS: m / z = 582 (M + H) + .
（実施例５９）（Ｒ）－Ｎ－（３－クロロ－４－（（イソブチル（４－（トリフルオロメチル）ベンジル）アミノ）メチル）フェニル）－１－（メチルスルホニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000192
 　参考例１１３の化合物の代わりに参考例１１６の化合物を用いて、それ以外は実施例５８と同様の手順により、表題化合物（以下、実施例５９の化合物）（０．１７２ｇ，０．３０７ｍｍｏｌ，８１％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８７（ｄ，Ｊ＝６．４Ｈｚ，６Ｈ），１．５０－１．５５（ｍ，１Ｈ），１．６０－１．７３（ｍ，３Ｈ），１．７６－１．８０（ｍ，１Ｈ），１．８６（ｄｄｄ，Ｊ＝１３．６，６．８，６．８Ｈｚ，１Ｈ），２．１８（ｄ，Ｊ＝７．２Ｈｚ，２Ｈ），２．４４（ｂｒｄ，Ｊ＝１０．０Ｈｚ，１Ｈ），３．０２（ｓ，３Ｈ），３．１８（ｄｄｄ，Ｊ＝１３．６，１３．６，２．４Ｈｚ，１Ｈ），３．５８（ｓ，２Ｈ），３．６１（ｓ，２Ｈ），３．８８－３．９３（ｍ，１Ｈ），４．５８－４．５９（ｍ，１Ｈ），７．３３（ｄｄ，Ｊ＝８．８，２．４Ｈｚ，１Ｈ），７．４６（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５３－７．５５（ｍ，３Ｈ），７．６９（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．１７（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５６０（Ｍ＋Ｈ）＋． Example 59 (R) -N- (3-chloro-4-((isobutyl (4- (trifluoromethyl) benzyl) amino) methyl) phenyl) -1- (methylsulfonyl) piperidine-2-carboxamide Synthesis:
Figure JPOXMLDOC01-appb-C000192
 Using the compound of Reference Example 116 instead of the compound of Reference Example 113, and using the same procedure as Example 58 except the above, the title compound (the compound of Example 59 below) (0.172 g, 0.307 mmol, 81) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.87 (d, J = 6.4 Hz, 6 H), 1.50-1.55 (m, 1 H), 1.60-1.73 (m, 3H), 1.76 to 1.80 (m, 1H), 1.86 (ddd, J = 13.6, 6.8, 6.8 Hz, 1H), 2.18 (d, J = 7.2 Hz) , 2H), 2.44 (brd, J = 10.0 Hz, 1 H), 3.02 (s, 3 H), 3.18 (ddd, J = 13.6, 13.6, 2.4 Hz, 1 H) , 3.58 (s, 2 H), 3.61 (s, 2 H), 3.88-3. 93 (m, 1 H), 4.58-4.59 (m, 1 H), 7.33 (dd) , J = 8.8, 2.4 Hz, 1 H), 7.46 (d, J = 8.0 Hz, 2 H), 7.5 3-5. 55 (m, 3 H), 7.69 (d, J = 2.4 Hz, 1 H , 8.17 (brs, 1H).
ESI-MS: m / z = 560 (M + H) + .
（参考例１１７）Ｎ－（２－クロロ－４－ニトロベンジル）－１－シクロプロピル－Ｎ－（４－（トリフルオロメチル）ベンジル）メタンアミンの合成：
Figure JPOXMLDOC01-appb-C000193
 　参考例６の化合物の代わりに参考例９４の化合物を用いて、それ以外は参考例７と同様の手順により、表題化合物（以下、参考例１１７の化合物）（０．２５４ｇ，０．６３７ｍｍｏｌ，９８％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．０５－０．０９（ｍ，２Ｈ），０．４８－０．５３（ｍ，２Ｈ），０．８７－０．９７（ｍ，１Ｈ），２．４０（ｄ，Ｊ＝６．４Ｈｚ，２Ｈ），３．８０（ｓ，２Ｈ），３．８４（ｓ，２Ｈ），７．５０（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５７（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．９０（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），８．１２（ｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），８．２１（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３９９（Ｍ＋Ｈ）＋． Reference Example 117 Synthesis of N- (2-chloro-4-nitrobenzyl) -1-cyclopropyl-N- (4- (trifluoromethyl) benzyl) methanamine:
Figure JPOXMLDOC01-appb-C000193
 Using the compound of Reference Example 94 instead of the compound of Reference Example 6, and using the same procedure as Reference Example 7 except for this, the title compound (hereinafter, the compound of Reference Example 117) (0.254 g, 0.637 mmol, 98) %) As a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.05-0.09 (m, 2 H), 0.48-0.53 (m, 2 H), 0.87-0.97 (m, 1 H) , 2.40 (d, J = 6.4 Hz, 2 H), 3. 80 (s, 2 H), 3. 84 (s, 2 H), 7. 50 (d, J = 8.0 Hz, 2 H), 7 8. 57 (d, J = 8.0 Hz, 2 H), 7. 90 (d, J = 8.4 Hz, 1 H), 8. 12 (d, J = 8.4, 2.4 Hz, 1 H), 8. 21 (d, J = 2.4 Hz, 1 H).
ESI-MS: m / z = 399 (M + H) <+> .
（参考例１１８）３－クロロ－４－（（（シクロプロピルメチル）（４－（トリフルオロメチル）ベンジル）アミノ）メチル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000194
 　参考例７の化合物の代わりに参考例１１７の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例１１８の化合物）（０．１７２ｇ，０．４６６ｍｍｏｌ，７３％）を黄色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．０１－０．０５（ｍ，２Ｈ），０．４４－０．４９（ｍ，２Ｈ），０．８６－０．９６（ｍ，１Ｈ），２．３３（ｄ，Ｊ＝６．８Ｈｚ，２Ｈ），３．６５（ｂｒｓ，２Ｈ），３．６８（ｓ，２Ｈ），３．６９（ｓ，２Ｈ），６．５６（ｄｄ，Ｊ＝８．０，２．４Ｈｚ，１Ｈ），６．６７（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），７．３１（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．５３（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３６９（Ｍ＋Ｈ）＋． Reference Example 118 Synthesis of 3-chloro-4-(((cyclopropylmethyl) (4- (trifluoromethyl) benzyl) amino) methyl) aniline:
Figure JPOXMLDOC01-appb-C000194
 Using the compound of Reference Example 117 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 118) (0.172 g, 0.466 mmol, 73 %) As a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.01 to 0.05 (m, 2 H), 0.44 to 0.49 (m, 2 H), 0.86 to 0.96 (m, 1 H) , 2.33 (d, J = 6.8 Hz, 2 H), 3. 65 (brs, 2 H), 3.68 (s, 2 H), 3.69 (s, 2 H), 6.56 (dd, J) = 8.0, 2.4 Hz, 1 H), 6.67 (d, J = 2.4 Hz, 1 H), 7.31 (d, J = 8.0 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 2 H), 7.53 (d, J = 8.4 Hz, 2 H).
ESI-MS: m / z = 369 (M + H) + .
（参考例１１９）（Ｒ）－２－（（３－クロロ－４－（（（シクロプロピルメチル）（４－（トリフルオロメチル）ベンジル）アミノ）メチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000195
 　参考例８の化合物の代わりに参考例１１８の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例１１９の化合物）（０．１８４ｇ，０．３１７ｍｍｏｌ，６８％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．０２－０．０６（ｍ，２Ｈ），０．４５－０．５０（ｍ，２Ｈ），０．８６－０．９７（ｍ，１Ｈ），１．４２－１．７１（ｍ，５Ｈ），１．５１（ｓ，９Ｈ），２．３０－２．３６（ｍ，１Ｈ），２．３５（ｄ，Ｊ＝６．８Ｈｚ，２Ｈ），２．８１（ｄｄｄ，Ｊ＝１３．２，１３．２，２．４Ｈｚ，１Ｈ），３．７２（ｓ，２Ｈ），３．７４（ｓ，２Ｈ），４．０５（ｂｒｓ，１Ｈ），４．８３－４．８５（ｍ，１Ｈ），７．２８（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．５２－７．５４（ｍ，３Ｈ），７．６７（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．２５（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５８０（Ｍ＋Ｈ）＋． (Reference Example 119) (R) -2-((3-chloro-4-(((cyclopropylmethyl) (4- (trifluoromethyl) benzyl) amino) methyl) phenyl) carbamoyl) piperidine-1-carboxylic acid Synthesis of tert-butyl:
Figure JPOXMLDOC01-appb-C000195
 The title compound (hereinafter, the compound of Reference Example 119) (0.184 g, 0.317 mmol, 68) was prepared by using the compound of Reference Example 118 instead of the compound of Reference Example 8 and using the same procedure as in Reference Example 9 except the above. %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.02 to 0.06 (m, 2 H), 0.45 to 0.50 (m, 2 H), 0.86 to 0.97 (m, 1 H) , 1.42-1.71 (m, 5H), 1.51 (s, 9H), 2.30-2.36 (m, 1H), 2.35 (d, J = 6.8 Hz, 2H) , 2.81 (ddd, J = 13.2, 13.2, 2.4 Hz, 1 H), 3.72 (s, 2 H), 3.74 (s, 2 H), 4.05 (brs, 1 H) , 4.83-4.85 (m, 1 H), 7.28 (dd, J = 8.4, 2.4 Hz, 1 H), 7.48 (d, J = 8.4 Hz, 2 H), 7. 52-7.54 (m, 3 H), 7.67 (d, J = 2.4 Hz, 1 H), 8. 25 (brs, 1 H).
ESI-MS: m / z = 580 (M + H) + .
（実施例６０）（Ｒ）－Ｎ－（３－クロロ－４－（（（シクロプロピルメチル）（４－（トリフルオロメチル）ベンジル）アミノ）メチル）フェニル）－１－（メチルスルホニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000196
 　参考例１１３の化合物の代わりに参考例１１９の化合物を用いて、それ以外は実施例５８と同様の手順により、表題化合物（以下、実施例６０の化合物）（０．１３７ｇ，０．２４５ｍｍｏｌ，７７％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．０２－０．０６（ｍ，２Ｈ），０．４５－０．５０（ｍ，２Ｈ），０．８７－０．９４（ｍ，１Ｈ），１．５０－１．５６（ｍ，１Ｈ），１．６１－１．８０（ｍ，４Ｈ），２．３５（ｄ，Ｊ＝６．８Ｈｚ，２Ｈ），２．４４（ｂｒｄ，Ｊ＝１２．０Ｈｚ，１Ｈ），３．０１（ｓ，３Ｈ），３．１８（ｄｄｄ，Ｊ＝１３．６，１３．２，２．８Ｈｚ，１Ｈ），３．７２（ｓ，２Ｈ），３．７５（ｓ，２Ｈ），３．８８－３．９２（ｍ，１Ｈ），４．５８－４．５９（ｍ，１Ｈ），７．３３（ｄｄ，Ｊ＝８．０，２．４Ｈｚ，１Ｈ），７．４８（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．５２－７．５７（ｍ，３Ｈ），７．６９（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．１７（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５５８（Ｍ＋Ｈ）＋． Example 60 (R) -N- (3-Chloro-4-(((cyclopropylmethyl) (4- (trifluoromethyl) benzyl) amino) methyl) phenyl) -1- (methylsulfonyl) piperidine- Synthesis of 2-carboxamide:
Figure JPOXMLDOC01-appb-C000196
 Using the compound of Reference Example 119 instead of the compound of Reference Example 113, and using the same procedure as Example 58 except the above, the title compound (the compound of Example 60 below) (0.137 g, 0.245 mmol, 77) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.02-0.06 (m, 2 H), 0.45-0.50 (m, 2 H), 0.87-0.94 (m, 1 H) , 1.50-1.56 (m, 1 H), 1.61-1.80 (m, 4 H), 2. 35 (d, J = 6.8 Hz, 2 H), 2.44 (brd, J = 12.0 Hz, 1 H), 3.01 (s, 3 H), 3.18 (ddd, J = 13.6, 13.2, 2.8 Hz, 1 H), 3.72 (s, 2 H), 3. 75 (s, 2 H), 3.88-3. 92 (m, 1 H), 4.58-4.59 (m, 1 H), 7.33 (dd, J = 8.0, 2.4 Hz, 1 H ), 7.48 (d, J = 8.4 Hz, 2 H), 7.52-7.57 (m, 3 H), 7.69 (d, J = 2.4 Hz, 1 H), 8.17 (brs) , 1 H).
ESI-MS: m / z = 558 (M + H) + .
（参考例１２０）Ｎ－（２－クロロ－４－ニトロベンジル）－Ｎ－（４－（トリフルオロメチル）ベンジル）ブタン－１－アミンの合成：
Figure JPOXMLDOC01-appb-C000197
 　参考例６の化合物の代わりに参考例８３の化合物を用いて、それ以外は参考例７と同様の手順により、表題化合物（以下、参考例１２０の化合物）（０．２２６ｇ，０．５６４ｍｍｏｌ，８７％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８７（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．３１（ｑｔ，Ｊ＝７．２，６．８Ｈｚ，２Ｈ），１．４９－１．５５（ｍ，２Ｈ），２．４８（ｔ，Ｊ＝７．６Ｈｚ，２Ｈ），３．６９（ｓ，２Ｈ），３．７３（ｓ，２Ｈ），７．４７（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．５５（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．８４（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），８．１１（ｄｄ，Ｊ＝８．８，２．４Ｈｚ，１Ｈ），８．２１（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４０１（Ｍ＋Ｈ）＋． Reference Example 120 Synthesis of N- (2-chloro-4-nitrobenzyl) -N- (4- (trifluoromethyl) benzyl) butane-1-amine:
Figure JPOXMLDOC01-appb-C000197
 Using the compound of Reference Example 83 instead of the compound of Reference Example 6, and according to the same procedure as Reference Example 7 except the above, the title compound (hereinafter, the compound of Reference Example 120) (0.226 g, 0.564 mmol, 87) %) As a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.87 (t, J = 7.2 Hz, 3 H), 1.31 (q t, J = 7.2, 6.8 Hz, 2 H), 1.49- 1.55 (m, 2 H), 2.48 (t, J = 7.6 Hz, 2 H), 3.69 (s, 2 H), 3.73 (s, 2 H), 7.47 (d, J = 8.4 Hz, 2 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.8 4 (d, J = 8.8 Hz, 1 H), 8.1 1 (dd, J = 8.8, 2 .4 Hz, 1 H), 8.21 (d, J = 2.4 Hz, 1 H).
ESI-MS: m / z = 401 (M + H) + .
（参考例１２１）４－（（ブチル（４－（トリフルオロメチル）ベンジル）アミノ）メチル）－３－クロロアニリンの合成：
Figure JPOXMLDOC01-appb-C000198
 　参考例７の化合物の代わりに参考例１２０の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例１２１の化合物）（０．１６０ｇ，０．４３１ｍｍｏｌ，７６％）を黄色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８３（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．２７（ｔｑ，Ｊ＝７．２，７．２Ｈｚ，２Ｈ），１．４５－１．５２（ｍ，２Ｈ），２．４１（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．５６（ｓ，２Ｈ），３．５９（ｓ，２Ｈ），３．６５（ｂｒｓ，２Ｈ），６．５５（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），６．６７（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），７．２８（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．４５（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．５３（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３７１（Ｍ＋Ｈ）＋． Reference Example 121 Synthesis of 4-((butyl (4- (trifluoromethyl) benzyl) amino) methyl) -3-chloroaniline:
Figure JPOXMLDOC01-appb-C000198
 Using the compound of Reference Example 120 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 121) (0.160 g, 0.431 mmol, 76) %) As a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.83 (t, J = 7.2 Hz, 3 H), 1.27 (tq, J = 7.2, 7.2 Hz, 2 H), 1.45- 1.52 (m, 2 H), 2.41 (t, J = 7.2 Hz, 2 H), 3.56 (s, 2 H), 3.59 (s, 2 H), 3.65 (brs, 2 H) , 6.55 (dd, J = 8.4, 2.4 Hz, 1 H), 6.67 (d, J = 2.4 Hz, 1 H), 7. 28 (d, J = 8.4 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 2 H), 7.53 (d, J = 8.0 Hz, 2 H).
ESI-MS: m / z = 371 (M + H) + .
（参考例１２２）（Ｒ）－２－（（４－（（ブチル（４－（トリフルオロメチル）ベンジル）アミノ）メチル）－３－クロロフェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000199
 　参考例８の化合物の代わりに参考例１２１の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例１２２の化合物）（０．１５８ｇ，０．２７１ｍｍｏｌ，４３％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８４（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．２８（ｔｑ，Ｊ＝８．０，７．２Ｈｚ，２Ｈ），１．５１（ｓ，９Ｈ），１．４５－１．７０（ｍ，７Ｈ），２．３２（ｂｒｄ，Ｊ＝１３．２Ｈｚ，１Ｈ），２．４３（ｔ，Ｊ＝７．６Ｈｚ，２Ｈ），２．８１（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），３．６１（ｓ，２Ｈ），３．６３（ｓ，２Ｈ），４．００－４．１０（ｍ，１Ｈ），４．８３－４．８５（ｍ，１Ｈ），７．２６－７．２９（ｍ，１Ｈ），７．４５（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．４９（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．５３（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．６７（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．２４（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５８２（Ｍ＋Ｈ）＋． (Reference Example 122) Synthesis of tert-butyl (R) -2-((4-((butyl (4- (trifluoromethyl) benzyl) amino) methyl) -3-chlorophenyl) carbamoyl) piperidine-1-carboxylate :
Figure JPOXMLDOC01-appb-C000199
 Using the compound of Reference Example 121 instead of the compound of Reference Example 8, and according to the same procedure as Reference Example 9 except the above, the title compound (hereinafter, the compound of Reference Example 122) (0.158 g, 0.271 mmol, 43) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.84 (t, J = 7.2 Hz, 3 H), 1.28 (t q, J = 8.0, 7.2 Hz, 2 H), 1.51 ( s, 9H), 1.45-1.70 (m, 7H), 2.32 (brd, J = 13.2 Hz, 1 H), 2.43 (t, J = 7.6 Hz, 2 H), 81 (d, J = 8.0 Hz, 2 H), 3.61 (s, 2 H), 3.63 (s, 2 H), 4.00-4. 10 (m, 1 H), 4.83-4. 85 (m, 1 H), 7. 26-7. 29 (m, 1 H), 7. 45 (d, J = 8.0 Hz, 2 H), 7. 49 (d, J = 8.8 Hz, 1 H), 7.53 (d, J = 8.0 Hz, 2 H), 7.67 (d, J = 2.4 Hz, 1 H), 8.24 (brs, 1 H).
ESI-MS: m / z = 582 (M + H) + .
（実施例６１）（Ｒ）－Ｎ－（４－（（ブチル（４－（トリフルオロメチル）ベンジル）アミノ）メチル）－３－クロロフェニル）－１－（メチルスルホニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000200
 　参考例１１３の化合物の代わりに参考例１２２の化合物を用いて、それ以外は実施例５８と同様の手順により、表題化合物（以下、実施例６１の化合物）（０．１２２ｇ，０．２１８ｍｍｏｌ，８０％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８５（ｔ，Ｊ＝７．６Ｈｚ，３Ｈ），１．２８（ｔｑ，Ｊ＝７．６，７．２Ｈｚ，２Ｈ），１．４６－１．５５（ｍ，３Ｈ）．１．６３－１．８０（ｍ，４Ｈ），２．４１－２．４５（ｍ，３Ｈ），３．０１（ｓ，３Ｈ），３．１８（ｄｄｄ，Ｊ＝１３．６，１３．６，２．８Ｈｚ，１Ｈ），３．６２（ｓ，２Ｈ），３．６４（ｓ，２Ｈ），３．８８－３．９３（ｍ，１Ｈ），４．５８－４．５９（ｍ，１Ｈ），７．３３（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），７．４５（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．５１－７．５５（ｍ，３Ｈ），７．６９（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．１６（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５６０（Ｍ＋Ｈ）＋． Example 61 Synthesis of (R) -N- (4-((Butyl (4- (trifluoromethyl) benzyl) amino) methyl) -3-chlorophenyl) -1- (methylsulfonyl) piperidine-2-carboxamide :
Figure JPOXMLDOC01-appb-C000200
 Using the compound of Reference Example 122 instead of the compound of Reference Example 113, and using the same procedure as Example 58 except the above, the title compound (the compound of Example 61 below) (0.122 g, 0.218 mmol, 80) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.85 (t, J = 7.6 Hz, 3 H), 1.28 (tq, J = 7.6, 7.2 Hz, 2 H), 1.46- 1.55 (m, 3H). 1.63-1.80 (m, 4H), 2.41-2.45 (m, 3H), 3.01 (s, 3H), 3.18 (ddd, J = 13.6, 13.6) , 2.8 Hz, 1 H), 3.62 (s, 2 H), 3.64 (s, 2 H), 3.88-3. 93 (m, 1 H), 4.58-4.59 (m, 1 H) ), 7.33 (dd, J = 8.4, 2.4 Hz, 1 H), 7. 45 (d, J = 8.4 Hz, 2 H), 7.51-7. 55 (m, 3 H), 7 .69 (d, J = 2.4 Hz, 1 H), 8. 16 (brs, 1 H).
ESI-MS: m / z = 560 (M + H) + .
（参考例１２３）２－クロロ－４－ニトロ－Ｎ－（プロパ－２－イン－１－イル）－Ｎ－プロピルアニリンの合成：
Figure JPOXMLDOC01-appb-C000201
 　プロパルギルアミン（０．５５１ｇ，１０．０ｍｍｏｌ）をジクロロメタン（２０．０ｍＬ）に溶解し、プロピオンアルデヒド（０．５８１ｇ，１０．０ｍｍｏｌ）及び硫酸ナトリウム（５．５ｇ）を室温で加えた。同温度で１５分間撹拌した後、メタノール（２０．０ｍＬ）及び水素化ホウ素ナトリウム（０．３７８ｇ，１０．０ｍｍｏｌ）を加えた。室温で１時間撹拌した後、反応液に蒸留水を加え、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物をＤＭＳＯ（１０．０ｍＬ）に溶解し、３－クロロ－４－フルオロニトロベンゼン（０．８７８ｇ，５．００ｍｍｏｌ）及びジイソプロピルエチルアミン（１．７５ｍＬ，１０．０ｍｍｏｌ）を室温で加えた。１２０℃で２３時間撹拌した後、反応液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１００／０～９５／５）で精製し、表題化合物（以下、参考例１２３の化合物）（０．５４３ｇ，２．１５ｍｍｏｌ，４３％）を茶色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９５（ｔ，Ｊ＝７．６Ｈｚ，３Ｈ），１．６３（ｔｑ，Ｊ＝８．０，７．６Ｈｚ，２Ｈ），２．２８（ｔ，Ｊ＝２．４Ｈｚ，１Ｈ），３．２３－３．２７（ｍ，２Ｈ），４．０５（ｄ，Ｊ＝２．４Ｈｚ，２Ｈ），７．２７（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），８．１０（ｄｄ，Ｊ＝８．８，２．８Ｈｚ，１Ｈ），８．２６（ｄ，Ｊ＝２．８Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２５３（Ｍ＋Ｈ）＋． Reference Example 123 Synthesis of 2-chloro-4-nitro-N- (prop-2-yn-1-yl) -N-propylaniline:
Figure JPOXMLDOC01-appb-C000201
 Propargylamine (0.551 g, 10.0 mmol) was dissolved in dichloromethane (20.0 mL) and propionaldehyde (0.581 g, 10.0 mmol) and sodium sulfate (5.5 g) were added at room temperature. After stirring for 15 minutes at the same temperature, methanol (20.0 mL) and sodium borohydride (0.378 g, 10.0 mmol) were added. After stirring at room temperature for 1 hour, distilled water was added to the reaction solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product was dissolved in DMSO (10.0 mL) and 3-chloro-4-fluoronitrobenzene (0.878 g, 5.00 mmol) and diisopropylethylamine (1.75 mL, 10.0 mmol) were added at room temperature . After stirring at 120 ° C. for 23 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100/0 to 95/5), and the title compound (hereinafter, the compound of Reference Example 123) (0.543 g, 2.15 mmol, 43) %) As a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.95 (t, J = 7.6 Hz, 3 H), 1.63 (tq, J = 8.0, 7.6 Hz, 2 H), 2.28 ( t, J = 2.4 Hz, 1 H), 3.23-3.27 (m, 2 H), 4.05 (d, J = 2.4 Hz, 2 H), 7.27 (d, J = 8.8 Hz , 1 H), 8.10 (dd, J = 8.8, 2.8 Hz, 1 H), 8.26 (d, J = 2.8 Hz, 1 H).
ESI-MS: m / z = 253 (M + H) + .
（参考例１２４）２－クロロ－Ｎ１－（プロパ－２－イン－１－イル）－Ｎ１－プロピルベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000202
 　参考例７の化合物の代わりに参考例１２３の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例１２４の化合物）（０．２４３ｇ，１．０９ｍｍｏｌ，９２％）を黄色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９０（ｔ，Ｊ＝７．６Ｈｚ，３Ｈ），１．４６（ｔｑ，Ｊ＝７．６，７．２Ｈｚ，２Ｈ），２．１８（ｔ，Ｊ＝２．４Ｈｚ，１Ｈ），３．０１（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．５７（ｂｒｓ，２Ｈ），３．７９（ｄ，Ｊ＝２．４Ｈｚ，２Ｈ），６．５５（ｄｄ，Ｊ＝８．４，２．８Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝２．８Ｈｚ，１Ｈ），７．１０（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２２３（Ｍ＋Ｈ）＋． (Reference Example 124) 2-Chloro -N 1 - (prop-2-yn-1-yl) -N 1 - Synthesis of propyl-1,4-diamine:
Figure JPOXMLDOC01-appb-C000202
 Using the compound of Reference Example 123 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 124) (0.243 g, 1.09 mmol, 92) %) As a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (t, J = 7.6 Hz, 3 H), 1.46 (tq, J = 7.6, 7.2 Hz, 2 H), 2.18 ( t, J = 2.4 Hz, 1 H), 3.01 (t, J = 7.2 Hz, 2 H), 3.57 (brs, 2 H), 3.79 (d, J = 2.4 Hz, 2 H), 6.55 (dd, J = 8.4, 2.8 Hz, 1 H), 6.73 (d, J = 2.8 Hz, 1 H), 7. 10 (d, J = 8.4 Hz, 1 H).
ESI-MS: m / z = 223 (M + H) + .
（参考例１２５）（Ｒ）－２－（（３－クロロ－４－（プロパ－２－イン－１－イル（プロピル）アミノ）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000203
 　参考例８の化合物の代わりに参考例１２４の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例１２５の化合物）（０．０５９９ｇ，０．１３８ｍｍｏｌ，８８％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９１（ｔ，Ｊ＝７．６Ｈｚ，３Ｈ），１．５１（ｓ，９Ｈ），１．３５－１．７４（ｍ，７Ｈ），２．１９（ｄ，Ｊ＝２．８Ｈｚ，１Ｈ），２．３３（ｂｒｄ，Ｊ＝１０．４Ｈｚ，１Ｈ），２．８１（ｄｄｄ，Ｊ＝１３．２，１３．２，２．８Ｈｚ，１Ｈ），３．０６（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．８６（ｄ，Ｊ＝２．８Ｈｚ，２Ｈ），３．９８－４．１６（ｍ，１Ｈ），４．８４（ｂｒｓ，１Ｈ），７．２０（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．３０（ｄｄ，Ｊ＝８．８，２．８Ｈｚ，１Ｈ），７．６７（ｄ，Ｊ＝２．８Ｈｚ，１Ｈ），８．１７（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４３４（Ｍ＋Ｈ）＋． Reference Example 125 Synthesis of tert-butyl (R) -2-((3-chloro-4- (prop-2-yn-1-yl (propyl) amino) phenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000203
 The title compound (hereinafter, the compound of Reference Example 125) (0.0599 g, 0.138 mmol, 88) was prepared by using the compound of Reference Example 124 instead of the compound of Reference Example 8 and using the same procedure as in Reference Example 9 except the above. %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (t, J = 7.6 Hz, 3 H), 1.51 (s, 9 H), 1.35-1.74 (m, 7 H), 2 .19 (d, J = 2.8 Hz, 1 H), 2. 33 (brd, J = 10.4 Hz, 1 H), 2.81 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H ), 3.06 (t, J = 7.2 Hz, 2 H), 3.86 (d, J = 2.8 Hz, 2 H), 3.98-4.16 (m, 1 H), 4.84 (brs) , 1 H), 7.20 (d, J = 8.8 Hz, 1 H), 7.30 (dd, J = 8.8, 2.8 Hz, 1 H), 7.67 (d, J = 2.8 Hz, 1H), 8.17 (brs, 1H).
ESI-MS: m / z = 434 (M + H) + .
（実施例６２）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（プロパ－２－イン－１－イル（プロピル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000204
 　参考例９の化合物の代わりに参考例１２５の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例６２の化合物）（０．０４８８ｇ，０．１３０ｍｍｏｌ，９４％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９０（ｔ，Ｊ＝７．６Ｈｚ，３Ｈ），１．４４－１．６２（ｍ，４Ｈ），１．６８－１．８０（ｍ，２Ｈ），１．８８－２．００（ｍ，１Ｈ），２．１８（ｔ，Ｊ＝２．４Ｈｚ，１Ｈ），２．２０（ｓ，３Ｈ），２．２７（ｂｒｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），３．０６（ｔ，Ｊ＝７．６Ｈｚ，２Ｈ），３．１５（ｄｄｄ，Ｊ＝１３．２，１３．２，２．８Ｈｚ，１Ｈ），３．７５（ｂｒｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），３．８５（ｄ，Ｊ＝２．４Ｈｚ，２Ｈ），５．２５（ｂｒｄ，Ｊ＝５．２Ｈｚ，１Ｈ），７．１８（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．３０（ｄｄ，Ｊ＝８．８，２．８Ｈｚ，１Ｈ），７．６７（ｄ，Ｊ＝２．８Ｈｚ，１Ｈ），８．５６（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３７６（Ｍ＋Ｈ）＋． Example 62 Synthesis of (R) -1-acetyl-N- (3-chloro-4- (prop-2-yn-1-yl (propyl) amino) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000204
 Using the compound of Reference Example 125 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 62 below) (0.0488 g, 0.130 mmol, 94) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (t, J = 7.6 Hz, 3 H), 1.44-1.62 (m, 4 H), 1.68-1.80 (m, 2H), 1.88-2.00 (m, 1H), 2.18 (t, J = 2.4 Hz, 1H), 2.20 (s, 3H), 2.27 (brd, J = 13. 6 Hz, 1 H), 3.06 (t, J = 7.6 Hz, 2 H), 3. 15 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3.75 (brd, J = 13.6 Hz, 1 H), 3.85 (d, J = 2.4 Hz, 2 H), 5.25 (brd, J = 5.2 Hz, 1 H), 7.18 (d, J = 8.8 Hz, 1H), 7.30 (dd, J = 8.8, 2.8 Hz, 1 H), 7.67 (d, J = 2.8 Hz, 1 H), 8.56 (brs, 1 H).
ESI-MS: m / z = 376 (M + H) + .
（実施例６３）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（プロパ－２－イン－１－イル（プロピル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000205
 　参考例４３の化合物の代わりに参考例１２５の化合物を、２－（１Ｈ－テトラゾール－１－イル）酢酸の代わりに１－イミダゾール酢酸を用いて、それ以外は実施例１３と同様の手順により、表題化合物（以下、実施例６３の化合物）（０．０４２４ｇ，０．０９５９ｍｍｏｌ，８３％）を淡黄色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９１（ｔ，Ｊ＝７．６Ｈｚ，３Ｈ），１．４４－１．５４（ｍ，４Ｈ），１．６４－１．７０（ｍ，１Ｈ），１．７４－１．８４（ｍ，２Ｈ），１．９４－２．０３（ｍ，１Ｈ），２．１９（ｔ，Ｊ＝２．４Ｈｚ，１Ｈ），２．２５（ｂｒｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），３．０６（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．３４－３．４１（ｍ，１Ｈ），３．６８（ｂｒｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），３．８６（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），４．８４（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），４．９０（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），５．１６（ｂｒｄ，Ｊ＝５．６Ｈｚ，１Ｈ），６．９７（ｂｒｓ，１Ｈ），７．１３（ｂｒｓ，１Ｈ），７．１８（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．２２（ｄｄ，Ｊ＝８．８，２．４Ｈｚ，１Ｈ），７．５２（ｂｒｓ，１Ｈ），７．６７（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．０５（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４４２（Ｍ＋Ｈ）＋． Example 63 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (3-chloro-4- (prop-2-yn-1-yl (propyl) amino) Synthesis of Phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000205
 The procedure of Example 13 is repeated using the compound of Reference Example 125 in place of the compound of Reference Example 43 and 1-imidazoleacetic acid instead of 2- (1H-tetrazol-1-yl) acetic acid The title compound (hereinafter, the compound of Example 63) (0.0424 g, 0.0959 mmol, 83%) was obtained as a pale yellow amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (t, J = 7.6 Hz, 3 H), 1.44-1.54 (m, 4 H), 1.64-1.70 (m, 1H), 1.74-1.84 (m, 2H), 1.94-2.03 (m, 1H), 2.19 (t, J = 2.4 Hz, 1 H), 2.25 (brd, b) J = 13.6 Hz, 1 H), 3.06 (t, J = 7.2 Hz, 2 H), 3.34-3. 41 (m, 1 H), 3.68 (brd, J = 13.6 Hz, 1 H ), 3.86 (d, J = 2.4 Hz, 1 H), 4. 84 (d, J = 16.8 Hz, 1 H), 4. 90 (d, J = 16.8 Hz, 1 H), 5.16 (Brd, J = 5.6 Hz, 1 H), 6.97 (brs, 1 H), 7.13 (brs, 1 H), 7.18 (d, J = 8.8 Hz, 1 H), 7.22 dd, J = 8.8,2.4Hz, 1H), 7.52 (brs, 1H), 7.67 (d, J = 2.4Hz, 1H), 8.05 (brs, 1H).
ESI-MS: m / z = 442 (M + H) + .
（実施例６４）（Ｒ）－１－（２－（１Ｈ－テトラゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（プロパ－２－イン－１－イル（プロピル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000206
 　参考例４３の化合物の代わりに参考例１２５の化合物を用いて、それ以外は実施例１３と同様の手順により、表題化合物（以下、実施例６４の化合物）（０．０５００ｇ０．１１３ｍｍｏｌ，９８％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９０（ｔ，Ｊ＝７．５Ｈｚ，３Ｈ），１．４４－１．９１（ｍ，７Ｈ），２．１８－２．２６（ｍ，２Ｈ），３．０３－３．０７（ｍ，２Ｈ），３．５０－３．５７（ｍ，１Ｈ），３．６６－３．７３（ｍ，１Ｈ），３．８６（ｂｒｓ，２Ｈ），５．１０－５．１５（ｍ，１Ｈ），５．３３－５．３８（ｍ，１Ｈ），５．４２－５．４７（ｍ，１Ｈ），７．１６－７．２５（ｍ，２Ｈ），７．６６－７．６７（ｍ，１Ｈ），８．０９（ｂｒｓ，１Ｈ），８．８４（ｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４４４（Ｍ＋Ｈ）＋． Example 64 (R) -1- (2- (1H-tetrazol-1-yl) acetyl) -N- (3-chloro-4- (prop-2-yn-1-yl (propyl) amino) Synthesis of Phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000206
 Using the compound of Reference Example 125 instead of the compound of Reference Example 43, and using the same procedure as Example 13 except the above, the title compound (the compound of Example 64 below) (0.0500 g 0.113 mmol, 98%) Was obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (t, J = 7.5 Hz, 3 H), 1.44-1.91 (m, 7 H), 2.18-2.26 (m, 2H), 3.03-3.07 (m, 2H), 3.50-3.57 (m, 1 H), 3.66-3.73 (m, 1 H), 3.86 (brs, 2 H) , 5.10-5.15 (m, 1 H), 5.33-5.38 (m, 1 H), 5.42-5. 47 (m, 1 H), 7.16-7. 25 (m, 2H), 7.66-7.67 (m, 1 H), 8.09 (brs, 1 H), 8.84 (s, 1 H).
ESI-MS: m / z = 444 (M + H) <+> .
（参考例１２６）Ｎ－（ブタ－２－イン－１－イル）－２－クロロ－４－ニトロ－Ｎ－プロピルアニリンの合成：
Figure JPOXMLDOC01-appb-C000207
 　２－ブチン－１－オール（０．５００ｇ，３．５２ｍｍｏｌ）をジクロロメタン（２０．０ｍＬ）に溶解し、臭化カリウム（０．８４９ｇ，７．１３ｍｍｏｌ）、６重量％次亜塩素酸ナトリウム水溶液（１３．３ｍＬ）及び飽和炭酸水素ナトリウム水溶液（２０．０ｍＬ）を室温で加えた後、ＴＥＭＰＯ（０．０２２３ｇ，０．１４３ｍｍｏｌ）を０℃で加えた。室温で１５時間撹拌した後、反応液に飽和チオ硫酸ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を飽和チオ硫酸ナトリウム水溶液及び飽和食塩水で順次洗浄した後、無水硫酸ナトリウムで乾燥、濾過した。濾液にプロピルアミン（０．４２２ｇ，７．１３ｍｍｏｌ）及び無水硫酸ナトリウム（５００ｍｇ）を加えた。室温で３時間撹拌した後、反応液にメタノール（２０ｍＬ）及び水素化ホウ素ナトリウム（０．２７０ｇ，７．１３ｍｍｏｌ）を加えた。室温で３時間撹拌した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物は精製すること無く、続く反応に用いた。
　上記の粗生成物をＤＭＳＯ（２．００ｍＬ）に溶解し、３－クロロ－４－フルオロニトロベンゼン（０．１７６ｇ，１．００ｍｍｏｌ）及びＮ－メチルモルホリン（０．２２０ｍＬ，２．００ｍｍｏｌ）を室温で加えた。１２０℃で１８時間撹拌した後、反応液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１００／０～９８／２）で精製し、表題化合物（以下、参考例１２６の化合物）（０．０９２０ｇ，０．３４５ｍｍｏｌ，３４％）を茶色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９４（ｔ，Ｊ＝７．６Ｈｚ，３Ｈ），１．５９－１．６８（ｍ，２Ｈ），１．８２（ｔ，Ｊ＝２．４Ｈｚ，３Ｈ），３．２２－３．２６（ｍ，２Ｈ），３．９８（ｑ，Ｊ＝２．４Ｈｚ，２Ｈ），７．２６（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），８．０８（ｄｄ，Ｊ＝８．８，２．４Ｈｚ，１Ｈ），８．２４（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２６７（Ｍ＋Ｈ）＋． Reference Example 126 Synthesis of N- (but-2-yn-1-yl) -2-chloro-4-nitro-N-propylaniline:
Figure JPOXMLDOC01-appb-C000207
 Dissolve 2-butyn-1-ol (0.500 g, 3.52 mmol) in dichloromethane (20.0 mL), add potassium bromide (0.849 g, 7.13 mmol), 6 wt% sodium hypochlorite aqueous solution After adding 13.3 mL) and saturated aqueous sodium hydrogen carbonate solution (20.0 mL) at room temperature, TEMPO (0.0223 g, 0.143 mmol) was added at 0 ° C. After stirring at room temperature for 15 hours, to the reaction mixture was added saturated aqueous sodium thiosulfate solution, and the mixture was extracted with dichloromethane. The organic layer was washed successively with saturated aqueous sodium thiosulfate solution and saturated brine, dried over anhydrous sodium sulfate and filtered. To the filtrate was added propylamine (0.422 g, 7.13 mmol) and anhydrous sodium sulfate (500 mg). After stirring for 3 hours at room temperature, methanol (20 mL) and sodium borohydride (0.270 g, 7.13 mmol) were added to the reaction solution. After stirring at room temperature for 3 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product obtained was used for the subsequent reaction without purification.
The above crude product is dissolved in DMSO (2.00 mL) and 3-chloro-4-fluoronitrobenzene (0.176 g, 1.00 mmol) and N-methylmorpholine (0.220 mL, 2.00 mmol) at room temperature added. After stirring at 120 ° C. for 18 hours, distilled water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100/0 to 98/2), and the title compound (hereinafter, the compound of Reference Example 126) (0.0920 g, 0.345 mmol, 34) %) As a brown oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.94 (t, J = 7.6 Hz, 3 H), 1.59-1.68 (m, 2 H), 1.82 (t, J = 2. 4 Hz, 3 H), 3.22-3.26 (m, 2 H), 3.98 (q, J = 2.4 Hz, 2 H), 7.26 (d, J = 8.8 Hz, 1 H), 8. 08 (dd, J = 8.8, 2.4 Hz, 1 H), 8.24 (d, J = 2.4 Hz, 1 H).
ESI-MS: m / z = 267 (M + H) + .
（参考例１２７）Ｎ１－（ブタ－２－イン－１－イル）－２－クロロ－Ｎ１－プロピルベンゼン－１，４－ジアミンの合成：
Figure JPOXMLDOC01-appb-C000208
 　参考例７の化合物の代わりに参考例１２６の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例１２７の化合物）（０．０５８２ｇ，０．２４６ｍｍｏｌ，７１％）を黄色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．８９（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．４４（ｔｑ，Ｊ＝７．６，７．２Ｈｚ，２Ｈ），１．８０（ｔ，Ｊ＝２．４Ｈｚ，３Ｈ），２．９９（ｔ，Ｊ＝７．６Ｈｚ，２Ｈ），３．５５（ｂｒｓ，２Ｈ），３．７１（ｑ，Ｊ＝２．４Ｈｚ，２Ｈ），６．５５（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），６．７３（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），７．０８（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２３７（Ｍ＋Ｈ）＋． (Reference Example 127) N 1 - (but-2-yn-1-yl) -2-chloro -N 1 - Synthesis of propyl-1,4-diamine:
Figure JPOXMLDOC01-appb-C000208
 Using the compound of Reference Example 126 instead of the compound of Reference Example 7, and according to the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 127) (0.0582 g, 0.246 mmol, 71 %) As a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.89 (t, J = 7.2 Hz, 3 H), 1.44 (t q, J = 7.6, 7.2 Hz, 2 H), 1.80 ( t, J = 2.4 Hz, 3 H), 2.99 (t, J = 7.6 Hz, 2 H), 3.55 (brs, 2 H), 3.7 1 (q, J = 2.4 Hz, 2 H), 6.55 (dd, J = 8.4, 2.4 Hz, 1 H), 6.73 (d, J = 2.4 Hz, 1 H), 7.08 (d, J = 8.4 Hz, 1 H).
ESI-MS: m / z = 237 (M + H) + .
（参考例１２８）（Ｒ）－２－（（４－（ブタ－２－イン－１－イル（プロピル）アミノ）－３－クロロフェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000209
 　参考例８の化合物の代わりに参考例１２７の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例１２８の化合物）（０．１０７ｇ，０．２３９ｍｍｏｌ，９７％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９０（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．４３－１．７０（ｍ，１６Ｈ），１．７９（ｔ，Ｊ＝２．４Ｈｚ，３Ｈ），２．２８－２．３６（ｍ，１Ｈ），２．７８－２．８５（ｍ，１Ｈ），３．０４（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．７９（ｑ，Ｊ＝２．４Ｈｚ，２Ｈ），４．０２－４．１０（ｍ，１Ｈ），４．８３－４．８５（ｍ，１Ｈ），７．１９（ｄ，Ｊ＝９．２Ｈｚ，１Ｈ），７．３２（ｄｄ，Ｊ＝９．２，２．４Ｈｚ，１Ｈ），７．６２（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．１３（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４４８（Ｍ＋Ｈ）＋． Reference Example 128 Synthesis of tert-butyl (R) -2-((4- (but-2-yn-1-yl (propyl) amino) -3-chlorophenyl) carbamoyl) piperidine-1-carboxylate:
Figure JPOXMLDOC01-appb-C000209
 Using the compound of Reference Example 127 instead of the compound of Reference Example 8, and according to the same procedure as Reference Example 9 except for this, the title compound (hereinafter, the compound of Reference Example 128) (0.107 g, 0.239 mmol, 97 %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (t, J = 7.2 Hz, 3 H), 1.43-1.70 (m, 16 H), 1.79 (t, J = 2. 4 Hz, 3 H), 2.28-2.36 (m, 1 H), 2.78-2. 85 (m, 1 H), 3.04 (t, J = 7.2 Hz, 2 H), 3.79 (3. q, J = 2.4 Hz, 2 H), 4.02-4. 10 (m, 1 H), 4.83-4. 85 (m, 1 H), 7.19 (d, J = 9.2 Hz, 1 H) ], 7.32 (dd, J = 9.2, 2.4 Hz, 1 H), 7.62 (d, J = 2.4 Hz, 1 H), 8.13 (brs, 1 H).
ESI-MS: m / z = 448 (M + H) + .
（実施例６５）（Ｒ）－１－アセチル－Ｎ－（４－（ブタ－２－イン－１－イル（プロピル）アミノ）－３－クロロフェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000210
 　参考例９の化合物の代わりに参考例１２８の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例６５の化合物）（０．０３３８ｇ，０．０８６７ｍｍｏｌ，７２％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９０（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．４３－１．６４（ｍ，４Ｈ），１．７０－１．８０（ｍ，５Ｈ），１．９１－１．９９（ｍ，１Ｈ），２．２０（ｓ，３Ｈ），２．２７（ｂｒｄ，Ｊ＝１８．８Ｈｚ，１Ｈ），３．０４（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．１５（ｄｄｄ，Ｊ＝１３．２，１３．２，２．８Ｈｚ，１Ｈ），３．７４－３．７９（ｍ，３Ｈ），５．２５（ｂｒｄ，Ｊ＝５．６Ｈｚ，１Ｈ），７．１６（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．３１（ｄｄ，Ｊ＝８．８，２．４Ｈｚ，１Ｈ），７．６３（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．３２（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝３９０（Ｍ＋Ｈ）＋． Example 65 Synthesis of (R) -1-acetyl-N- (4- (but-2-yn-1-yl (propyl) amino) -3-chlorophenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000210
 Using the compound of Reference Example 128 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 65 below) (0.0338 g, 0.0867 mmol, 72) %) As a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (t, J = 7.2 Hz, 3 H), 1.43-1.64 (m, 4 H), 1.70-1.80 (m, 5H), 1.91-1.99 (m, 1H), 2.20 (s, 3H), 2.27 (brd, J = 18.8 Hz, 1H), 3.04 (t, J = 7. 2 Hz, 2 H), 3. 15 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3.74-3. 79 (m, 3 H), 5.25 (brd, J = 5 .6 Hz, 1 H), 7.16 (d, J = 8.8 Hz, 1 H), 7.31 (dd, J = 8.8, 2.4 Hz, 1 H), 7.63 (d, J = 2. 4 Hz, 1 H), 8.32 (brs, 1 H).
ESI-MS: m / z = 390 (M + H) + .
（実施例６６）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（４－（ブタ－２－イン－１－イル（プロピル）アミノ）－３－クロロフェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000211
 　参考例４３の化合物の代わりに参考例１２８の化合物を、２－（１Ｈ－テトラゾール－１－イル）酢酸の代わりに１－イミダゾール酢酸を用いて、それ以外は実施例１３と同様の手順により、表題化合物（以下、実施例６６の化合物）（０．０３５８ｇ，０．０７８５ｍｍｏｌ，６５％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９０（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．４３－１．５０（ｍ，３Ｈ），１．５８－１．６６（ｍ，１Ｈ），１．７０－１．７３（ｍ，１Ｈ），１．７９（ｔ，Ｊ＝２．４Ｈｚ，３Ｈ），１．８３－１．９５（ｍ，２Ｈ），２．２０（ｂｒｄ，Ｊ＝１３．２Ｈｚ，１Ｈ），３．０３（ｔ，Ｊ＝７．６Ｈｚ，２Ｈ），３．４５（ｄｄｄ，Ｊ＝１３．２，１３．２，２．８Ｈｚ，１Ｈ），３．６４－３．６７（ｍ，１Ｈ），３．７８（ｑ，Ｊ＝２．４Ｈｚ，２Ｈ），４．８１（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），４．８７（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），５．１６（ｂｒｄ，Ｊ＝５．２Ｈｚ，１Ｈ），６．９４（ｂｒｓ，１Ｈ），７．０９（ｂｒｓ，１Ｈ），７．１５（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．２３（ｄｄ，Ｊ＝８．８，２．４Ｈｚ，１Ｈ），７．５０（ｂｒｓ，１Ｈ），７．５９（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．４８（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４５６（Ｍ＋Ｈ）＋． (Example 66) (R) -1- (2- (1H-imidazol-1-yl) acetyl) -N- (4- (but-2-yn-1-yl (propyl) amino) -3-chlorophenyl ) Synthesis of piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000211
 The procedure of Example 13 is repeated using the compound of Reference Example 128 in place of the compound of Reference Example 43 and 1-imidazoleacetic acid instead of 2- (1H-tetrazol-1-yl) acetic acid The title compound (hereinafter, the compound of Example 66) (0.0358 g, 0.0785 mmol, 65%) was obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (t, J = 7.2 Hz, 3 H), 1.43-1.50 (m, 3 H), 1.58-1.66 (m, 1H), 1.70-1.73 (m, 1H), 1.79 (t, J = 2.4 Hz, 3 H), 1.83-1.95 (m, 2 H), 2.20 (brd, J = 13.2 Hz, 1 H), 3.03 (t, J = 7.6 Hz, 2 H), 3.45 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3.64 -3.67 (m, 1 H), 3.78 (q, J = 2.4 Hz, 2 H), 4. 81 (d, J = 16.8 Hz, 1 H), 4.87 (d, J = 16). 8 Hz, 1 H), 5.16 (brd, J = 5.2 Hz, 1 H), 6.94 (brs, 1 H), 7.09 (brs, 1 H), 7.15 (d, J = 8.8 Hz 1H), 7.23 (dd, J = 8.8, 2.4 Hz, 1 H), 7. 50 (brs, 1 H), 7.59 (d, J = 2.4 Hz, 1 H), 8.48 ( brs, 1 H).
ESI-MS: m / z = 456 (M + H) + .
（参考例１２９）（Ｒ）－２－（（３－クロロ－４－（プロピル（４，４，４－トリフルオロブタ－２－イン－１－イル）アミノ）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000212
 　ヨウ化銅（０．３００ｇ，１．５８ｍｍｏｌ）、テトラメチルエチレンジアミン（以下、ＴＭＥＤＡ）（０．２３８ｍＬ，１．５８ｍｍｏｌ）及び炭酸カリウム（０．４３６ｇ，３．１５ｍｍｏｌ）をＤＭＦ（３．２５ｍＬ）に懸濁させた。空気雰囲気下で３０分間激しく撹拌した後、（トリフルオロメチル）トリメチルシラン（０．５９８ｇ，４．２０ｍｍｏｌ）を加えた。空気雰囲気下で３０分間激しく撹拌した後、参考例１２５の化合物（０．２２８ｇ，０．５２５ｍｍｏｌ）及び（トリフルオロメチル）トリメチルシラン（０．５９８ｇ，４．２０ｍｍｏｌ）をＤＭＦ（２．００ｍＬ）に溶解させ、０℃に冷却した溶液を０℃で反応液に加えた。室温で２２時間撹拌した後、反応液に蒸留水を加え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１００／０～８０／２０）で精製し、表題化合物（以下、参考例１２９の化合物）（０．２０６ｇ，０．４１０ｍｍｏｌ，７８％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９１（ｔ，７．６Ｈｚ，３Ｈ），１．４３－１．５０（ｍ，４Ｈ），１．５２（ｓ，９Ｈ），１．５４－１．５９（ｍ，１Ｈ），１．６６－１．７０（ｍ，２Ｈ），２．３３（ｂｒｄ，Ｊ＝１１．６Ｈｚ，１Ｈ），２．８３（ｄｄｄ，Ｊ＝１２．８，１２．８，２．４Ｈｚ，１Ｈ），３．０６（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．９７（ｑ，Ｊ＝３．２Ｈｚ，２Ｈ），４．０４－４．０８（ｍ，１Ｈ），４．８５（ｂｒｄ，Ｊ＝３．６Ｈｚ，１Ｈ），７．１４（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．２９（ｄｄ，Ｊ＝８．８，２．４Ｈｚ，１Ｈ），７．７４（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．２１（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５０２（Ｍ＋Ｈ）＋． (Reference Example 129) (R) -2-((3-Chloro-4- (propyl (4,4,4-trifluorobut-2-yn-1-yl) amino) phenyl) carbamoyl) piperidine-1- (R) Synthesis of tert-butyl carboxylic acid:
Figure JPOXMLDOC01-appb-C000212
 Copper iodide (0.300 g, 1.58 mmol), tetramethylethylenediamine (below, TMEDA) (0.238 mL, 1.58 mmol) and potassium carbonate (0.436 g, 3.15 mmol) in DMF (3.25 mL) It was suspended. After vigorous stirring for 30 minutes under air atmosphere, (trifluoromethyl) trimethylsilane (0.598 g, 4.20 mmol) was added. After vigorously stirring for 30 minutes under an air atmosphere, the compound of Reference Example 125 (0.228 g, 0.525 mmol) and (trifluoromethyl) trimethylsilane (0.598 g, 4.20 mmol) in DMF (2.00 mL) The solution which had been dissolved and cooled to 0 ° C. was added to the reaction at 0 ° C. After stirring at room temperature for 22 hours, distilled water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100/0 to 80/20), and the title compound (hereinafter, the compound of Reference Example 129) (0.206 g, 0.410 mmol, 78) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (t, 7.6 Hz, 3 H), 1.43-1.50 (m, 4 H), 1.52 (s, 9 H), 1.54 -1.59 (m, 1H), 1.66-1.70 (m, 2H), 2.33 (brd, J = 11.6 Hz, 1 H), 2.83 (ddd, J = 12.8, 12.8, 2.4 Hz, 1 H), 3.06 (t, J = 7.2 Hz, 2 H), 3.97 (q, J = 3.2 Hz, 2 H), 4.04-4. 08 (m , 1 H), 4.85 (brd, J = 3.6 Hz, 1 H), 7. 14 (d, J = 8.8 Hz, 1 H), 7. 29 (dd, J = 8.8, 2.4 Hz, 1H), 7.74 (d, J = 2.4 Hz, 1 H), 8.21 (brs, 1 H).
ESI-MS: m / z = 502 (M + H) + .
（実施例６７）（Ｒ）－１－アセチル－Ｎ－（３－クロロ－４－（プロピル（４，４，４－トリフルオロブタ－２－イン－１－イル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000213
 　参考例９の化合物の代わりに参考例１２９の化合物を用いて、それ以外は実施例２と同様の手順により、表題化合物（以下、実施例６７の化合物）（０．０８５７ｇ，０．１９３ｍｍｏｌ，９２％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９１（ｔ，Ｊ＝７．６Ｈｚ，３Ｈ），１．４２－１．５１（ｔｑ，Ｊ＝７．６，７．６Ｈｚ，２Ｈ），１．５１－１．６０（ｍ，２Ｈ），１．７１－１．７８（ｍ，２Ｈ），１．９０－２．０２（ｍ，１Ｈ），２．２１（ｓ，３Ｈ），２．２７（ｂｒｄ，Ｊ＝１３．６Ｈｚ，１Ｈ），３．０５（ｔ，Ｊ＝７．６Ｈｚ，２Ｈ），３．１５（ｄｄｄ，Ｊ＝１３．２，１３．２，２．８Ｈｚ，１Ｈ），３．７６（ｂｒｄ，Ｊ＝１４．８Ｈｚ，１Ｈ），３．９６（ｑ，Ｊ＝３．２Ｈｚ，２Ｈ），５．２５（ｂｒｄ，Ｊ＝５．６Ｈｚ，１Ｈ），７．１２（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．３１（ｄｄ，Ｊ＝８．８，２．８Ｈｚ，１Ｈ），７．７１（ｄ，Ｊ＝２．８Ｈｚ，１Ｈ），８．４１（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４４４（Ｍ＋Ｈ）＋． Example 67 (R) -1-Acetyl-N- (3-chloro-4- (propyl (4,4,4-trifluorobut-2-yn-1-yl) amino) phenyl) piperidine-2 -Synthesis of carboxamide:
Figure JPOXMLDOC01-appb-C000213
 Using the compound of Reference Example 129 instead of the compound of Reference Example 9, and using the same procedure as Example 2 except for the above, the title compound (the compound of Example 67 below) (0.0857 g, 0.193 mmol, 92) %) As a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (t, J = 7.6 Hz, 3 H), 1.42-1.51 (tq, J = 7.6, 7.6 Hz, 2 H), 1.51-1.60 (m, 2H), 1.71-1. 78 (m, 2H), 1.90-2.02 (m, 1H), 2.21 (s, 3H), 27 (brd, J = 13.6 Hz, 1 H), 3.05 (t, J = 7.6 Hz, 2 H), 3. 15 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H) , 3.76 (brd, J = 14.8 Hz, 1 H), 3.96 (q, J = 3.2 Hz, 2 H), 5.25 (brd, J = 5.6 Hz, 1 H), 7.12 ( d, J = 8.8 Hz, 1 H), 7.31 (dd, J = 8.8, 2.8 Hz, 1 H), 7.71 (d, J = 2.8 Hz, 1 H), 8.41 (br , 1H).
ESI-MS: m / z = 444 (M + H) <+> .
（実施例６８）（Ｒ）－１－（２－（１Ｈ－イミダゾール－１－イル）アセチル）－Ｎ－（３－クロロ－４－（プロピル（４，４，４－トリフルオロブタ－２－イン－１－イル）アミノ）フェニル）ピペリジン－２－カルボキサミドの合成：
Figure JPOXMLDOC01-appb-C000214
 　参考例４３の化合物の代わりに参考例１２９の化合物を、２－（１Ｈ－テトラゾール－１－イル）酢酸の代わりに１－イミダゾール酢酸を用いて、それ以外は実施例１３と同様の手順により、表題化合物（以下、実施例６８の化合物）（０．０７７２ｇ，０．１５１ｍｍｏｌ，７２％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９１（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．４３－１．５４（ｍ，３Ｈ），１．６５－１．７１（ｍ，１Ｈ），１．７３－１．８４（ｍ，２Ｈ），１．９２－２．０２（ｍ，１Ｈ），２．２４（ｂｒｄ，Ｊ＝１４．４Ｈｚ，１Ｈ），３．０５（ｔ，Ｊ＝７．２Ｈｚ，２Ｈ），３．９０（ｄｄｄ，Ｊ＝１３．２，１３．２，２．４Ｈｚ，１Ｈ），３．６９（ｂｒｄ，Ｊ＝１４．０Ｈｚ，１Ｈ），３．９６（ｑ，Ｊ＝３．２Ｈｚ，２Ｈ），４．８４（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），４．９０（ｄ，Ｊ＝１６．８Ｈｚ，１Ｈ），５．１６－５．１７（ｍ，１Ｈ），６．９６（ｓ，１Ｈ），７．１１－７．１３（ｍ，２Ｈ），７．２３（ｄｄ，Ｊ＝Ｊ＝８．８，２．４Ｈｚ，１Ｈ），７．５２（ｓ，１Ｈ），７．６９（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．１７（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝５１０（Ｍ＋Ｈ）＋． Example 68 (R) -1- (2- (1H-Imidazol-1-yl) acetyl) -N- (3-chloro-4- (propyl (4,4,4-trifluorobuta-2-) Synthesis of in-1-yl) amino) phenyl) piperidine-2-carboxamide:
Figure JPOXMLDOC01-appb-C000214
 The procedure of Example 13 is repeated except that the compound of Reference Example 129 is used instead of the compound of Reference Example 43, and 1-imidazoleacetic acid is used instead of 2- (1H-tetrazol-1-yl) acetic acid. The title compound (hereinafter, the compound of Example 68) (0.0772 g, 0.151 mmol, 72%) was obtained as a white amorphous.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (t, J = 7.2 Hz, 3 H), 1.43-1.54 (m, 3 H), 1.65-1. 71 (m, 1H), 1.73-1.84 (m, 2H), 1.92-2.02 (m, 1H), 2.24 (brd, J = 14.4 Hz, 1H), 3.05 (t, t) J = 7.2 Hz, 2H), 3.90 (ddd, J = 13.2, 13.2, 2.4 Hz, 1 H), 3.69 (brd, J = 14.0 Hz, 1 H), 3.96 (Q, J = 3.2 Hz, 2 H), 4. 84 (d, J = 16.8 Hz, 1 H), 4. 90 (d, J = 16.8 Hz, 1 H), 5.16-5.17 ( m, 1 H), 6.96 (s, 1 H), 7.1 1-7. 13 (m, 2 H), 7.2 3 (dd, J = J = 8.8, 2.4 Hz, 1 H), 7. 52 ( , 1H), 7.69 (d, J = 2.4Hz, 1H), 8.17 (brs, 1H).
ESI-MS: m / z = 510 (M + H) + .
（参考例１３０）Ｎ－（２－クロロ－４－ニトロベンジル）－Ｎ－プロピルプロパ－２－イン－１－アミンの合成：
Figure JPOXMLDOC01-appb-C000215
 　プロパルギルアミン（０．５５１ｇ，１０．０ｍｍｏｌ）をジクロロメタン（２０．０ｍＬ）に溶解し、プロピオンアルデヒド（０．５８１ｇ，１０．０ｍｍｏｌ）及び硫酸ナトリウム（５．５ｇ）を室温で加えた。同温度で１５分間撹拌した後、メタノール（２０．０ｍＬ）及び水素化ホウ素ナトリウム（０．３７８ｇ，１０．０ｍｍｏｌ）を加えた。室温で１時間撹拌した後、反応液に蒸留水を加え、ジクロロメタンで抽出した。有機層を無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた粗生成物（０．６３２ｇ）は精製すること無く、続く反応に用いた。
　上記の粗生成物（０．２３６ｇ）をジクロロメタン（２．４５ｍＬ）に溶解し、２－クロロ－４－ニトロベンズアルデヒド（０．１５０ｇ，０．８０８ｍｍｏｌ）、水素化トリアセトキシホウ素ナトリウム（０．３４３ｇ，１．６２ｍｍｏｌ）及び酢酸（０．０２３１ｍＬ，４０４ｍｍｏｌ）を０℃で加えた。室温で６時間撹拌した後、反応液に飽和炭酸水素ナトリウム水溶液を加え、ジクロロメタンで抽出した。有機層を飽和食塩水で洗浄した後、無水硫酸ナトリウムで乾燥、濾過し、濾液を減圧濃縮した。得られた残渣をシリカゲルカラムクロマトグラフィー（ｎ－ヘキサン／酢酸エチル＝１００／０～８０／２０）で精製し、表題化合物（以下、参考例１３０の化合物）（０．１１８ｇ，０．４４２ｍｍｏｌ，５５％）を黄色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９２（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．５２（ｔｑ，Ｊ＝７．６，７．２Ｈｚ，２Ｈ），２．２５（ｔ，Ｊ＝２．４Ｈｚ，１Ｈ），２．５６（ｔ，Ｊ＝７．６Ｈｚ，２Ｈ），３．３８（ｄ，Ｊ＝２．４Ｈｚ，２Ｈ），３．８２（ｓ，２Ｈ），７．７６（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），８．１０（ｄｄ，Ｊ＝８．８，２．４Ｈｚ，１Ｈ），８．２３（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２６７（Ｍ＋Ｈ）＋． Reference Example 130 Synthesis of N- (2-chloro-4-nitrobenzyl) -N-propylprop-2-yn-1-amine:
Figure JPOXMLDOC01-appb-C000215
 Propargylamine (0.551 g, 10.0 mmol) was dissolved in dichloromethane (20.0 mL) and propionaldehyde (0.581 g, 10.0 mmol) and sodium sulfate (5.5 g) were added at room temperature. After stirring for 15 minutes at the same temperature, methanol (20.0 mL) and sodium borohydride (0.378 g, 10.0 mmol) were added. After stirring at room temperature for 1 hour, distilled water was added to the reaction solution, and extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product (0.632 g) was used for the subsequent reaction without purification.
The above crude product (0.236 g) is dissolved in dichloromethane (2.45 mL) and 2-chloro-4-nitrobenzaldehyde (0.150 g, 0.808 mmol), sodium triacetoxyborohydride (0.343 g, 1.62 mmol) and acetic acid (0.0231 mL, 404 mmol) were added at 0 ° C. After stirring at room temperature for 6 hours, to the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate = 100/0 to 80/20) to give the title compound (hereinafter referred to as the compound of Reference Example 130) (0.118 g, 0.442 mmol, 55) %) As a yellow oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.92 (t, J = 7.2 Hz, 3 H), 1.52 (t q, J = 7.6, 7.2 Hz, 2 H), 2. 25 ( t, J = 2.4 Hz, 1 H), 2.56 (t, J = 7.6 Hz, 2 H), 3. 38 (d, J = 2.4 Hz, 2 H), 3.82 (s, 2 H), 7.76 (d, J = 8.8 Hz, 1 H), 8.10 (dd, J = 8.8, 2.4 Hz, 1 H), 8.23 (d, J = 2.4 Hz, 1 H).
ESI-MS: m / z = 267 (M + H) + .
（参考例１３１）３－クロロ－４－（（プロパ－２－イン－１－イル（プロピル）アミノ）メチル）アニリンの合成：
Figure JPOXMLDOC01-appb-C000216
 　参考例７の化合物の代わりに参考例１３０の化合物を用いて、それ以外は参考例８と同様の手順により、表題化合物（以下、参考例１３１の化合物）（０．０７６５ｇ，０．３２３ｍｍｏｌ，７３％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９１（ｔ，Ｊ＝７．６Ｈｚ，３Ｈ），１．５３（ｔｑ，Ｊ＝７．６，７．６Ｈｚ，２Ｈ），２．２２（ｔ，Ｊ＝２．４Ｈｚ，１Ｈ），２．５１（ｔ，Ｊ＝７．６Ｈｚ，２Ｈ），３．３４（ｄ，Ｊ＝２．４Ｈｚ，２Ｈ），３．６１（ｓ，２Ｈ），３．６６（ｂｒｓ，２Ｈ），６．５４（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），６．７０（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），７．２１（Ｊ＝８．４Ｈｚ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝２３７（Ｍ＋Ｈ）＋． Reference Example 131 Synthesis of 3-chloro-4-((prop-2-yn-1-yl (propyl) amino) methyl) aniline:
Figure JPOXMLDOC01-appb-C000216
 Using the compound of Reference Example 130 instead of the compound of Reference Example 7, and using the same procedure as Reference Example 8 except for this, the title compound (hereinafter, the compound of Reference Example 131) (0.0765 g, 0.323 mmol, 73) %) As a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.91 (t, J = 7.6 Hz, 3 H), 1.53 (tq, J = 7.6, 7.6 Hz, 2 H), 2.22 ( t, J = 2.4 Hz, 1 H), 2.51 (t, J = 7.6 Hz, 2 H), 3.34 (d, J = 2.4 Hz, 2 H), 3.61 (s, 2 H), 3.66 (brs, 2 H), 6.54 (dd, J = 8.4, 2.4 Hz, 1 H), 6. 70 (d, J = 2.4 Hz, 1 H), 7.21 (J = 8) .4 Hz, 1 H).
ESI-MS: m / z = 237 (M + H) + .
（参考例１３２）（Ｒ）－２－（（３－クロロ－４－（（プロパ－２－イン－１－イル（プロピル）アミノ）メチル）フェニル）カルバモイル）ピペリジン－１－カルボン酸　ｔｅｒｔ－ブチルの合成：
Figure JPOXMLDOC01-appb-C000217
 　参考例８の化合物の代わりに参考例１３１の化合物を用いて、それ以外は参考例９と同様の手順により、表題化合物（以下、参考例１３２の化合物）（０．１４１ｇ，０．３１５ｍｍｏｌ，９７％）を無色油状物として得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤＣｌ３）δ：０．９０（ｔ，Ｊ＝７．２Ｈｚ，３Ｈ），１．４５－１．６９（ｍ，７Ｈ），１．５２（ｓ，９Ｈ），２．２２（ｔ，Ｊ＝２．４Ｈｚ，１Ｈ），２．３３（ｂｒｄ，Ｊ＝１１．６Ｈｚ，１Ｈ），２．５２（ｔ，Ｊ＝７．６Ｈｚ，２Ｈ），２．８２（ｄｄｄ，Ｊ＝１３．２，１３．２，２．８Ｈｚ，１Ｈ），３．３４（ｄ，Ｊ＝２．４Ｈｚ，２Ｈ），３．６９（ｓ，２Ｈ），４．０２－４．１０（ｍ，１Ｈ），４．８４－４．８５（ｍ，１Ｈ），７．２９（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），７．４２（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．６７（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），８．２３（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４４８（Ｍ＋Ｈ）＋． (Reference Example 132) (R) -2-((3-Chloro-4-((prop-2-yn-1-yl (propyl) amino) methyl) phenyl) carbamoyl) piperidine-1-carboxylic acid tert-butyl Composition of:
Figure JPOXMLDOC01-appb-C000217
 Using the compound of Reference Example 131 instead of the compound of Reference Example 8, and according to the same procedure as Reference Example 9 except for this, the title compound (hereinafter, the compound of Reference Example 132) (0.141 g, 0.315 mmol, 97 %) As a colorless oil.
1 H-NMR (400 MHz, CDCl 3 ) δ: 0.90 (t, J = 7.2 Hz, 3 H), 1.45-1.69 (m, 7 H), 1.52 (s, 9 H), 2 .22 (t, J = 2.4 Hz, 1 H), 2. 33 (brd, J = 11.6 Hz, 1 H), 2.52 (t, J = 7.6 Hz, 2 H), 2.82 (ddd, J = 13.2, 13.2, 2.8 Hz, 1 H), 3.34 (d, J = 2.4 Hz, 2 H), 3.69 (s, 2 H), 4.02-4. 10 (m , 1 H), 4.84-4.85 (m, 1 H), 7. 29 (dd, J = 8.4, 2.4 Hz, 1 H), 7.42 (d, J = 8.4 Hz, 1 H) , 7.67 (d, J = 2.4 Hz, 1 H), 8.23 (brs, 1 H).
ESI-MS: m / z = 448 (M + H) + .
（実施例６９）（Ｒ）－Ｎ－（３－クロロ－４－（（プロパ－２－イン－１－イル（プロピル）アミノ）メチル）フェニル）－１－（メチルスルホニル）ピペリジン－２－カルボキサミド　塩酸塩の合成：
Figure JPOXMLDOC01-appb-C000218
 　参考例３の化合物の代わりに参考例１３２の化合物を用いて、それ以外は実施例１と同様の手順により、表題化合物（以下、実施例６９の化合物）（０．０３５５ｇ，０．０８３３ｍｍｏｌ，３６％）を白色アモルファスとして得た。
１Ｈ－ＮＭＲ（４００ＭＨｚ，ＣＤ３ＯＤ）δ：１．０３（ｔ，Ｊ＝７．６Ｈｚ，３Ｈ），１．４７－１．６２（ｍ，２Ｈ），１．７１－１．９６（ｍ，６Ｈ），２．１８（ｂｒｄ，Ｊ＝１４．８Ｈｚ，１Ｈ），２．９３－２．９４（ｍ，３Ｈ），３．２３－３．２６（ｍ，２Ｈ），３．４１－３．４３（ｍ，１Ｈ），３．６２（ｄｄｄ，Ｊ＝１２．４，１２．４，２．８Ｈｚ，１Ｈ），３．６７－３．７１（ｍ，１Ｈ），４．０６（ｂｒｓ，２Ｈ），４．５２（ｂｒｓ，１Ｈ），４．６７（ｄｄ，Ｊ＝６．０，２．４Ｈｚ，１Ｈ），７．５９（ｂｒｓ，２Ｈ），７．９８（ｂｒｓ，１Ｈ）．
ＥＳＩ－ＭＳ：ｍ／ｚ＝４２６（Ｍ＋Ｈ）＋． EXAMPLE 69 (R) -N- (3-Chloro-4-((prop-2-yn-1-yl (propyl) amino) methyl) phenyl) -1- (methylsulfonyl) piperidine-2-carboxamide Hydrochloride Synthesis:
Figure JPOXMLDOC01-appb-C000218
 Using the compound of Reference Example 132 instead of the compound of Reference Example 3, and using the same procedure as Example 1 except for the above, the title compound (the compound of Example 69 below) (0.0355 g, 0.0833 mmol, 36) %) As a white amorphous.
1 H-NMR (400 MHz, CD 3 OD) δ: 1.03 (t, J = 7.6 Hz, 3 H), 1.47-1.62 (m, 2 H), 1.71-1.96 (m , 6H), 2.18 (brd, J = 14.8 Hz, 1H), 2.93-2.94 (m, 3H), 3.23-3.26 (m, 2H), 3.41-3 .43 (m, 1 H), 3.62 (ddd, J = 12.4, 12.4, 2.8 Hz, 1 H), 3.67-3. 71 (m, 1 H), 4.06 (brs, brs, 2H), 4.52 (brs, 1 H), 4.67 (dd, J = 6.0, 2.4 Hz, 1 H), 7.59 (brs, 2 H), 7.98 (brs, 1 H).
ESI-MS: m / z = 426 (M + H) + .
（実施例７０）ＲＯＲγ－コアクチベーター結合阻害作用：
　ＲＯＲγのリガンド結合ドメイン（以下、ＲＯＲγ－ＬＢＤ）とコアクチベーターとの結合に対する、環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩の阻害作用を、時間分解蛍光エネルギー移動（ＴＲ－ＦＲＥＴ）を利用したｉｎｖｉｔｒｏｇｅｎ社のＬａｎｔｈａＳｃｒｅｅｎＴＭ　ＴＲ－ＦＲＥＴ　Ｒｅｔｉｎｏｉｄ－Ｒｅｌａｔｅｄ　Ｏｒｐｈａｎ　Ｒｅｃｅｐｔｏｒ　（ＲＯＲ）　ｇａｍｍａ　Ｃｏａｃｔｉｖａｔｏｒ　Ａｓｓａｙキットを用いて評価した。 (Example 70) RORγ-coactivator binding inhibitory action:
Cyclic amine derivative (I), stereoisomer or hydrate thereof, or pharmacologically acceptable thereof for binding of RORγ ligand binding domain (hereinafter RORγ-LBD) to coactivator the inhibitory effect of the salt, was assessed using a time-resolved fluorescence energy transfer LanthaScreen TM TR-FRET of (TR-FRET) invitrogen, Inc. using retinoid-Related Orphan Receptor (ROR) gamma Coactivator Assay kit.
　被験化合物はＤＭＳＯに溶解した後、５ｍｍｏｌ／Ｌ　ＤＴＴ含有ＴＲ－ＦＲＥＴ　Ｃｏｒｅｇｕｌａｔｏｒ　Ｂｕｆｆｅｒ　Ｄ（ｉｎｖｉｔｏｇｅｎ社）でＤＭＳＯ最終濃度が１％となるように希釈して使用した。３８４ウェル黒色プレート（Ｃｏｒｎｉｎｇ社）の各ウェルに、上記バッファーで希釈した４ｎｍｏｌ／ＬのＧＳＴ融合ＲＯＲγ－ＬＢＤ（ｉｎｖｉｔｏｇｅｎ社）及び被験化合物を添加した。なお、被験化合物非添加かつＧＳＴ融合ＲＯＲγ－ＬＢＤ非添加（バックグラウンド）、及び、被験化合物非添加かつＧＳＴ融合ＲＯＲγ－ＬＢＤ添加（コントロール）のウェルを設けた。次に、上記バッファーで希釈した１５０ｎｍｏｌ／ＬのＦｌｕｒｅｓｃｅｉｎ標識ＴＲＡＰ２２０／ＤＲＩＰ－２（ｉｎｖｉｔｏｇｅｎ社）と、３２ｎｍｏｌ／Ｌのテルビウム標識抗ＧＳＴ抗体（ｉｎｖｉｔｏｇｅｎ社）を各ウェルに添加した。プレートを室温で１６～２４時間インキュベートした後、各ウェルについて３２０ｎｍで励起したときの４９５ｎｍ及び５２０ｎｍの蛍光を測定し、Ｒａｔｉｏ（５２０ｎｍの蛍光値／４９５ｎｍの蛍光値）を算出した。 The test compound was dissolved in DMSO and then diluted with a 5 mmol / L DTT-containing TR-FRET Coregulator Buffer D (invitogen) to a final DMSO concentration of 1%. To each well of a 384 well black plate (Corning), 4 nmol / L GST-fused RORγ-LBD (invitogen) diluted with the above buffer and a test compound were added. A test compound-free and GST-fused RORγ-LBD-free (background), and a test compound-free and GST-fused RORγ-LBD-added (control) wells were provided. Next, 150 nmol / L Flurescein-labeled TRAP220 / DRIP-2 (invitogen) diluted with the above buffer and 32 nmol / L terbium-labeled anti-GST antibody (invitogen) were added to each well. After incubating the plate at room temperature for 16 to 24 hours, the fluorescence at 495 nm and 520 nm when excited at 320 nm was measured for each well, and the Ratio (fluorescence at 520 nm / fluorescence at 495 nm) was calculated.
　被験化合物添加時のＦｏｌｄ　ｃｈａｎｇｅ（被験化合物添加時のＲａｔｉｏ／バックグラウンドのＲａｔｉｏ）、コントロールのＦｏｌｄ　ｃｈａｎｇｅ（コントロールのＲａｔｉｏ／バックグラウンドのＲａｔｉｏ）、及び、バックグラウンドのＦｏｌｄ　ｃｈａｎｇｅ（バックグラウンドのＲａｔｉｏ／バックグラウンドのＲａｔｉｏ）を算出した後、ＲＯＲγ－ＬＢＤとコアクチベーターとの結合阻害率（以下、ＲＯＲγ－コアクチベーター結合阻害率）（％）を下式１から算出した。
 
　ＲＯＲγ－コアクチベーター結合阻害率（％）＝（１－（（被験化合物添加時のＦｏｌｄ　ｃｈａｎｇｅ）－（バックグラウンドのＦｏｌｄ　ｃｈａｎｇｅ））／（（コントロールのＦｏｌｄ　ｃｈａｎｇｅ）－（バックグラウンドのＦｏｌｄ　ｃｈａｎｇｅ）））×１００・・・式１
  Fold change at the time of test compound addition (Ratio at the time of test compound addition / Ratio of background), Fold change of control (Ratio of control / Ratio of background), and Fold change of background (Ratio of background / background) After calculating the ratio of the ground, the binding inhibition rate of RORγ-LBD and the coactivator (hereinafter, RORγ-coactivator binding inhibition rate) (%) was calculated from the following formula 1.

RORγ-coactivator binding inhibition rate (%) = (1 − ((Fold change upon addition of test compound) − (Fold change)) / ((Fold change) − (Fold change) )) × 100 ... Formula 1
　被験化合物３３μｍｏｌ／ＬでのＲＯＲγ－コアクチベーター結合阻害率（％）を表２－１及び表２－２に示す。 The RORγ-coactivator binding inhibition rate (%) at 33 μmol / L of the test compound is shown in Table 2-1 and Table 2-2.
Figure JPOXMLDOC01-appb-T000219
Figure JPOXMLDOC01-appb-T000219
Figure JPOXMLDOC01-appb-T000220
Figure JPOXMLDOC01-appb-T000220
　この結果から、環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩は、ＲＯＲγ－ＬＢＤとコアクチベーターとの結合を著しく阻害することが明らかとなった。 From this result, cyclic amine derivative (I), its stereoisomer or hydrate thereof, or pharmacologically acceptable salts thereof significantly inhibit the binding of RORγ-LBD to coactivator. It became clear.
（実施例７１）マウス脾細胞におけるＩＬ－１７産生抑制作用：
　マウス脾細胞を用いて、ＩＬ－２３刺激によるＩＬ－１７産生に対する環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩の抑制作用を、Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｂｉｏｌｏｇｉｃａｌ　Ｃｈｅｍｉｓｔｒｙ、２００３年、第２７８巻、３号、ｐ．１９１０－１９１４に記載の方法を一部改変して評価した。 (Example 71) IL-17 production inhibitory effect in mouse splenocytes:
Inhibitory action of cyclic amine derivative (I), its stereoisomer or hydrates thereof, or their pharmacologically acceptable salts on IL-23 production by IL-23 stimulation using mouse splenocytes , The Journal of Biological Chemistry, 2003, 278, No. 3, p. The method described in 1910-1914 was partially modified and evaluated.
　Ｃ５７ＢＬ／６Ｊマウス（雄、６～３１週齢）（日本チャールス・リバー株式会社）の脾臓から単一細胞浮遊液を調製し、Ｈｉｓｔｏｐａｑｕｅ－１０８３（Ｓｉｇｍａ社）を用いて脾細胞を調製した。培養培地はＲＰＭＩ１６４０培地（Ｇｉｂｃｏ社）に１０％ＦＢＳ（Ｇｉｂｃｏ社）、５０Ｕ／ｍＬペニシリン・５０μｇ／ｍＬストレプトマイシン（Ｇｉｂｃｏ社）、５０μｍｏｌ／Ｌ　２－メルカプトエタノール（Ｇｉｂｃｏ社）及び１００Ｕ／ｍＬ　ヒトＩＬ－２（株式会社細胞科学研究所）を添加して使用した。被験化合物はＤＭＳＯに溶解した後、培養培地でＤＭＳＯの最終濃度が０．１％となるように希釈して使用した。９６ウェル平底プレート（コーニング社）のウェルに、培養培地で調製した脾細胞（３×１０５個／ウェル）を播種し、被験化合物及び１０ｎｇ／ｍＬのヒトＩＬ－２３（Ｒ＆Ｄ　ｓｙｓｔｅｍｓ社）を加えて、３７℃、５％ＣＯ２の条件下で３日間培養した。なお、ヒトＩＬ－２３非添加かつ被験化合物非添加、及び、ヒトＩＬ－２３添加かつ被験化合物非添加のウェルを設けた。培養終了後、培養上清を採取して上清中のＩＬ－１７産生量をＥＬＩＳＡ法（Ｒ＆Ｄ　ｓｙｓｔｅｍｓ社）により定量した。 A single cell suspension was prepared from the spleen of a C57BL / 6J mouse (male, 6 to 31 weeks old) (Nihon Charles River Co., Ltd.), and splenocytes were prepared using Histopaque-1083 (Sigma). The culture medium is RPMI 1640 medium (Gibco), 10% FBS (Gibco), 50 U / mL penicillin, 50 μg / mL streptomycin (Gibco), 50 μmol / L 2-mercaptoethanol (Gibco) and 100 U / mL human IL- 2 (Cell Science Research Institute, Inc.) was added and used. The test compound was dissolved in DMSO and then diluted to a final concentration of 0.1% in culture medium. Splenocytes (3 × 10 5 cells / well) prepared in culture medium are seeded in wells of a 96 well flat bottom plate (Corning Co.), and a test compound and 10 ng / mL of human IL-23 (R & D systems) are added. The cells were cultured at 37 ° C. and 5% CO 2 for 3 days. In addition, a human IL-23 non-added and a test compound non-added, and a human IL-23 added and test compound non-added well were provided. After completion of the culture, the culture supernatant was collected, and the amount of IL-17 produced in the supernatant was quantified by ELISA (R & D systems).
　ＩＬ－１７産生抑制率（％）は下式２から算出した。
 
　ＩＬ－１７産生抑制率（％）＝（１－（（ＩＬ－２３添加かつ被験化合物添加時のＩＬ－１７産生量）－（ＩＬ－２３非添加かつ被験化合物非添加時のＩＬ－１７産生量））／（（ＩＬ－２３添加かつ被験化合物非添加時のＩＬ－１７産生量）－（ＩＬ－２３非添加かつ被験化合物非添加時のＩＬ－１７産生量）））×１００・・・式２
  The IL-17 production inhibition rate (%) was calculated from the following formula 2.

IL-17 production suppression rate (%) = (1- ((IL-23 production amount with addition of IL-23 and test compound))-(IL-17 production amount without IL-23 addition and without test compound) )) / ((The amount of IL-17 produced with addition of IL-23 and no test compound)-(the amount of IL-17 produced without addition of IL-23 and no test compound))) × 100 ··· Formula 2
　被験化合物５μｍｏｌ／ＬでのＩＬ－１７産生抑制率（％）を表３－１及び表３－２に示す。 The inhibition ratio (%) of IL-17 production at 5 μmol / L of the test compound is shown in Table 3-1 and Table 3-2.
Figure JPOXMLDOC01-appb-T000221
Figure JPOXMLDOC01-appb-T000221
Figure JPOXMLDOC01-appb-T000222
Figure JPOXMLDOC01-appb-T000222
　この結果から、環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩は、ＩＬ－１７産生を抑制することが明らかとなった。 From this result, it was revealed that cyclic amine derivative (I), its stereoisomer or hydrates thereof, or their pharmacologically acceptable salts suppress IL-17 production.
（実施例７２）イミキモド誘発マウス乾癬モデルに対する症状抑制効果：
　耳介の厚みの増加を症状悪化の指標として、イミキモド誘発マウス乾癬モデルにおける環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩の作用を評価した。イミキモド誘発マウス乾癬モデルは、Ｓｃｈａｐｅｒらの方法（Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｄｅｒｍａｔｏｌｏｇｉｃａｌ　Ｓｃｉｅｎｃｅ、２０１３年、第７１巻、第１号、ｐ．２９－３６）を一部改変して作製した。 (Example 72) Suppressive effects on imiquimod-induced mouse psoriasis model:
Cyclic amine derivative (I), its stereoisomer or these hydrates, or their pharmacologically acceptable salts thereof in the imiquimod-induced mouse psoriasis model, using an increase in thickness of the auricle as an indicator of symptom deterioration The action was evaluated. The imiquimod-induced mouse psoriasis model was prepared by partially modifying the method of Schaper et al. (The Journal of Dermatological Science, 2013, 71, No. 1, p. 29-36).
　ＢＡＬＢ／ｃ系マウス（雄、７週齢）（日本チャールス・リバー株式会社）を、予備飼育の後、８週齢で使用した。乾癬様症状を誘発する為、イミキモド初回投与日（以下、誘発日）から誘発後７日目までの８日間、ベセルナクリーム５％を１日１回、マウス左右耳介の外側に各５ｍｇ塗布した（イミキモド投与量０．５ｍｇ／ｂｏｄｙ／ｄａｙ）。 BALB / c mice (male, 7 weeks old) (Nihon Charles River Co., Ltd.) were used at 8 weeks of age after preliminary breeding. In order to induce psoriasis-like symptoms, 5 mg of Becelna cream was applied once a day on the outside of the left and right auricle of the mouse for 8 days from the first day of imiquimod administration (hereinafter, induction day) to 7 days after induction. (Imikimod dose 0.5 mg / body / day).
　誘発後３日目から誘発後７日目までの５日間、マウスに被験化合物を１０ｍｇ／ｋｇの用量で１日１回投与した。被験化合物として、実施例５の化合物を用いた。なお、実施例５の化合物は、０．５ｗ／ｖ％メチルセルロース溶液に懸濁して経口投与した。マウスに実施例５の化合物を投与した群を、実施例５の化合物投与群とした。溶媒投与群には、各被験化合物の溶媒（０．５ｗ／ｖ％メチルセルロース溶液）を同様に投与した。 The test compound was administered at a dose of 10 mg / kg once a day to the mice for 5 days from the 3rd day to the 7th day after induction. The compound of Example 5 was used as a test compound. In addition, the compound of Example 5 was suspended in 0.5 w / v% methylcellulose solution and orally administered. The group to which the compound of Example 5 was administered to mice was taken as the compound administration group of Example 5. The vehicle administration group was similarly administered the solvent (0.5 w / v% methylcellulose solution) of each test compound.
　誘発日のイミキモド投与前（誘発前）の左右の耳介の厚みと、誘発後８日目の左右の耳介の厚みを、デジタルマイクロメーター（ミツトヨ社）を用いて測定した。左右の耳介の厚みの平均値を耳介厚とし、その変化（誘発後８日目の耳介厚－誘発前の耳介厚）を薬効評価の指標とした。 On the day of induction, the thickness of the left and right auricles before (immune) administration of imiquimod and the thickness of the left and right auricles on day 8 after induction were measured using a digital micrometer (Mitsutoyo). The average thickness of the left and right auricles was taken as the auricle thickness, and the change (the auricular thickness on the 8th day after induction-the auricular thickness before the induction) was used as an index for drug efficacy evaluation.
　結果を図１に示す。縦軸は耳介厚の変化（ｍｍ）（平均値±標準誤差、ｎ＝６）を示す。横軸の「溶媒」は、溶媒投与群を示し、「実施例５の化合物」は、実施例５の化合物投与群を示す。＊印は溶媒投与群との比較（Ａｓｐｉｎ－Ｗｅｌｃｈのｔ検定）で統計学的に有意であることを示す（＊：Ｐ＜０．０５）。 The results are shown in FIG. The vertical axis represents the change in ear thickness (mm) (mean value ± standard error, n = 6). The “solvent” on the horizontal axis represents a solvent administration group, and the “compound of Example 5” represents a compound administration group of Example 5. * Indicates statistical significance in comparison with vehicle administration group (Aspin-Welch's t-test) (*: P <0.05).
　イミキモド誘発により、溶媒投与群の誘発後８日目の耳介厚は、誘発前の耳介厚に対して０．２７ｍｍ増加した。この耳介厚の増加は、実施例５の化合物の投与により、統計学的に有意に抑制された。 Due to imiquimod induction, the auricle thickness at day 8 after induction in the solvent administration group increased by 0.27 mm relative to the auricle thickness before induction. This increase in ear thickness was statistically significantly suppressed by the administration of the compound of Example 5.
　この結果から、環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩は、乾癬に対して著しい症状抑制効果を示すことが明らかとなった。 From these results, it is clear that the cyclic amine derivative (I), its stereoisomer or hydrates thereof, or their pharmacologically acceptable salts show a remarkable symptom suppressing effect on psoriasis. became.
　本発明の環状アミン誘導体（Ｉ）、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩は、優れたＲＯＲγアンタゴニスト活性を有するため、ＲＯＲγの機能を抑制することによって病態の改善又は症状の寛解が期待できる疾患に対する医薬として利用することができる。特に、乾癬等の自己免疫疾患の治療剤又は予防剤として利用できる。
  The cyclic amine derivative (I) of the present invention, its stereoisomer or hydrates thereof, or their pharmacologically acceptable salts inhibit the function of RORγ because they have excellent RORγ antagonist activity. Thus, it can be used as a medicine for a disease that can be expected to improve the pathological condition or ameliorate the symptoms. In particular, it can be used as a therapeutic or preventive agent for autoimmune diseases such as psoriasis.

Claims (8)

  1. 　下記の一般式（Ｉ）で示される環状アミン誘導体、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩。
    Figure JPOXMLDOC01-appb-C000001
     ［式中、Ｒ１は、ハロゲン原子を表し、Ｘは、－Ｃ（＝Ｏ）－（ＣＨ２）ｎ－Ｒ２又は－Ｓ（＝Ｏ）２－Ｒ３を表し、ｎは、０～３の整数を表し、Ｒ２は、水素原子、炭素数１～３のアルキル基、炭素数３～６のシクロアルキル基、炭素数４～６のシクロアルキルアルキル基又はヘテロアリール基を表し、Ｒ３は、炭素数１～３のアルキル基を表し、ｍは、０又は１を表し、Ａは、下記の一般式（ＩＩ－１）又は（ＩＩ－２）で示される基を表す。
    Figure JPOXMLDOC01-appb-C000002
     （式中、Ｒ４は、水素原子、ハロゲン原子又はメチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）を表し、ｐは、０～２の整数を表し、ｑは、１又は２を表し、Ｒ５は、炭素数１～６のアルキル基、炭素数４～６のシクロアルキルアルキル基又は－（ＣＨ２）ｒ－ＯＲ７を表し、Ｒ６は、フェニル基（該フェニル基は、１個の任意の水素原子が、ハロゲン原子、メチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）若しくはメトキシ基（該メトキシ基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）、で置換されていてもよい。）又はエチニル基（該エチニル基は、水素原子が、メチル基（該メチル基は、１個～３個の任意の水素原子がハロゲン原子で置換されていてもよい。）で置換されていてもよい。）を表し、ｒは、２～４の整数を表し、Ｒ７は、水素原子又は炭素数１～３のアルキル基を表す。）］     Cyclic amine derivatives represented by the following general formula (I), stereoisomers or hydrates thereof, or pharmacologically acceptable salts thereof.
    Figure JPOXMLDOC01-appb-C000001
     [Wherein, R 1 represents a halogen atom, X represents -C (= O)-(CH 2 ) n -R 2 or -S (= O) 2 -R 3 , n represents 0 to R 2 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or a heteroaryl group, 3 represents an alkyl group having 1 to 3 carbon atoms, m represents 0 or 1, and A represents a group represented by the following general formula (II-1) or (II-2).
    Figure JPOXMLDOC01-appb-C000002
     (Wherein R 4 represents a hydrogen atom, a halogen atom or a methyl group (in the methyl group, one to three arbitrary hydrogen atoms may be substituted with a halogen atom), and p represents Represents an integer of 0 to 2, q represents 1 or 2, and R 5 represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or-(CH 2 ) r -OR 7 R 6 represents a phenyl group (wherein the optional one hydrogen atom is a halogen atom, and the methyl group (wherein the optional methyl group is a hydrogen atom of one to three substituted by a halogen atom) Or methoxy group (in the methoxy group, one to three arbitrary hydrogen atoms may be substituted with halogen atoms), or ethynyl. Group (the ethynyl group is a hydrogen atom, a methyl group (the methyl group is one) Three arbitrary hydrogen atom may be substituted with a halogen atom.) May be substituted with.) Represent, r is an integer of 2 ~ 4, R 7 is hydrogen or C Represents an alkyl group of 1 to 3).
  2. 　Ｒ１は、フッ素原子又は塩素原子であり、
    　ｎは、０～２の整数であり、
    　Ｒ２は、水素原子、炭素数１～３のアルキル基、炭素数３～６のシクロアルキル基、炭素数４～６のシクロアルキルアルキル基又は１個～４個の窒素原子を含む５員環ヘテロアリール基であり、
    　Ｒ４は、水素原子、フッ素原子、塩素原子又はメチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）であり、
    　ｐは、０又は１であり、
    　Ｒ５は、炭素数１～４のアルキル基、炭素数４～６のシクロアルキルアルキル基又は－（ＣＨ２）ｒ－ＯＲ７であり、
    　Ｒ６は、フェニル基（該フェニル基は、１個の任意の水素原子が、フッ素原子、塩素原子、メチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）若しくはメトキシ基（該メトキシ基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）、で置換されていてもよい。）又はエチニル基（該エチニル基は、水素原子が、メチル基（該メチル基は、１個～３個の任意の水素原子がフッ素原子若しくは塩素原子で置換されていてもよい。）で置換されていてもよい。）であり、
    　ｒは、２であり、
    　Ｒ７は、水素原子又はメチル基である、請求項１記載の環状アミン誘導体、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩。     R 1 is a fluorine atom or a chlorine atom,
    n is an integer of 0 to 2,
    R 2 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or a 5-membered ring containing 1 to 4 nitrogen atoms A heteroaryl group,
    R 4 is a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group (in the methyl group, 1 to 3 arbitrary hydrogen atoms may be substituted with a fluorine atom or a chlorine atom),
    p is 0 or 1;
    R 5 is an alkyl group having 1 to 4 carbon atoms, a cycloalkyl alkyl group having 4 to 6 carbon atoms, or-(CH 2 ) r -OR 7 ,
    R 6 is a phenyl group (wherein the optional one hydrogen atom is a fluorine atom, a chlorine atom, a methyl group (the methyl group is an optional hydrogen atom of 1 to 3 is a fluorine atom or chlorine Optionally substituted by an atom) or methoxy group (in the methoxy group, 1 to 3 arbitrary hydrogen atoms may be substituted by a fluorine atom or a chlorine atom), Or ethynyl group (the ethynyl group may be a hydrogen atom, a methyl group (the methyl group may be optionally substituted with 1 to 3 hydrogen atoms, a fluorine atom or a chlorine atom)). And may be replaced by
    r is 2 and
    The cyclic amine derivative according to claim 1, wherein R 7 is a hydrogen atom or a methyl group, a stereoisomer or a hydrate thereof, or a pharmacologically acceptable salt thereof.
  3. 　Ｒ１は、フッ素原子又は塩素原子であり、
    　ｎは、０又は１であり、
    　Ｒ２は、水素原子、メチル基、シクロプロピル基、イミダゾリル基、トリアゾリル基又はテトラゾリル基であり、
    　Ｒ３は、メチル基であり、
    　Ｒ４は、塩素原子又はトリフルオロメチル基であり、
    　ｐは、１であり、
    　ｑは、２であり、
    　Ｒ５は、プロピル基、ブチル基、イソブチル基又はシクロプロピルメチル基であり、
    　Ｒ６は、フェニル基（該フェニル基は、１個の任意の水素原子が、フッ素原子、塩素原子、トリフルオロメチル基若しくはトリフルオロメトキシ基、で置換されていてもよい。）、１－プロピニル基又は３，３，３－トリフルオロプロピニル基である、請求項１記載の環状アミン誘導体、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩。     R 1 is a fluorine atom or a chlorine atom,
    n is 0 or 1 and
    R 2 is a hydrogen atom, a methyl group, a cyclopropyl group, an imidazolyl group, a triazolyl group or a tetrazolyl group,
    R 3 is a methyl group,
    R 4 is a chlorine atom or a trifluoromethyl group,
    p is 1 and
    q is 2, and
    R 5 is a propyl group, a butyl group, an isobutyl group or a cyclopropylmethyl group,
    R 6 is a phenyl group (in the phenyl group, one arbitrary hydrogen atom may be substituted with a fluorine atom, a chlorine atom, a trifluoromethyl group or a trifluoromethoxy group), 1-propynyl The cyclic amine derivative according to claim 1, which is a group or 3,3,3-trifluoropropynyl group, a stereoisomer thereof or a hydrate thereof, or a pharmacologically acceptable salt thereof.
  4. 　Ｒ１は、塩素原子であり、
    　Ｘは、－Ｃ（＝Ｏ）－（ＣＨ２）ｎ－Ｒ２であり、
    　ｎは、１であり、
    　Ｒ２は、水素原子、イミダゾリル基又はテトラゾリル基であり、
    　Ｒ４は、トリフルオロメチル基であり、
    　ｐは、１であり、
    　ｑは、２であり、
    　Ｒ５は、プロピル基、ブチル基又はイソブチル基であり、
    　Ｒ６は、フェニル基（該フェニル基は、１個の任意の水素原子が、フッ素原子、塩素原子、トリフルオロメチル基又はトリフルオロメトキシ基、で置換されていてもよい。）である、請求項１記載の環状アミン誘導体、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩。     R 1 is a chlorine atom,
    X is -C (= O)-(CH 2 ) n -R 2 ,
    n is 1 and
    R 2 is a hydrogen atom, an imidazolyl group or a tetrazolyl group,
    R 4 is a trifluoromethyl group,
    p is 1 and
    q is 2, and
    R 5 is a propyl group, a butyl group or an isobutyl group,
    R 6 is a phenyl group (the phenyl group may be optionally substituted with one hydrogen atom, a fluorine atom, a chlorine atom, a trifluoromethyl group or a trifluoromethoxy group). 6. The cyclic amine derivative according to item 1, its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof.
  5. 　請求項１～４のいずれか一項記載の環状アミン誘導体、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩を有効成分として含有する、医薬。 A medicament comprising the cyclic amine derivative according to any one of claims 1 to 4, its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient.
  6. 　請求項１～４のいずれか一項記載の環状アミン誘導体、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩を有効成分として含有する、レチノイド関連オーファン受容体γアンタゴニスト。 A retinoid-related orphan comprising the cyclic amine derivative according to any one of claims 1 to 4, its stereoisomer or a hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient Receptor gamma antagonist.
  7. 　請求項１～４のいずれか一項記載の環状アミン誘導体、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩を有効成分として含有する、自己免疫疾患の治療剤又は予防剤。 An autoimmune disease comprising the cyclic amine derivative according to any one of claims 1 to 4, its stereoisomer or a hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient Therapeutic or prophylactic agent.
  8. 　請求項１～４のいずれか一項記載の環状アミン誘導体、その立体異性体若しくはこれらの水和物、又は、それらの薬理学的に許容される塩を有効成分として含有する、乾癬の治療剤又は予防剤。
          A therapeutic agent for psoriasis, comprising the cyclic amine derivative according to any one of claims 1 to 4, its stereoisomer or hydrate thereof, or a pharmacologically acceptable salt thereof as an active ingredient Or preventive agent.
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