Substituted piperidine compounds and uses thereof

Abstract

Provided are substituted piperidine compounds having orexin type 2 receptor agonistic activity. Compounds represented by the formula (I), wherein each symbol is as described in the specification, or a salt thereof, have orexin type 2 receptor agonistic activity, and are useful as a prophylactic or therapeutic agent for narcolepsy.

Description

[0001] This application is a divisional application of the invention application filed on February 1, 2017, with Chinese application number 201780021073.0 and entitled "Substituted Piperidine Compounds and Their Uses". [Technical Field]

[0002] This invention relates to substituted piperidine compounds, and more particularly to substituted piperidine compounds having orexin type II receptor agonist activity.

[0003] (Background of the Invention)

[0004] Orexin is a neuropeptide specifically produced by neurons that are sparsely distributed in the lateral hypothalamus and its surrounding areas, and it consists of two subtypes: orexin A and orexin B. Orexin A and orexin B are endogenous ligands of the orexin receptor, a G protein-coupled receptor, which is mainly located in the brain, and the two subtypes, type I and type II, are the two known types of orexin receptors (Non-Patent Literature 1).

[0005] Because the neurons that produce orexin (orexin neurons) are located near the feeding center, intraventricular administration of orexin peptides can increase food intake, and orexin, as a neuropeptide with a regulatory role in feeding behavior, has begun to attract attention. However, subsequent reports have suggested that canine narcolepsy is caused by genetic variations in the orexin type II receptor (Non-Patent Literature 2), and have also led to discussions on the role of orexin in controlling sleep and wakefulness.

[0006] Studies using transgenic mice with degenerated orexin neurons and double transgenic mice obtained by crossing these mice with transgenic mice overexpressing orexin showed that drowsiness symptoms caused by the degeneration of orexin neurons disappeared due to the continued expression of orexin. Similarly, when orexin was administered intraventrally to transgenic mice with degenerated orexin neurons, improvement in drowsiness symptoms was also observed (Non-Patent Literature 3). Studies of orexin type II receptor knockout mice demonstrated that orexin type II receptors are important for maintaining wakefulness (Non-Patent Literature 4, Non-Patent Literature 5). This suggests that orexin type II receptor agonists could be therapeutic agents for narcolepsy or other sleep disorders exhibiting excessive sleepiness (Non-Patent Literature 6).

[0007] In addition, it has been suggested that, due to the high-fat diet of mice, peptide agonists that selectively act on orexin type II receptors can improve obesity (Non-Patent Literature 7).

[0008] In addition, it has been suggested that intraventricular administration of appetite peptides can reduce the duration of systemic anesthesia in rats (Non-Patent Literature 8).

[0009] In addition, it has been suggested that low concentrations of appetite peptide A have been observed in the plasma of patients with sleep apnea syndrome (Non-Patent Literature 9).

[0010] In addition, it has been proposed that intraventricular administration of appetite peptides can improve memory retention in accelerated aging model mice (SAMP8) with cognitive impairment (Non-Patent Literature 10).

[0011] In addition, some have proposed that orexin type II receptor agonists are therapeutic agents for heart failure (Patent Document 1, Non-Patent Document 11).

[0012] In addition, it has been suggested that daytime sleepiness in Parkinson's disease patients is caused by the loss of orexin neurons (Non-Patent Literature 12).

[0013] In addition, it has been proposed that orexin regulates bone formation and bone loss, and that orexin type II receptor agonists could be therapeutic agents for diseases associated with bone loss, such as osteoporosis, rheumatoid arthritis, etc. (Patent Document 2).

[0014] In addition, it has been suggested that since the continuous administration of orexin to the periphery of septic shock model mice can significantly increase mortality, orexin receptor agonists may be used to prevent or treat sepsis, severe sepsis and septic shock (Patent Document 3).

[0015] Therefore, compounds with orexin type II receptor agonist activity can be used as novel therapeutic agents for narcolepsy, spontaneous somnolence, hypersomnia, sleep-apnea syndrome, altered consciousness (e.g., coma, etc.), narcolepsy syndrome with narcolepsy symptoms, narcolepsy syndrome with daytime sleepiness (e.g., Parkinson's disease, acute infectious polyneuritis, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, etc. Furthermore, they can be used as anesthetic antagonists and as preventive or therapeutic agents for side effects and complications caused by anesthesia.

[0016] Some of these compounds have been reported (Patent Document 4, Patent Document 5, Patent Document 6, Non-Patent Document 13).

[0017] For example, such compounds include those represented by the following formula.

[0018]

[0019] Additionally, for example, such compounds include those represented by the following formula:

[0020]

[0021] Furthermore, for example, such compounds include compounds represented by the following formula:

[0022]

[0023] However, this compound is considered unsatisfactory in terms of activity, pharmacokinetics, or safety, so there is still a need to develop compounds with appetite peptide type II receptor agonist activity.

[0024] [List of References]

[0025] [Patent Literature]

[0026] Patent Document 1: WO 2015 / 073707 A1

[0027] Patent Document 2: WO 2015 / 048091 A1

[0028] Patent Document 3: WO 2015 / 147240 A1

[0029] Patent Document 4: US 8,258,163 B2

[0030] Patent Document 5: WO 2015 / 088000 A1

[0031] Patent Document 6: WO 2014 / 198880 A1

[0032] [Non-patent literature]

[0033] Non-patent literature 1: Cell, Vol. 92, 573-585, 1998

[0034] Non-patent literature 2: Cell, Vol. 98, 365-376, 1999

[0035] Non-patent literature 3: Proc. Natl. Acad. Sci. USA, Vol. 101, 4649-4654, 2004

[0036] Non-patent literature 4: Cell, Vol. 98, 437-451, 1999

[0037] Non-patent literature 5: Neuron, Vol. 38, 715-730, 2003

[0038] Non-patent literature 6: CNS Drugs, Vol. 27, 83-90, 2013

[0039] Non-patent literature 7: Cell Metabolism, Vol. 9, 64–76, 2009

[0040] Non-patent literature 8: Neuroscience, Vol. 121, 855-863, 2003

[0041] Non-patent literature 9: Respiration, Vol. 71, 575-579, 2004

[0042] Non-patent literature 10: Peptides, Vol. 23, 1683-1688, 2002

[0043] Non-patent literature 11: Journal of the American College of Cardiology. Vol. 66, 2015, pp. 2522-2533.

[0044] Non-patent literature 12: Brain, Vol. 130, 2007, pp. 1586-1595.

[0045] Non-patent literature 13: Journal of Medicinal Chemistry. Vol. 58, pp. 7931-7937

[0046] [Overview of the Invention]

[0047] [The problem solved by this invention]

[0048] The object of this invention is to provide substituted piperidine compounds having appetite peptide type II receptor agonist activity.

[0049] [Solutions to the problem]

[0050] The inventors discovered that compounds represented by the following formula (I) or salts thereof (sometimes referred to as compound (I)) possess appetite peptide type II receptor agonist activity. As a result of further research, they completed this invention.

[0051] Accordingly, the present invention relates to

[0052] [1] The compounds represented by the following formula:

[0053]

[0054] in

[0055] R 1 It is an acyl group or a hydrogen atom;

[0056] R 2 It is an optional substituted 3- to 6-membered saturated cyclic group;

[0057] R 3 C is an optional substitute 1-6 Alkyl, mono- or di-C 1-6Alkylamino or C 3-6 cycloalkyl,

[0058] or its salt;

[0059] [2][1] compounds, wherein R 3 C is an optional substitute 1-6 Alkyl, or mono- or di-C 1-6 Alkylamino groups, or their salts;

[0060] Compounds of [3][1] or [2] are represented by the following formula:

[0061]

[0062] Among them, R 1 R 2 and R 3 As defined in [1], or its salts;

[0063] Compounds of [4][1], [2] or [3], wherein R 1 It is an acyl group, or a salt thereof;

[0064] Compounds of [5][1], [2], [3] or [4], wherein R 2 It is a C substituted with an optional phenyl group. 3-6 cycloalkyl groups, or their salts;

[0065] Compounds of [6][1], [2], [3], [4] or [5], wherein R 3 C is an optional substitute 1-6 Alkyl groups, or their salts;

[0066] Compounds of [7][1], [2] or [3], wherein R 1 yes

[0067] (1) Hydrogen atom,

[0068] (2) C with optional substitution 1-6 alkyl-carbonyl,

[0069] (3) C can be arbitrarily substituted 3-10 cycloalkyl-carbonyl,

[0070] (4) C can be arbitrarily substituted 1-6 alkoxy-carbonyl,

[0071] (5) C with optional substitution 3-10 Cycloalkyloxy-carbonyl,

[0072] (6) C with optional substitution 6-14 aryl-carbonyl,

[0073] (7) C with optional substitution 6-14 aryloxy-carbonyl,

[0074] (8) Optionally substituted 5- to 14-membered aromatic heterocyclic carbonyl groups,

[0075] (9) Optionally substituted 3 to 14-membered non-aromatic heterocyclic carbonyl groups

[0076] (10) Optional substitution of mono- or di-C 1-6 alkyl-carbamoyl,

[0077] (11) Optional substitution of mono- or di-C 3-10 cycloalkyl-carbamoyl,

[0078] (12) Optional substitution of mono- or di-C 6-14 aryl-carbamoyl,

[0079] (13) C with optional substitution 1-6 alkylsulfonyl,

[0080] (14) C can be arbitrarily substituted 3-10 Cycloalkylsulfonyl,

[0081] (15) C with optional substitution 6-14 arylsulfonyl,

[0082] (16) Optionally substituted heterocyclic sulfonyl group,

[0083] (17) Optional substitution of mono- or di-C 1-6 alkyl-aminosulfonyl, or

[0084] (18) C with optional substitution 1-6 alkyl-carbonyl-carbonyl;

[0085] R 2 It is C 3-6 Cycloalkyl or 3 to 6-membered saturated monocyclic nonaromatic heterocyclic groups, each optionally substituted by 1 to 3 substituents selected from the following:

[0086] (1) Deuterium,

[0087] (2) Halogen atoms,

[0088] (3) Hydroxyl group,

[0089] (4) Choose any C to be replaced 1-6 alkyl,

[0090] (5)C 3-10 cycloalkyl,

[0091] (6) C with optional substitution 1-6 Alkoxy

[0092] (7) Choose any C to be replaced. 6-14 Aryl,

[0093] (8)C 6-14 aryloxy,

[0094] (9) Tri-C 1-6 Alkylsilyloxy,

[0095] (10) Optionally substituted 5- to 14-membered aromatic heterocyclic groups, and

[0096] (11) C with optional substitution 6-14 aryl-carbonyl;

[0097] R 3 It is selected from 1 to 3 atoms chosen from halogen atoms and C. 6-14 Aryl substituents substituted C 1-6 Alkyl, or mono- or di-C 1-6 Alkylamino groups, or their salts;

[0098] Compounds of [8][1], [2] or [3], wherein R 1 yes

[0099] (1) Hydrogen atom,

[0100] (2) C16 cells substituted with 1 to 7 substituents selected from the following groups. 1-6 Alkyl-carbonyl:

[0101] (i) halogen atom, (ii) cyano group, (iii) hydroxyl group, (iv) C 3-10 Cycloalkyl, (v)C 1-6 Alkoxy, (vi)C 6-14 Aryl, (vii)C 6-14 aryloxy group, (viii) pyrazolyl, thiazolyl, pyrimidinyl or pyridazinyl, each optionally substituted with an oxygen, (ix) optionally substituted with 1 to 3 carbon atoms. 1-6 Alkyl-substituted pyrazoloxy, (x)C 1-6 Alkyl-carbonyl, (xi)C 1-6 Alkoxy-carbonyl, (xii)C 1-6 Alkyl-carbonyloxy group, (xiii)C 1-6 alkylsulfonyl, (xiv) mono- or di-C 1-6 Alkylamino, (xv)C 1-6 Alkyl-carbonylamino, (xvi)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino,

[0102] (3) Select one to three atoms chosen from halogen, cyano, hydroxyl, oxo, and C. 1-6Alkyl substituents substituted C 3-10 cycloalkyl-carbonyl,

[0103] (4) Select 1 to 6 atoms chosen from deuterium, halogen atoms and C. 6-14 Aryl substituents substituted C 1-6 alkoxy-carbonyl,

[0104] (5) Select 1 to 3 from C. 1-6 Alkyl substituents substituted C 3-10 Cycloalkyloxy-carbonyl,

[0105] (6) Selected from 1 to 3 atoms chosen from halogen atoms and C 6-14 Aryl substituents substituted C 6-14 aryl-carbonyl,

[0106] (7)C 6-14 aryloxy-carbonyl,

[0107] (8) furanylcarbonyl, thienylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl, or pyridylcarbonyl, each optionally selected from 1 to 3 C 1-6 Alkyl substituents,

[0108] (9) Azahexacyclic butylcarbonyl, oxacyclobutylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl or morpholinylcarbonyl, each optionally selected from 1 to 3 oxo, C 1-6 alkyl-carbonyl, C 1-6 alkoxy-carbonyl and C 1-6 Substitution of alkyl sulfonyl groups,

[0109] (10) Selected from 1 to 3 atoms chosen from halogen atoms, cyano groups, hydroxyl groups, and C 1-6 Alkoxy substituents of single or double-C 1-6 alkyl-carbamoyl,

[0110] (11) Single or di-C 3-10 cycloalkyl-carbamoyl,

[0111] (12) Single or di-C 6-14 aryl-carbamoyl,

[0112] (13)C 1-6 alkylsulfonyl,

[0113] (14)C 3-10 Cycloalkylsulfonyl,

[0114] (15) C atoms that are substituted with 1 to 3 halogen atoms by choice 6-14 arylsulfonyl,

[0115] (16) Thiophenesulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridinylsulfonyl, or dihydrochromenylsulfonyl, each optionally consisting of 1 to 3 selected from C 1-6 Alkyl substituents,

[0116] (17) Mono- or di-C 1-6 alkyl-aminosulfonyl, or

[0117] (18)C 1-6 alkyl-carbonyl-carbonyl;

[0118] R 2 It is C 3-6 Cycloalkyl, pyrrolidinyl, piperidinyl, or dioxyl, each optionally substituted with 1 to 3 substituents selected from the following:

[0119] (1) Deuterium,

[0120] (2) Halogen atoms,

[0121] (3) Hydroxyl group,

[0122] (4) Selected from 1 to 3 atoms chosen from halogen atoms and C 6-14 Aryl substituents substituted C 1-6 alkyl,

[0123] (5)C 3-10 cycloalkyl,

[0124] (6) Randomly select C 3-10 Cycloalkyl-substituted C 1-6 Alkoxy

[0125] (7) C16 cells substituted with 1 to 3 substituents selected from the following groups. 6-14 Aryl group: halogen atom, cyano group, C group optionally substituted with 1 to 3 halogen atoms 1-6 Alkyl groups, C atoms optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy and hydroxyl groups

[0126] (8)C 6-14 aryloxy,

[0127] (9) Tri-C 1-6 Alkylsilyloxy,

[0128] (10) pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl, or isoquinolinyl, each optionally composed of 1 to 3 atoms selected from halogen atoms, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups, and

[0129] (11)C 6-14 aryl-carbonyl;

[0130] R 3 It is C 1-6 Alkyl, mono- or di-C 1-6 Alkylamino groups, or their salts;

[0131] Compounds of [9][1], [2] or [3], wherein R 1 yes

[0132] (1) Hydrogen atom,

[0133] (2) C substituted with hydroxyl group by choice 1-6 alkyl-carbonyl,

[0134] (3) Cyclopropylcarbonyl,

[0135] (4)C 1-6 alkoxy-carbonyl, or

[0136] (5) Mono- or di-C 1-6 alkyl-carbamoyl;

[0137] R 2 yes

[0138] (A) Cyclohexyl groups optionally substituted with 1 to 3 substituents selected from the following:

[0139] (1)C 1-6 Alkyl groups, and

[0140] (2) A phenyl group optionally substituted with 1 to 3 substituents selected from the following: halogen atom, C group optionally substituted with 1 to 3 halogen atoms. 1-6 Alkyl and C 1-6 alkoxy, or

[0141] (B)

[0142] R 3 It is C 1-6 Alkyl or di-C 1-6 Alkylamino groups, or their salts;

[0143] Compounds of

[10] [1], [2] or [3], wherein R 1 yes

[0144] (1) C substituted with hydroxyl group by choice 1-6 alkyl-carbonyl,

[0145] (2)C 1-6 alkoxy-carbonyl, or

[0146] (3) Mono- or di-C 1-6 alkyl-carbamoyl;

[0147] R 2It is a cyclohexyl group that is optionally substituted by 1 to 3 substituents selected from the following:

[0148] (1)C 1-6 Alkyl groups, and

[0149] (2) A phenyl group that is optionally substituted with 1 to 3 halogen atoms;

[0150] R 3 It is C 1-6 Alkyl groups, or their salts;

[0151]

[11] (2R,3S)-3-((methanesulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylic acid methyl ester, or a salt thereof;

[0152]

[12] N-((2R,3S)-1-ethanolacyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide, or a salt thereof;

[0153]

[13] (2R,3S)-N-ethyl-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)-3-((methanesulfonyl)amino)piperidine-1-carboxamide, or a salt thereof;

[0154]

[14] Drugs containing compounds or salts thereof of [1]-

[13] ;

[0155]

[15]

[14] drugs, which are orexin type II receptor agonists;

[0156]

[16]

[14] drugs, which are preventive or therapeutic agents for narcolepsy;

[0157]

[17] [1]-

[13] compounds or their salts, for the prevention or treatment of narcolepsy;

[0158]

[18] A method for activating the type II receptor for appetite peptide in mammals, the method comprising: administering to mammals an effective amount of the compound of [1]-

[13] or a salt thereof;

[0159]

[19] A method for preventing or treating narcolepsy in mammals, the method comprising: administering to the mammal an effective amount of a compound of [1]-

[13] or a salt thereof;

[0160] The use of compounds of

[20] [1]-

[13] or salts thereof for the preparation of preventive or therapeutic agents for narcolepsy.

[0161] [Effects of the Invention]

[0162] The compounds of the present invention have appetite peptide type II receptor agonist activity and are used as preventive or therapeutic agents for narcolepsy.

[0163] [Brief description of the attached diagram]

[0164] Figure 1 This is the powder X-ray diffraction pattern of the crystal obtained in Example 5(2).

[0165] (Detailed Description of the Invention)

[0166] The definition of each substituent used in this specification is described in detail below. Unless otherwise stated, each substituent has the following definition.

[0167] In this specification, examples of "halogen atoms" include fluorine, chlorine, bromine, and iodine.

[0168] In this specification, "C" 1-6 Examples of "alkyl" include: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

[0169] In this specification, "optionally halogenated C" 1-6 Examples of "alkyl" include C atoms that optionally have 1 to 7 halogen atoms. 1-6 Alkyl groups, preferably with 1 to 5 halogen atoms. Specific examples include: methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2-trifluoroethyl, tetrafluoroethyl, pentafluoroethyl, propyl, 2,2-difluoropropyl, 3,3,3-trifluoropropyl, isopropyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 5,5,5-trifluoropentyl, hexyl, and 6,6,6-trifluorohexyl.

[0170] In this specification, "C" 2-6 Examples of "alkenyl" include: vinyl, 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, and 5-hexenyl.

[0171] In this specification, "C" 2-6 Examples of "alkynyl" include: ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl.

[0172] In this specification, "C"3-10 Examples of “cycloalkyl” include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl and adamantyl.

[0173] In this specification, "optionally halogenated C" 3-10 Examples of "cycloalkyl" include C atoms optionally having 1 to 7 halogen atoms. 3-10 Cycloalkyl groups, preferably with 1 to 5 halogen atoms. Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0174] In this specification, "C" 3-10 Examples of "cycloalkenyl" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0175] In this specification, "C" 6-14 Examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthrayl, 2-anthrayl, and 9-anthrayl.

[0176] In this specification, "C" 7-16 Examples of "aralkyl" include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0177] In this specification, "C" 1-6 Examples of "alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, and hexoxy.

[0178] In this specification, "optionally halogenated C" 1-6 Examples of "alkoxy" groups include C groups that optionally have 1 to 7 halogen atoms. 1-6 Alkoxy groups, preferably with 1 to 5 halogen atoms. Specific examples include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentoxy, and hexoxy.

[0179] In this specification, "C" 3-10 Examples of “cycloalkyloxy” include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0180] In this specification, "C" 1-6 Examples of "alkylthio" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio.

[0181] In this specification, "optionally halogenated C" 1-6 Examples of "alkylthio" include C groups that optionally have 1 to 7 halogen atoms. 1-6 Alkylthio group, preferably with 1 to 5 halogen atoms. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

[0182] In this specification, "C" 1-6 Examples of "alkyl-carbonyl" include acetyl, propionyl, butyryl, 2-methylpropionyl, valeryl, 3-methylbutyryl, 2-methylbutyryl, 2,2-dimethylpropionyl, hexanoyl, and heptanoyl.

[0183] In this specification, "optionally halogenated C" 1-6 Examples of "alkyl-carbonyl" include C groups that optionally have 1 to 7 halogen atoms. 1-6 Alkyl-carbonyl, preferably with 1 to 5 halogen atoms. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propionyl, butyryl, valeryl, and hexanoyl.

[0184] In this specification, "C" 1-6 Examples of "alkoxy-carbonyl" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentoxycarbonyl, and hexoxycarbonyl.

[0185] In this specification, "C" 6-14 Examples of "aryl-carbonyl" include benzoyl, 1-naphthyl, and 2-naphthyl.

[0186] In this specification, "C" 7-16 Examples of "aralkyl-carbonyl" include phenylacetyl and phenylpropionyl.

[0187] In this specification, examples of "5 to 14 membered aromatic heterocyclic carbonyl groups" include nicotinyl, isonicotinyl, thiophenecarboxyl, and furoyl.

[0188] In this specification, examples of "3 to 14 membered non-aromatic heterocyclic carbonyl groups" include morpholinocarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0189] In this specification, "single or di-C" 1-6 Examples of "alkyl-carbamoyl" include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl.

[0190] In this specification, "single or di-C" 7-16Examples of "aralkyl-carbamoyl" include benzylcarbamoyl and phenylethylcarbamoyl.

[0191] In this specification, "C" 1-6 Examples of "alkyl sulfonyl" include methanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropanesulfonyl, butanesulfonyl, sec-butanesulfonyl, and tert-butanesulfonyl.

[0192] In this specification, "optionally halogenated C" 1-6 Examples of "alkylsulfonyl" include C groups that optionally have 1 to 7 halogen atoms. 1-6 The alkyl sulfonyl group preferably has 1 to 5 halogen atoms. Specific examples include methanesulfonyl, difluoromethanesulfonyl, trifluoromethanesulfonyl, ethanesulfonyl, propanesulfonyl, isopropylsulfonyl, butanesulfonyl, 4,4,4-trifluorobutanesulfonyl, pentanesulfonyl, and hexanesulfonyl.

[0193] In this specification, "C" 6-14 Examples of "arylsulfonyl" include benzenesulfonyl, 1-naphthalenesulfonyl, and 2-naphthalenesulfonyl.

[0194] In this specification, examples of "substituents" include halogen atoms, cyano groups, nitro groups, optionally substituted hydrocarbon groups, optionally substituted heterocyclic groups, acyl groups, optionally substituted amino groups, optionally substituted carbamoyl groups, optionally substituted thiocarbamoyl groups, optionally substituted aminosulfonyl groups, optionally substituted hydroxyl groups, optionally substituted mercapto (SH) groups, and optionally substituted silyl groups.

[0195] In this specification, examples of "hydrocarbon group" (including "hydrocarbon group" of "optionally substituted hydrocarbon group") include C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl and C 7-16 Aryl group.

[0196] In this specification, examples of "optionally substituted hydrocarbon groups" include hydrocarbon groups that optionally have substituents selected from substituent group A below.

[0197] [Substituted base set A]

[0198] (1) Halogen atom,

[0199] (2) Nitro group

[0200] (3) Cyano group,

[0201] (4) Oxygenation,

[0202] (5) Hydroxyl group,

[0203] (6) Optional halogenated C 1-6 Alkoxy

[0204] (7)C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy),

[0205] (8)C 7-16 Aryl alkoxy groups (e.g., benzyl alkoxy groups),

[0206] (9) 5 to 14 membered aromatic heterocyclic hydroxyl groups (e.g., pyridyl hydroxyl groups),

[0207] (10) 3 to 14 membered non-aromatic heterocyclic oxy groups (e.g., morpholinyloxy, piperidinyloxy),

[0208] (11)C 1-6 Alkyl-carbonyloxy groups (e.g., acetoxy, propionyloxy),

[0209] (12)C 6-14 Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy),

[0210] (13)C 1-6 Alkyloxy-carbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy),

[0211] (14) Mono- or di-C 1-6 Alkyl-carbamoyloxy (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy),

[0212] (15)C 6-14 Aryl-carbamoyloxy (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy),

[0213] (16) 5 to 14 membered aromatic heterocyclic carbonyl oxy groups (e.g., nicotinoxy groups),

[0214] (17) 3 to 14 membered non-aromatic heterocyclic carbonyloxy groups (e.g., morpholinyl carbonyloxy, piperidinyl carbonyloxy),

[0215] (18) Optional halogenated C 1-6 Alkylsulfonyloxy (e.g., methanesulfonyloxy, trifluoromethylsulfonyloxy),

[0216] (19) Selective selection of C 1-6 Alkyl-substituted C 6-14 Arylsulfonyloxy (e.g., phenylsulfonyloxy, toluenesulfonyloxy),

[0217] (20) Optional halogenated C 1-6Alkylthio,

[0218] (21) 5 to 14 membered aromatic heterocyclic groups,

[0219] (22) 3 to 14 membered non-aromatic heterocyclic groups,

[0220] (23) Formyl group,

[0221] (24) Carboxyl group,

[0222] (25) Optional halogenated C 1-6 alkyl-carbonyl,

[0223] (26)C 6-14 aryl-carbonyl,

[0224] (27) 5 to 14 membered aromatic heterocyclic carbonyl groups,

[0225] (28) 3 to 14 membered non-aromatic heterocyclic carbonyl groups,

[0226] (29)C 1-6 alkoxy-carbonyl,

[0227] (30)C 6-14 Aryloxycarbonyl (e.g., phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl),

[0228] (31)C 7-16 Aryl alkoxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl),

[0229] (32) Carbamoyl group

[0230] (33) Thiocarbamoyl group,

[0231] (34) Mono- or di-C 1-6 alkyl-carbamoyl,

[0232] (35)C 6-14 Aryl-carbamoyl (e.g., phenylcarbamoyl),

[0233] (36) 5 to 14 membered aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl, thiophenylcarbamoyl),

[0234] (37) 3 to 14 membered non-aromatic heterocyclic carbamoyl groups (e.g., morpholinocarbamoyl, piperidinylcarbamoyl),

[0235] (38) Optional halogenated C 1-6 alkylsulfonyl,

[0236] (39)C 6-14 arylsulfonyl,

[0237] (40) 5 to 14 membered aromatic heterocyclic sulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl),

[0238] (41) Optional halogenated C 1-6 alkylsulfinyl,

[0239] (42)C 6-14 Aryl sulfinyl (e.g., benzenesulfinyl, 1-naphthyl sulfinyl, 2-naphthyl sulfinyl),

[0240] (43) 5 to 14 membered aromatic heterocyclic sulfinyl groups (e.g., pyridyl sulfinyl, thienyl sulfinyl),

[0241] (44) Amino,

[0242] (45) Mono- or di-C 1-6 Alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino),

[0243] (46) Mono- or di-C 6-14 Aromatic amino groups (e.g., phenylamino groups),

[0244] (47) 5- to 14-membered aromatic heterocyclic amino groups (e.g., pyridine amino groups),

[0245] (48)C 7-16 Arylamino (e.g., benzylamino),

[0246] (49) Formamide,

[0247] (50)C 1-6 Alkyl-carbonylamino groups (e.g., acetamido, propionyl, butyrylamino),

[0248] (51)(C 1-6 Alkyl)(C 1-6 (alkyl-carbonyl)amino (e.g., N-acetyl-N-methylamino),

[0249] (52)C 6-14 Aryl-carbonylamino (e.g., phenylcarbonylamino, naphthylcarbonylamino),

[0250] (53)C 1-6 Alkoxy-carbonylamino (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino),

[0251] (54)C 7-16 Arylalkoxy-carbonylamino (e.g., benzyloxycarbonylamino),

[0252] (55)C 1-6 Alkylsulfonamides (e.g., methylsulfonamides, ethylsulfonamides),

[0253] (56) Selective selection of C 1-6 Alkyl-substituted C 6-14 Arylsulfonamides (e.g., benzenesulfonamides, toluenesulfonamides),

[0254] (57) Optional halogenated C 1-6 alkyl,

[0255] (58)C 2-6 alkenyl,

[0256] (59)C 2-6 alkynyl group,

[0257] (60)C 3-10 cycloalkyl,

[0258] (61)C 3-10 Cycloalkenyl, and

[0259] (62)C 6-14 Aryl.

[0260] In the “optionally substituted hydrocarbon groups”, the number of the aforementioned substituents is, for example, 1 to 5, preferably 1 to 3. When the number of substituents is two or more, the corresponding substituents may be the same or different.

[0261] In this specification, examples of "heterocyclic groups" (including "heterocyclic groups with optional substitution") include: (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups, and (iii) 7- to 10-membered bridging heterocyclic groups, which, as atoms constituting the ring, each contain 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms.

[0262] In this specification, examples of "aromatic heterocyclic groups" (including "5- to 14-membered aromatic heterocyclic groups") include: 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups, which, as atoms constituting the ring, contain 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms.

[0263] Preferred examples of "aromatic heterocyclic groups" include: 5- or 6-membered monocyclic aromatic heterocyclic groups, such as thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, triazinyl, etc.;

[0264] Eight to 14 fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocyclic groups, such as benzothiophene, benzofuran, benzimidazol, benzoxazol, benzoisoxazol, benzothiazolyl, benzoisothiazolyl, benzotriazol, imidazopyridyl, thienopyridyl, furanopyridyl, pyrrolopyridyl, pyrazolopyridyl, oxazolopyridyl, thiazopyridyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, thienopyrimidinyl, Furanopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thiazopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thiopheneyl, (with)oxothionyl, indolyl, isoindolyl, 1H-indazoleyl, purineyl, isoquinolinyl, quinolinyl, phthalazinyl, naphridinyl, quinoxolinyl, zolinyl, carbazoyl, β-carolinyl, phenanthidyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, etc.

[0265] In this specification, examples of "non-aromatic heterocyclic groups" (including "3- to 14-membered non-aromatic heterocyclic groups") include: 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups, which, as atoms constituting the ring, contain 1 to 4 heteroatoms selected from nitrogen, sulfur and oxygen atoms in addition to carbon atoms.

[0266] Preferred examples of "non-aromatic heterocyclic groups" include: 3- to 8-membered monocyclic non-aromatic heterocyclic groups, such as aziridinyl, oxetyl, thiapropyl, aziridine, oxetyl, thiapropyl, tetrahydrothiophene, tetrahydrofuranyl, pyrrolinyl, pyrrolylalkyl, imidazolinyl, imidazolinyl, oxazolinyl, oxazolinyl, pyrazolinyl, pyrazolinyl, thiazolinyl, thiazolinyl, tetrahydro ... Hydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azircyclic heptyl, diazacyclic heptyl, azircyclic hepttrienyl, oxacyclic heptyl, azircyclic octyl, diazacyclic octyl, etc.; and

[0267] Nine to fourteen fused polycyclic (preferably bicyclic or tricyclic) non-aromatic heterocyclic groups, such as dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thiopheneyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 4H-quinazinyl, dihydroindolyl, isodihydroindolyl, tetrahydrothieno[2,3-c]pyridyl, tetrahydrobenzozazelinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridineyl, hexahydrophenthiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphridinyl, tetrahydroquinazolinyl, tetrahydrozolinyl, tetrahydrocarbazoleyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanyl, octahydroisoquinolinyl, etc.

[0268] In this specification, preferred examples of “7- to 10-membered bridged heterocyclic groups” include quinine cycloyl and 7-azabicyclo[2.2.1]heptyl.

[0269] In this specification, examples of "nitrogen-containing heterocyclic groups" include "heterocyclic groups" that contain at least one nitrogen atom as a ring-forming atom.

[0270] In this specification, examples of "optionally substituted heterocyclic groups" include heterocyclic groups that optionally have substituents selected from substituent group A above.

[0271] In “optionally substituted heterocyclic groups”, the number of substituents is, for example, 1 to 3. When the number of substituents is two or more, the corresponding substituents may be the same or different.

[0272] In this specification, examples of "acyl" include: formyl, carboxyl, carbamoyl, thiocarbamoyl, sulfinyl, sulfonyl, aminosulfonyl, and phosphonyl, each optionally having "one or two substituents selected from the following: C 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 3-10 Cycloalkenyl, C 6-14 Aryl, C 7-16 Aryl alkyl groups, 5- to 14-membered aromatic heterocyclic groups, and 3- to 14-membered non-aromatic heterocyclic groups, each optionally having 1 to 3 substituents selected from the following: halogen atoms, optionally halogenated C atoms, etc. 1-6 Alkoxy, hydroxy, nitro, cyano, amino, and carbamoyl groups.

[0273] Examples of "acyl" also include hydrocarbon sulfonyl, heterocyclic sulfonyl, hydrocarbon sulfinyl, and heterocyclic sulfinyl.

[0274] In this article, alkyl sulfonyl group refers to a sulfonyl group bonded to a hydrocarbon group, heterocyclic sulfonyl group refers to a sulfonyl group bonded to a heterocyclic group, alkyl-sulfinyl group refers to a sulfinyl group bonded to a hydrocarbon group, and heterocyclic sulfinyl group refers to a sulfinyl group bonded to a heterocyclic group.

[0275] Preferred examples of "acyl" groups include: formyl, carboxyl, C 1-6 alkyl-carbonyl, C 2-6 Alkenyl-carbonyl (e.g., crotonyl), C 3-10 Cycloalkyl-carbonyl (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C 3-10 Cycloalkenyl-carbonyl (e.g., 2-cyclohexenecarbonyl), C 6-14 aryl-carbonyl, C 7-16 Arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C1-6 Alkoxy-carbonyl, C 6-14 Aryloxy-carbonyl (e.g., phenoxycarbonyl, naphthoxycarbonyl), C 7-16 Aryl alkoxy-carbonyl (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl, mono- or di-C 1-6 alkyl-carbamoyl, mono- or di-C 2-6 Alkenyl-carbamoyl (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 aryl-carbamoyl (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aryl-carbamoyl, 5- to 14-membered aromatic heterocyclic carbamoyl (e.g., pyridylcarbamoyl), thiocarbamoyl, mono- or di-C 1-6 Alkyl-thiocarbamoyl (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl (e.g., diallyl-thiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 aryl-thiocarbamoyl (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aryl-thiocarbamoyl (e.g., benzyl thiocarbamoyl, phenethyl thiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl (e.g., pyridyl thiocarbamoyl), sulfinyl, C 1-6 alkyl sulfinyl (e.g., methyl sulfinyl, ethyl sulfinyl), sulfonyl, C 1-6 alkylsulfonyl, C 6-14 arylsulfonyl, phosphonyl and mono- or di-C 1-6 Alkylphosphonoyl (e.g., dimethylphosphonoyl, diethylphosphonoyl, diisopropylphosphonoyl, dibutylphosphonoyl).

[0276] In this specification, examples of "optionally substituted amino groups" include amino groups that optionally have "one or two C12 groups selected from C12". 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-16 Aryl alkyl, C 1-6 alkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 Arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6alkoxy-carbonyl, 5 to 14 membered aromatic heterocyclic groups, carbamoyl, mono- or di-C 1-6 alkyl-carbamoyl, mono- or di-C 7-16 Aryl-carbamoyl, C 1-6 alkylsulfonyl and C 6-14 The arylsulfonyl substituents, each of which may optionally have 1 to 3 substituents selected from substituent group A.

[0277] Preferred examples of optionally substituted amino groups include: amino, mono- or di-(optionally halogenated C-12) 1-6 Alkyl)amino (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 alkenylamino (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Aromatic amino groups (e.g., phenylamino groups), mono- or di-C 7-16 Arylamino (e.g., benzylamino, dibenzylamino), mono- or di-(optionally halogenated C) 1-6 Alkyl)-carbonylamino (e.g., acetamido, propionylamino), mono- or di-C 6-14 aryl-carbonylamino (e.g., benzoylamino), mono- or di-C 7-16 Arylalkyl-carbonylamino (e.g., benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclic carbonylamino (e.g., nicotinamide, isonicotinamide), mono- or di-3 to 14-membered non-aromatic heterocyclic carbonylamino (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 alkoxy-carbonylamino (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino (e.g., pyridineamino), carbamoylamino, (mono- or di-C) 1-6 alkyl-carbamoyl)amino (e.g., methylcarbamoylamino), (mono- or di-C) 7-16 Arylalkyl-carbamoyl)amino (e.g., benzylcarbamoylamino), C 1-6 Alkylsulfonamides (e.g., methylsulfonamides, ethylsulfonamides), C 6-14 Arylsulfonamides (e.g., benzenesulfonamides), (C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino (e.g., N-acetyl-N-methylamino) and (C 1-6 Alkyl)(C 6-14 Aryl-carbonyl)amino (e.g., N-benzoyl-N-methylamino).

[0278] In this specification, examples of "optionally substituted carbamoyl groups" include carbamoyl groups that optionally have "one or two C-groups selected from C64." 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-16 Aryl alkyl, C 1-6 alkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 Arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6 alkoxy-carbonyl, 5 to 14 membered aromatic heterocyclic groups, carbamoyl, mono- or di-C 1-6 alkyl-carbamoyl and mono- or di-C 7-16 Aryl-carbamoyl substituents, each of which may optionally have 1 to 3 substituents selected from substituent group A.

[0279] Preferred examples of optionally substituted carbamoyl groups include: carbamoyl, mono- or di-C 1-6 alkyl-carbamoyl, mono- or di-C 2-6 Alkenyl-carbamoyl (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 aryl-carbamoyl (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aryl-carbamoyl, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 Aryl-carbonyl-carbamoyl (e.g., benzoylcarbamoyl) and 5 to 14 membered aromatic heterocyclic carbamoyl (e.g., pyridylcarbamoyl).

[0280] In this specification, examples of "optionally substituted thiocarbamoyl groups" include thiocarbamoyl groups, which optionally have "one or two C-groups selected from C64." 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-16 Aryl alkyl, C 1-6 alkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 Arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6 alkoxy-carbonyl, 5 to 14 membered aromatic heterocyclic groups, carbamoyl, mono- or di-C 1-6alkyl-carbamoyl and mono- or di-C 7-16 Aryl-carbamoyl substituents, each of which may optionally have 1 to 3 substituents selected from substituent group A.

[0281] Preferred examples of optionally substituted thiocarbamoyl groups include: thiocarbamoyl, mono- or di-C 1-6 Alkyl-thiocarbamoyl (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl (e.g., diallyl-thiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 aryl-thiocarbamoyl (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aryl-thiocarbamoyl (e.g., benzyl thiocarbamoyl, phenethyl thiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14 Aryl-carbonyl-thiocarbamoyl (e.g., benzoylthiocarbamoyl) and 5 to 14-membered aromatic heterocyclic thiocarbamoyl (e.g., pyridylthiocarbamoyl).

[0282] In this specification, examples of "optionally substituted aminosulfonyl groups" include aminosulfonyl groups, which optionally have "one or two C-groups selected from C60, C70, C80, C9 ... 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-16 Aryl alkyl, C 1-6 alkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 Arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6 alkoxy-carbonyl, 5 to 14 membered aromatic heterocyclic groups, carbamoyl, mono- or di-C 1-6 alkyl-carbamoyl and mono- or di-C 7-16 Aryl-carbamoyl substituents, each of which may optionally have 1 to 3 substituents selected from substituent group A.

[0283] Preferred examples of optionally substituted aminosulfonyl groups include: aminosulfonyl, mono- or di-C 1-6Alkyl-aminosulfonyl (e.g., methylaminosulfonyl, ethylaminosulfonyl, dimethylaminosulfonyl, diethylaminosulfonyl, N-ethyl-N-methylaminosulfonyl), mono- or di-C 2-6 Alkenyl-aminosulfonyl (e.g., diallylaminosulfonyl), mono- or di-C 3-10 Cycloalkyl-aminosulfonyl (e.g., cyclopropylaminosulfonyl, cyclohexylaminosulfonyl), mono- or di-C 6-14 aryl-aminosulfonyl (e.g., phenylaminosulfonyl), mono- or di-C 7-16 Aryl alkyl aminosulfonyl (e.g., benzyl aminosulfonyl, phenethyl aminosulfonyl), mono- or di-C 1-6 Alkyl-carbonyl-aminosulfonyl (e.g., acetylaminosulfonyl, propionylaminosulfonyl), mono- or di-C 6-14 Aryl-carbonyl-aminosulfonyl (e.g., benzoylaminosulfonyl) and 5 to 14-membered aromatic heterocyclic aminosulfonyl (e.g., pyridylaminosulfonyl).

[0284] In this specification, examples of "optionally substituted hydroxyl groups" include hydroxyl groups that optionally have a "selected from C" shape. 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-16 Aryl alkyl, C 1-6 alkyl-carbonyl, C 6-14 aryl-carbonyl, C 7-16 Arylalkyl-carbonyl, 5- to 14-membered aromatic heterocyclic carbonyl, 3- to 14-membered non-aromatic heterocyclic carbonyl, C 1-6 alkoxy-carbonyl, 5 to 14 membered aromatic heterocyclic groups, carbamoyl, mono- or di-C 1-6 alkyl-carbamoyl, mono- or di-C 7-16 Aryl-carbamoyl, C 1-6 alkylsulfonyl and C 6-14 The arylsulfonyl substituents, each of which may optionally have 1 to 3 substituents selected from substituent group A.

[0285] Preferred examples of optionally substituted hydroxyl groups include: hydroxyl, C 1-6 Alkoxy, C 2-6 Alkenyloxy groups (e.g., allyloxy, 2-butenoxy, 2-pentenoxy, 3-hexenoxy), C 3-10 Cycloalkyloxy (e.g., cyclohexyloxy), C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy), C 7-16 Aryl alkoxy groups (e.g., benzyloxy, phenethyloxy), C 1-6 Alkyl-carbonyloxy groups (e.g., acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeryloxy), C6-14 aryl-carbonyloxy groups (e.g., benzoyloxy groups), C 7-16 Arylalkyl-carbonyloxy (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclic carbonyloxy (e.g., nicotinyloxy), 3- to 14-membered non-aromatic heterocyclic carbonyloxy (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy-oxy (e.g., pyridyloxy), carbamoyloxy, C 1-6 Alkyl-carbamoyloxy (e.g., methylcarbamoyloxy), C 7-16 Aryl alkyl carbamoyloxy (e.g., benzyl carbamoyloxy), C 1-6 Alkylsulfonyloxy (e.g., methanesulfonyloxy, ethylsulfonyloxy) and C 6-14 Arylsulfonyloxy (e.g., phenylsulfonyloxy).

[0286] In this specification, examples of "optionally substituted thiol groups" include thiol groups that optionally have a "selected from C" group. 1-6 Alkyl, C 2-6 alkenyl, C 3-10 cycloalkyl, C 6-14 Aryl, C 7-16 Aryl alkyl, C 1-6 alkyl-carbonyl, C 6-14 Substituents of aryl-carbonyl and 5 to 14-membered aromatic heterocyclic groups, each optionally having 1 to 3 substituents selected from substituent group A, and halothio groups.

[0287] Preferred examples of optionally substituted thiol groups include: thiol (-SH), C 1-6 Alkylthio, C 2-6 alkenyl thio (e.g., allyl thio, 2-butenyl thio, 2-pentenyl thio, 3-hexenyl thio), C 3-10 Cycloalkyl thiols (e.g., cyclohexyl thiols), C 6-14 Aryl thiols (e.g., phenylthiols, naphthiols), C 7-16 Aryl alkyl thiols (e.g., benzyl thiols, phenethyl thiols), C 1-6 Alkyl-carbonyl thio group (e.g., acetyl thio, propionyl thio, butyryl thio, isobutyryl thio, neopentyl thio), C 6-14 Aryl-carbonyl thio (e.g., benzoyl thio), 5 to 14-membered aromatic heterocyclic thio (e.g., pyridyl thio) and halothio (e.g., pentafluorothio).

[0288] In this specification, examples of "optionally substituted silyl groups" include: optionally having "1 to 3 C16 groups". 1-6 Alkyl, C 2-6 alkenyl, C3-10 cycloalkyl, C 6-14 Aryl and C 7-16 The aralkyl substituents, each substituent optionally having 1 to 3 substituents selected from substituent group A, are silyl groups.

[0289] Preferred examples of optionally substituted silyl groups include: tri-C 1-6 Alkyl silyl (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl).

[0290] In this specification, "C" 3-6 Examples of "cycloalkyl" include the aforementioned "C" 3-10 "Cycloalkyl", in which the number of carbon atoms is 3 to 6.

[0291] In this specification, examples of "3- to 6-membered saturated cyclic groups" include the aforementioned "C" groups with 3 to 6 carbon atoms. 3-10 cycloalkyl (C 3-6 cycloalkyl groups), 3 to 6 saturated monocyclic nonaromatic heterocyclic groups (3 to 6 saturated monocyclic nonaromatic heterocyclic groups).

[0292] In this specification, "single or di-C" 1-6 Examples of "alkylamino" include those described above with "C" 1-6 Alkyl" mono- or di-substituted amino group. When it is di-C 1-6 In the case of alkylamino, the two Cs 1-6 The alkyl groups can be the same or different (e.g., N-ethyl-N-methylamino, etc.).

[0293] The definition of each symbol in equation (I) is described in detail below.

[0294] R 1 It is an acyl group or a hydrogen atom.

[0295] For R 1 The "acyl group" can be any of the above-mentioned "acyl groups".

[0296] Preferred, R 1 It is: (1) a hydrogen atom, (2) an optionally substituted C atom. 1-6 Alkyl-carbonyl (e.g., methylcarbonyl, ethoxycarbonyl, propylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, neopentylcarbonyl), (3) optionally substituted C 3-10 (Preferred C) 3-6 ) cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl, cyclobutyrylcarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl), (4) optional substituted C 1-6 Alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl), (5) optionally substituted C 3-10Cycloalkyloxy-carbonyl (e.g., cyclopropyloxycarbonyl), (6) optionally substituted C 6-14 aryl-carbonyl (e.g., phenylcarbonyl), (7) optional substituted C 6-14 (8) aryloxy-carbonyl (e.g., phenoxycarbonyl), (9) optionally substituted 5- to 14-membered aromatic heterocyclic carbonyl (e.g., furanylcarbonyl, thiophenylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl), (10) optionally substituted 3- to 14-membered non-aromatic heterocyclic carbonyl (e.g., aza-butylcarbonyl, oxo-butylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl, morpholinylcarbonyl), (11) optionally substituted mono- or di-C 1-6 Alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, dimethylcarbamoyl), (11) optionally substituted mono- or di-C 3-10 Cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl), (12) optionally substituted mono- or di-C 6-14 aryl-carbamoyl (e.g., phenylcarbamoyl), (13) optionally substituted C 1-6 alkylsulfonyl (e.g., methanesulfonyl), (14) optionally substituted C 3-10 Cycloalkylsulfonyl (e.g., cyclopropylsulfonyl), (15) optionally substituted C 6-14 arylsulfonyl (e.g., benzenesulfonyl), (16) optionally substituted heterocyclic sulfonyl (e.g., thienylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridinylsulfonyl, dihydrochromenylsulfonyl), (17) optionally substituted mono- or di-C 1-6 Alkyl-aminosulfonyl (e.g., dimethylaminosulfonyl), (18) optionally substituted C 1-6 Alkyl-carbonyl-carbonyl (e.g., methyl carbonyl carbonyl).

[0297] More preferably, R 1 It is: (1) a hydrogen atom, (2) a C atom optionally substituted with 1 to 7 substituents selected from the following 1-6 Alkyl-carbonyl (e.g., methylcarbonyl, ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, neopentylcarbonyl): halogen atom (e.g., fluorine atom), cyano group, hydroxyl group C 3-10 Cycloalkyl (e.g., cyclopropyl), C 1-6 Alkoxy (e.g., methoxy), C 6-14 Aryl (e.g., phenyl), C 6-14Aryloxy group (e.g., phenoxy), 5- to 14-membered aromatic heterocyclic group optionally substituted with oxygen (e.g., pyrazolyl, thiazolyl, pyrimidinyl, pyridazinyl), 5- to 14-membered aromatic heterocyclic oxy group optionally substituted with 1 to 3 substituents selected from the following: C 1-6 Alkyl (e.g., methyl), C 1-6 Alkyl-carbonyl (e.g., methyl carbonyl), C 1-6 Alkoxy-carbonyl (e.g., methoxycarbonyl), C 1-6 Alkyl-carbonyloxy groups (e.g., methylcarbonyloxy groups), C 1-6 Alkyl sulfonyl (e.g., methanesulfonyl), mono- or di-C 1-6 Alkylamino (e.g., dimethylamino), C 1-6 alkyl-carbonylamino (e.g., acetamido) and (C 1-6 Alkyl)(C 1-6 (3) Alkyl-carbonyl)amino (e.g., N-acetyl-N-methylamino), optionally substituted with 1 to 3 substituents selected from the following 3-10 (Preferred C) 3-6 Cycloalkyl-carbonyl groups (e.g., cyclopropylcarbonyl, cyclobutyrylcarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl): halogen atom (e.g., fluorine atom), cyano group, hydroxyl group, oxo group, and C group. 1-6 Alkyl (e.g., methyl), (4) C substituted with 1 to 6 substituents selected from the following 1-6 Alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl): deuterium, halogen atom (e.g., fluorine atom) and C 6-14 Aryl (e.g., phenyl), (5) optionally with 1 to 3 selected from C 1-6 C substituents of alkyl (e.g., methyl) 3-10 Cycloalkyloxycarbonyl (e.g., cyclopropyloxycarbonyl), (6) optionally surrounded by 1 to 3 atoms selected from halogen atoms (e.g., fluorine atoms, chlorine atoms) and C 6-14 C substituents of aryl (e.g., phenyl) 6-14 aryl-carbonyl (e.g., phenylcarbonyl), (7)C 6-14 aryloxy-carbonyl (e.g., phenoxycarbonyl), (8) optionally composed of 1 to 3 groups selected from C 1-6 5- to 14-membered aromatic heterocyclic carbonyl groups substituted with alkyl groups (e.g., methyl) (e.g., furanylcarbonyl, thiophenylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl), (9) 3- to 14-membered non-aromatic heterocyclic carbonyl groups optionally substituted with 1 to 3 substituents selected from the following (e.g., azahexacyclic butylcarbonyl, oxacyclic butylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl, morpholinylcarbonyl): oxo, C 1-6Alkyl-carbonyl (e.g., methyl carbonyl), C 1-6 Alkoxy-carbonyl (e.g., tert-butoxycarbonyl) and C 1-6 Alkyl sulfonyl (e.g., methanesulfonyl), (10) optionally substituted with 1 to 3 substituents selected from the following mono- or di-C 1-6 Alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, dimethylcarbamoyl): halogen atom (e.g., fluorine atom), cyano group, hydroxyl group, and C. 1-6 Alkoxy (e.g., methoxy), (11) mono- or di-C 3-10 cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl), (12) mono- or di-C 6-14 aryl-carbamoyl (e.g., phenylcarbamoyl), (13)C 1-6 Alkyl sulfonyl (e.g., methyl sulfonyl), (14)C 3-10 Cycloalkylsulfonyl (e.g., cyclopropylsulfonyl), (15) C atoms optionally substituted with 1 to 3 halogen atoms (e.g., chlorine atoms) 6-14 arylsulfonyl (e.g., benzenesulfonyl), (16) optionally contains 1 to 3 groups selected from C 1-6 Alkyl (e.g., methyl) substituents of heterocyclic sulfonyl groups (e.g., thienylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridinylsulfonyl, dihydrochromenylsulfonyl), (17) mono- or di-C 1-6 Alkyl-aminosulfonyl (e.g., dimethylaminosulfonyl), or (18)C 1-6 Alkyl-carbonyl-carbonyl (e.g., methyl carbonyl carbonyl).

[0298] In another embodiment of the invention, preferably, R 1 It is an acyl group.

[0299] In another embodiment of the invention, preferably, R 1 It is a C that is optionally replaced by a hydroxyl group. 1-6 alkyl-carbonyl, C 1-6 Alkoxy-carbonyl, C 3-6 Cycloalkyl-carbonyl or mono- or di-C 1-6 Alkyl-carbamoyl group.

[0300] In yet another embodiment of the invention, preferably, R 1 It is a hydrogen atom.

[0301] In another embodiment of the invention, preferably, R 1 Yes: (1) hydrogen atom, (2) C atoms optionally substituted with hydroxyl groups 1-6 alkyl-carbonyl, (3) cyclopropylcarbonyl, (4) C 1-6alkoxy-carbonyl, or (5) mono- or di-C 1-6 Alkyl-carbamoyl group.

[0302] In another embodiment of the invention, preferably, R 1 Yes: (1) C substituted with hydroxyl group by choice 1-6 Alkyl-carbonyl, (2)C 1-6 alkoxy-carbonyl, or (3) mono- or di-C 1-6 Alkyl-carbamoyl group.

[0303] In another embodiment of the invention, preferably, R 1 It is C 1-6 Alkoxy-carbonyl (preferably methoxycarbonyl).

[0304] In another embodiment of the invention, preferably, R 1 C is optionally substituted with a hydroxyl group 1-6 Alkyl-carbonyl.

[0305] In another embodiment of the invention, preferably, R 1 Is it single or double-C? 1-6 Alkyl-carbamoyl group.

[0306] R 2 It is an optionally substituted 3- to 6-membered saturated cyclic group;

[0307] For R 2 The "optionally substituted 3- to 6-membered saturated cyclic group" can be C 3-6 Cycloalkyl (e.g., cyclobutyl, cyclopentyl, cyclohexyl) or 3 to 6-membered saturated monocyclic non-aromatic heterocyclic groups (e.g., pyrrolidinyl, piperidinyl, dioxane).

[0308] For R 2 The substituents of "optionally substituted 3 to 6-membered saturated cyclic groups" may refer to the aforementioned "substituents", preferably (1) deuterium, (2) a halogen atom (e.g., a fluorine atom), (3) a hydroxyl group, and (4) an optional substituted C 1-6 Alkyl (e.g., methyl, isopropyl), (5)C 3-10 Cycloalkyl (e.g., cyclohexyl), (6) optionally substituted C 1-6 Alkyl groups (e.g., methoxy groups), (7) optionally substituted C 6-14 Aryl (e.g., phenyl), (8)C 6-14 Aryloxy (e.g., phenoxy), (9) tri-C 1-6Alkyl silyloxy (e.g., tert-butyl(dimethyl)silyloxy), (10) optionally substituted 5 to 14-membered aromatic heterocycles (e.g., pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl, isoquinolinyl) or (11) optionally substituted C 6-14 aryl-carbonyl (e.g., benzoyl), more preferably, (1) deuterium, (2) a halogen atom (e.g., fluorine atom), (3) a hydroxyl group, (4) optionally composed of 1 to 3 atoms selected from a halogen atom (e.g., fluorine atom) and C 6-14 Aryl substituents substituted C 1-6 Alkyl (e.g., methyl, isopropyl), (5)C 3-10 Cycloalkyl (e.g., cyclohexyl), (6) optionally C 3-10 Cycloalkyl (e.g., cyclopropyl) substituted C 1-6 alkoxy (e.g., methoxy), (7) C substituted with 1 to 3 substituents selected from the following 6-14 Aryl (e.g., phenyl): halogen atom (e.g., fluorine atom, chlorine atom), cyano group, C group optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom) 1-6 Alkyl groups (e.g., methyl, ethyl), C atoms optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methoxy groups) and hydroxyl groups, (8)C 6-14 Aryloxy (e.g., phenoxy), (9) tri-C 1-6 Alkyl silyloxy (e.g., tert-butyl(dimethyl)silyloxy), (10) a 5- to 14-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the following (e.g., pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl, isoquinolinyl): halogen atom (e.g., fluorine atom, chlorine atom), C 1-6 Alkyl (e.g., methyl) and C 1-6 Alkoxy (e.g., methoxy), or (11)C 6-14 Aryl-carbonyl (e.g., benzoyl).

[0309] In this specification, when R 2 When the "optionally substituted 3- to 6-membered saturated cyclic group" has two substituents on one carbon of the "3- to 6-membered saturated cyclic group", it includes the following embodiments: the two substituents are bonded to each other to form a spirocyclic system together with the "3- to 6-membered saturated cyclic group" (e.g., 3H-spiro[2-benzofuran-1,1'-cyclohexane]-4'-yl, 1,4-dioxaspiro[4.5]dec-8-yl).

[0310] Preferred, R 2 It is C 3-6Cycloalkyl (e.g., cyclobutyl, cyclopentyl, cyclohexyl) or 3 to 6 membered saturated monocyclic nonaromatic heterocyclic groups (e.g., pyrrolidinyl, piperidinyl, dioxyl), each optionally substituted with 1 to 3 substituents selected from: (1) deuterium, (2) a halogen atom (e.g., a fluorine atom), (3) a hydroxyl group, (4) an optionally substituted C 1-6 Alkyl (e.g., methyl, isopropyl), (5)C 3-10 Cycloalkyl (e.g., cyclohexyl), (6) optionally substituted C 1-6 Alkyl groups (e.g., methoxy groups), (7) optionally substituted C 6-14 Aryl (e.g., phenyl), (8)C 6-14 Aryloxy (e.g., phenoxy), (9) tri-C 1-6 Alkyl silyloxy (e.g., tert-butyl(dimethyl)silyloxy), (10) optionally substituted 5- to 14-membered aromatic heterocycles (e.g., pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl, isoquinolinyl) and (11) optionally substituted C 6-14 aryl-carbonyl (e.g., benzoyl), more preferably, C 3-6 Cycloalkyl (e.g., cyclobutyl, cyclopentyl, cyclohexyl) or 3 to 6 membered saturated monocyclic nonaromatic heterocyclic groups (e.g., pyrrolidinyl, piperidinyl, dioxyl), each optionally substituted with 1 to 3 substituents selected from: (1) deuterium, (2) a halogen atom (e.g., fluorine atom), (3) a hydroxyl group, (4) optionally substituted with 1 to 3 substituents selected from a halogen atom (e.g., fluorine atom) and C. 6-14 Aryl substituents substituted C 1-6 Alkyl (e.g., methyl, isopropyl), (5)C 3-10 Cycloalkyl (e.g., cyclohexyl), (6) optionally C 3-10 Cycloalkyl (e.g., cyclopropyl) substituted C 1-6 alkoxy (e.g., methoxy), (7) C substituted with 1 to 3 substituents selected from the following 6-14 Aryl (e.g., phenyl): halogen atom (e.g., fluorine atom, chlorine atom), cyano group, C group optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom) 1-6 Alkyl groups (e.g., methyl, ethyl), C atoms optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methoxy groups) and hydroxyl groups, (8)C 6-14 Aryloxy (e.g., phenoxy), (9) tri-C 1-6Alkyl silyloxy (e.g., tert-butyl(dimethyl)silyloxy), (10) a 5- to 14-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the following (e.g., pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl, isoquinolinyl): halogen atom (e.g., fluorine atom, chlorine atom), C 1-6 Alkyl (e.g., methyl) and C 1-6 Alkyl groups (e.g., methoxy groups), and (11)C 6-14 Aryl-carbonyl (e.g., benzoyl).

[0311] Even more preferably, R 2 Yes: (A) C substituted with 1 to 3 substituents selected from the following 3-6 Cycloalkyl (e.g., cyclobutyl, cyclopentyl, cyclohexyl): (1) deuterium, (2) a halogen atom (e.g., fluorine atom), (3) a hydroxyl group, (4) optionally surrounded by 1 to 3 atoms selected from a halogen atom (e.g., fluorine atom) and C 6-14 Aryl substituents substituted C 1-6 Alkyl (e.g., methyl, isopropyl), (5)C 3-10 Cycloalkyl (e.g., cyclohexyl), (6) optionally C 3-10 Cycloalkyl (e.g., cyclopropyl) substituted C 1-6 alkoxy (e.g., methoxy), (7) C substituted with 1 to 3 substituents selected from the following 6-14 Aryl (e.g., phenyl): halogen atom (e.g., fluorine atom, chlorine atom), cyano group, C group optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom) 1-6 Alkyl groups (e.g., methyl, ethyl), C atoms optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkyl groups (e.g., methoxy groups) and hydroxyl groups, (8)C 6-14 Aryloxy (e.g., phenoxy), (9) tri-C 1-6 Alkyl silyloxy (e.g., tert-butyl(dimethyl)silyloxy), (10) a 5- to 14-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the following (e.g., pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl, isoquinolinyl): halogen atom, C 1-6 Alkyl (e.g., methyl) and C 1-6 Alkyl groups (e.g., methoxy groups), and (11)C 6-14 Aryl-carbonyl (e.g., benzoyl), or (B) a 3- to 6-membered saturated monocyclic nonaromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the following: (1) a halogen atom (e.g., a fluorine atom), (2) a C 1-6Alkyl (e.g., methyl), (3) C substituted with 1 to 3 substituents selected from the following 6-14 Aryl (e.g., phenyl): a halogen atom (e.g., fluorine atom, chlorine atom), C atoms optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom). 1-6 Alkyl (e.g., methyl) and C 1-6 Alkoxy (e.g., methoxy), and (4) a 5- to 14-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the following (e.g., thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl, isoquinolinyl): halogen atom (e.g., fluorine atom, chlorine atom), C 1-6 Alkyl (e.g., methyl) and C 1-6 Alkyl groups (e.g., methoxy groups).

[0312] In another embodiment of the invention, preferably, R 2 It is a C substituted with an optional phenyl group. 3-6 Cycloalkyl.

[0313] In another embodiment of the invention, preferably, R 2 It is a C substituted with a phenyl group. 3-6 Cycloalkyl, wherein the phenyl group is optionally substituted with 1 to 3 substituents selected from the following: halogen atom, C group optionally substituted with 1 to 3 halogen atoms. 1-6 Alkyl and C 1-6 Alkyl group.

[0314] In another embodiment of the invention, preferably, R 2 It is a piperidinium group substituted with a pyrimidinium group.

[0315] In another embodiment of the invention, preferably, R 2 It is C 3-6 Cycloalkyl, pyrrolidinyl, piperidinyl, or dioxyl, each optionally substituted with 1 to 3 substituents selected from the following: (1) deuterium, (2) halogen atom, (3) hydroxyl group, (4) optionally substituted with 1 to 3 substituents selected from halogen atom and C. 6-14 Aryl substituents substituted C 1-6 Alkyl, (5)C 3-10 cycloalkyl, (6) optionally C 3-10 Cycloalkyl-substituted C 1-6 alkoxy, (7) C-terminus optionally substituted with 1 to 3 substituents selected from the following 6-14 Aryl group: halogen atom, cyano group, C group optionally substituted with 1 to 3 halogen atoms 1-6 Alkyl groups, C atoms optionally substituted with 1 to 3 halogen atoms 1-6 Alkyl and hydroxyl groups, (8)C 6-14 aryloxy group, (9) tri-C 1-6alkylsilyloxy, (10) pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl or isoquinolinyl, each optionally surrounded by 1 to 3 atoms selected from halogen atoms, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups, and (11)C 6-14 Aryl-carbonyl.

[0316] In another embodiment of the invention, preferably, R 2 It is cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl, piperidinyl, or dioxyl, each optionally substituted with 1 to 3 substituents selected from the following: (1) deuterium, (2) halogen atom, (3) hydroxyl, (4) C-terminal alkyl group optionally substituted with 1 to 3 substituents selected from halogen atom and phenyl group. 1-6 Alkyl, (5) cyclohexyl, (6) C-substituted with cyclopropyl 1-6 Alkoxy, (7) a phenyl group optionally substituted with 1 to 3 substituents selected from the following: halogen atom, cyano group, C group optionally substituted with 1 to 3 halogen atoms. 1-6 Alkyl groups, C atoms optionally substituted with 1 to 3 halogen atoms 1-6 Alkyl and hydroxyl groups, (8) phenoxy groups, (9) tri-C 1-6 alkylsilyloxy, (10) pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl or isoquinolinyl, each optionally surrounded by 1 to 3 atoms selected from halogen atoms, C 1-6 Alkyl and C 1-6 Alkoxy substituents, and (11) benzoyl group.

[0317] In another embodiment of the invention, preferably, R 2 Yes: (A) Cyclohexyl groups substituted with 1 to 3 of the following substituents: (1) C 1-6 Alkyl groups, and (2) phenyl groups optionally substituted with 1 to 3 substituents selected from the following: halogen atom, C group optionally substituted with 1 to 3 halogen atoms. 1-6 Alkyl and C 1-6 Alkoxy, or (B) piperidinium, optionally substituted with 1 to 3 pyrimidinyl groups.

[0318] In another embodiment of the invention, preferably, R 2 It is a cyclohexyl group that is optionally substituted by 1 to 3 substituents selected from the following: (1) C 1-6 Alkyl group, and (2) phenyl group optionally substituted with 1 to 3 halogen atoms.

[0319] In another embodiment of the invention, preferably, R 2 It is a cyclohexyl group that can be optionally substituted with a phenyl group.

[0320] In another embodiment of the invention, preferably, R 2 It is a cyclohexyl group optionally substituted with a phenyl group, wherein the phenyl group is optionally substituted with 1 to 3 halogen atoms.

[0321] In another embodiment of the invention, preferably, R 2 It is optional to be C 1-6 Alkyl-substituted cyclohexyl groups.

[0322] R 3 C is an optional substitute 1-6 Alkyl, mono- or di-C 1-6 Alkylamino or C 3-6 cycloalkyl; preferably, optionally substituted C 1-6 Alkyl or mono- or di-C 1-6 Alkylamino.

[0323] For R 3 "Optional replacement of C" 1-6 The substituent for "alkyl" can be any of the substituents mentioned above, preferably a halogen atom (e.g., a fluorine atom) or a C-shaped atom. 6-14 Aryl (e.g., phenyl).

[0324] Preferred, R 3 It is optionally composed of 1 to 3 atoms selected from halogen atoms (e.g., fluorine atoms) and C. 6-14 C substituents of aryl (e.g., phenyl) 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, isobutyl), or mono- or di-C 1-6 Alkylamino (e.g., ethylamino, dimethylamino), more preferably, C 1-6 Alkyl (e.g., methyl), or mono- or di-C 1-6 Alkylamino (e.g., dimethylamino).

[0325] In another embodiment of the invention, preferably, R 3 C is an optional substitute 1-6 alkyl.

[0326] In another embodiment of the invention, preferably, R 3 It is C 1-6 Alkyl or di-C 1-6 Alkylamino, more preferably C 1-6 Alkyl (preferably methyl).

[0327] In a preferred embodiment of the present invention, compound (I) is represented by the following formula:

[0328]

[0329] Among them, R 1 R2 and R 3 As stated above.

[0330] As a preferred embodiment of compound (I), the following compounds may be used.

[0331] [Compound I-1]

[0332] Compound (I), wherein R 1 It is: (1) a hydrogen atom, (2) an optionally substituted C atom. 1-6 Alkyl-carbonyl (e.g., methylcarbonyl, ethoxycarbonyl, propylcarbonyl, isopropylcarbonyl, isobutylcarbonyl, tert-butylcarbonyl, neopentylcarbonyl), (3) optionally substituted C 3-10 (Preferred C) 3-6 ) cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl, cyclobutyrylcarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl), (4) optional substituted C 1-6 Alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl), (5) optionally substituted C 3-10 Cycloalkyloxy-carbonyl (e.g., cyclopropyloxycarbonyl), (6) optionally substituted C 6-14 aryl-carbonyl (e.g., phenylcarbonyl), (7) optional substituted C 6-14 (8) aryloxy-carbonyl (e.g., phenoxycarbonyl), (9) optionally substituted 5- to 14-membered aromatic heterocyclic carbonyl (e.g., furanylcarbonyl, thiophenylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl), (10) optionally substituted 3- to 14-membered non-aromatic heterocyclic carbonyl (e.g., aza-butylcarbonyl, oxo-butylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl, morpholinylcarbonyl), (11) optionally substituted mono- or di-C 1-6 Alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, dimethylcarbamoyl), (11) optionally substituted mono- or di-C 3-10 Cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl), (12)(13) optionally substituted C 1-6 alkylsulfonyl (e.g., methanesulfonyl), (14) optionally substituted C 3-10 Cycloalkylsulfonyl (e.g., cyclopropylsulfonyl), (15) optionally substituted C 6-14 arylsulfonyl (e.g., benzenesulfonyl), (16) optionally substituted heterocyclic sulfonyl (e.g., thienylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridinylsulfonyl, dihydrochromenylsulfonyl), (17) optionally substituted mono- or di-C 1-6 Alkyl-aminosulfonyl (e.g., dimethylaminosulfonyl), or (18) optionally substituted C 1-6Alkyl-carbonyl-carbonyl (e.g., methylcarbonylcarbonyl);

[0333] R 2 It is C 3-6 Cycloalkyl (e.g., cyclobutyl, cyclopentyl, cyclohexyl) or 3 to 6 membered saturated monocyclic nonaromatic heterocyclic groups (e.g., pyrrolidinyl, piperidinyl, dioxyl), each optionally substituted with 1 to 3 substituents selected from: (1) deuterium, (2) a halogen atom (e.g., a fluorine atom), (3) a hydroxyl group, (4) an optionally substituted C 1-6 Alkyl (e.g., methyl, isopropyl), (5)C 3-10 Cycloalkyl (e.g., cyclohexyl), (6) optionally substituted C 1-6 Alkyl groups (e.g., methoxy groups), (7) optionally substituted C 6-14 Aryl (e.g., phenyl), (8)C 6-14 Aryloxy (e.g., phenoxy), (9) tri-C 1-6 Alkyl silyl (e.g., tert-butyl(dimethyl)silyl), and (10) optionally substituted 5 to 14-membered aromatic heterocyclic groups (e.g., pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl, isoquinolinyl);

[0334] R 3 It is optionally composed of 1 to 3 atoms selected from halogen atoms (e.g., fluorine atoms) and C. 6-14 C substituents of aryl (e.g., phenyl) 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, isobutyl), or mono- or di-C 1-6 Alkylamino (e.g., ethylamino, dimethylamino).

[0335] [Compound I-2]

[0336] Compound (I), wherein R 1 It is: (1) a hydrogen atom, (2) a C atom optionally substituted with 1 to 7 substituents selected from the following 1-6 Alkyl-carbonyl groups (e.g., methyl carbonyl, ethyl carbonyl, propyl carbonyl, isopropyl carbonyl, isobutyl carbonyl, tert-butyl carbonyl, neopentyl carbonyl): halogen atom (e.g., fluorine atom), cyano group, hydroxyl group, C 3-10 Cycloalkyl (e.g., cyclopropyl), C 1-6 Alkoxy (e.g., methoxy), C 6-14 Aryl (e.g., phenyl), C 6-14 Aromatic oxygen groups (e.g., phenoxy groups), 5- to 14-membered aromatic heterocyclic groups optionally substituted with oxygen (e.g., pyrazolyl, thiazolyl, pyrimidinyl, pyridazinyl), and 5- to 14-membered aromatic heterocyclic oxy groups optionally substituted with 1 to 3 substituents selected from the following: C 1-6Alkyl (e.g., methyl), C 1-6 Alkyl-carbonyl (e.g., methyl carbonyl), C 1-6 Alkoxy-carbonyl (e.g., methoxycarbonyl), C 1-6 Alkyl-carbonyloxy groups (e.g., methylcarbonyloxy groups), C 1-6 Alkyl sulfonyl (e.g., methanesulfonyl), mono- or di-C 1-6 Alkylamino (e.g., dimethylamino), C 1-6 alkyl-carbonylamino (e.g., acetamido) and (C 1-6 Alkyl)(C 1-6 (3) Alkyl-carbonyl)amino (e.g., N-acetyl-N-methylamino), optionally substituted with 1 to 3 substituents selected from the following 3-10 (Preferred C) 3-6 Cycloalkyl-carbonyl groups (e.g., cyclopropylcarbonyl, cyclobutyrylcarbonyl, cyclopentanecarbonyl, cyclohexylcarbonyl): halogen atom (e.g., fluorine atom), cyano group, hydroxyl group, oxo group, and C group. 1-6 Alkyl (e.g., methyl), (4) C substituted with 1 to 6 substituents selected from the following 1-6 Alkoxy-carbonyl (e.g., methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonyl): deuterium, halogen atom (e.g., fluorine atom) and C 6-14 Aryl (e.g., phenyl), (5) optionally with 1 to 3 selected from C 1-6 C substituents of alkyl (e.g., methyl) 3-10 Cycloalkyloxycarbonyl (e.g., cyclopropyloxycarbonyl), (6) optionally surrounded by 1 to 3 atoms selected from halogen atoms (e.g., fluorine atoms, chlorine atoms) and C 6-14 C substituents of aryl (e.g., phenyl) 6-14 aryl-carbonyl (e.g., phenylcarbonyl), (7)C 6-14 aryloxy-carbonyl (e.g., phenoxycarbonyl), (8) optionally composed of 1 to 3 groups selected from C 1-6 5- to 14-membered aromatic heterocyclic carbonyl groups substituted with alkyl groups (e.g., methyl) (e.g., furanylcarbonyl, thiophenylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl, pyridylcarbonyl), (9) 3- to 14-membered non-aromatic heterocyclic carbonyl groups optionally substituted with 1 to 3 substituents selected from the following (e.g., azahexacyclic butylcarbonyl, oxacyclic butylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl, morpholinylcarbonyl): oxo, C 1-6 Alkyl-carbonyl (e.g., methyl carbonyl), C 1-6 Alkoxy-carbonyl (e.g., tert-butoxycarbonyl) and C 1-6 Alkyl sulfonyl (e.g., methanesulfonyl), (10) optionally substituted with 1 to 3 substituents selected from the following mono- or di-C 1-6Alkyl-carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, dimethylcarbamoyl): halogen atom (e.g., fluorine atom), cyano group, hydroxyl group, and C. 1-6 Alkoxy (e.g., methoxy), (11) mono- or di-C 3-10 cycloalkyl-carbamoyl (e.g., cyclopropylcarbamoyl), (12) mono- or di-C 6-14 aryl-carbamoyl (e.g., phenylcarbamoyl), (13)(14)C 3-10 Cycloalkylsulfonyl (e.g., cyclopropylsulfonyl), (15) C atoms optionally substituted with 1 to 3 halogen atoms (e.g., chlorine atoms) 6-14 arylsulfonyl (e.g., benzenesulfonyl), (16) optionally contains 1 to 3 groups selected from C 1-6 Alkyl (e.g., methyl) substituents of heterocyclic sulfonyl groups (e.g., thienylsulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridinylsulfonyl, dihydrochromenylsulfonyl), (17) mono- or di-C 1-6 Alkyl-aminosulfonyl (e.g., dimethylaminosulfonyl), or (18)C 1-6 Alkyl-carbonyl-carbonyl (e.g., methylcarbonylcarbonyl);

[0337] R 2 It is C 3-6 Cycloalkyl (e.g., cyclobutyl, cyclopentyl, cyclohexyl) or 3 to 6 membered saturated monocyclic nonaromatic heterocyclic groups (e.g., pyrrolidinyl, piperidinyl, dioxyl), each optionally substituted with 1 to 3 substituents selected from the following: (1) deuterium, (2) halogen atom (e.g., fluorine atom), (3) hydroxyl group, (4) C-terminal halogen atom optionally substituted with 1 to 3 substituents selected from the following. 1-6 Alkyl groups (e.g., methyl, isopropyl): halogen atoms (e.g., fluorine atoms) and C 6-14 Aryl (e.g., phenyl), (5)C 3-10 Cycloalkyl (e.g., cyclohexyl), (6) optionally C 3-10 Cycloalkyl (e.g., cyclopropyl) substituted C 1-6 alkoxy (e.g., methoxy), (7) C substituted with 1 to 3 substituents selected from the following 6-14 Aryl (e.g., phenyl): halogen atom (e.g., fluorine atom, chlorine atom), cyano group, C group optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom) 1-6 Alkyl groups (e.g., methyl, ethyl), C atoms optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) 1-6 Alkoxy (e.g., methoxy), (8)C 6-14 Aryloxy (e.g., phenoxy), (9) tri-C 1-6Alkylsilyl (e.g., tert-butyl(dimethyl)silyl), (10) a 5- to 14-membered aromatic heterocyclic group optionally substituted with 1 to 3 substituents selected from the following (e.g., pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl, isoquinolinyl): halogen atom (e.g., fluorine atom, chlorine atom), C 1-6 Alkyl (e.g., methyl) and C 1-6 Alkyl groups (e.g., methoxy groups);

[0338] R 3 It is C 1-6 Alkyl (e.g., methyl), or mono- or di-C 1-6 Alkylamino (e.g., dimethylamino).

[0339] [Compound I-3]

[0340] Compound (I), wherein R 1 Yes: (1) C substituted with hydroxyl group by choice 1-6 Alkyl-carbonyl (e.g., methyl carbonyl), (2)C 3-6 cycloalkyl-carbonyl (e.g., cyclopropylcarbonyl), (3)C 1-6 Alkoxy-carbonyl (e.g., methoxycarbonyl, isopropoxycarbonyl), or (4) mono- or di-C 1-6 Alkyl-carbamoyl (e.g., ethylcarbamoyl);

[0341] R 2 Yes: (A) C substituted with 1 to 3 substituents selected from the following 3-6 Cycloalkyl (e.g., cyclohexyl): (1) C 1-6 Alkyl (e.g., isopropyl), and (2) C groups optionally substituted with 1 to 3 substituents selected from the following 6-14 Aryl (e.g., phenyl): a halogen atom (e.g., fluorine atom), C atoms optionally substituted with 1 to 3 halogen atoms (e.g., fluorine atom). 1-6 Alkyl (e.g., methyl) and C 1-6 Alkoxy (e.g., methoxy), or (B) a 3- to 6-membered saturated monocyclic non-aromatic heterocyclic group (e.g., piperidinyl) optionally substituted with 1 to 3 substituents selected from 5 to 14-membered aromatic heterocyclic groups (e.g., pyrimidinyl);

[0342] R 3 It is C 1-6 Alkyl (e.g., methyl), or di-C 1-6 Alkylamino (e.g., dimethylamino).

[0343] [Compound I-4]

[0344] Compound (I), which is the compound described above [7].

[0345] [Compound I-5]

[0346] Compound (I), wherein R 1 yes

[0347] (1) Hydrogen atom,

[0348] (2) C16 cells substituted with 1 to 7 substituents selected from the following groups. 1-6 Alkyl-carbonyl: (i) halogen atom, (ii) cyano group, (iii) hydroxyl group, (iv) C 3-10 Cycloalkyl, (v)C 1-6 Alkoxy, (vi)C 6-14 Aryl, (vii)C 6-14 aryloxy group, (viii) optionally substituted with an oxygen-substituted 5- to 14-membered aromatic heterocyclic group, (ix) optionally substituted with 1 to 3 carbon atoms 1-6 Alkyl-substituted 5- to 14-membered aromatic heterocyclic oxy groups, (x)C 1-6 Alkyl-carbonyl, (xi)C 1-6 Alkoxy-carbonyl, (xii)C 1-6 Alkyl-carbonyloxy group, (xiii)(xiv) mono- or di-C 1-6 Alkylamino, (xv)C 1-6 alkyl-carbonylamino, and (xvi)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino,

[0349] (3) Select one to three atoms chosen from halogen, cyano, hydroxyl, oxo, and C. 1-6 Alkyl substituents substituted C 3-10 cycloalkyl-carbonyl,

[0350] (4) Select 1 to 6 atoms chosen from deuterium, halogen atoms and C. 6-14 Aryl substituents substituted C 1-6 alkoxy-carbonyl,

[0351] (5) Select 1 to 3 from C. 1-6 Alkyl substituents substituted C 3-10 Cycloalkyloxy-carbonyl,

[0352] (6) Selected from 1 to 3 atoms chosen from halogen atoms and C 6-14 Aryl substituents substituted C 6-14 aryl-carbonyl,

[0353] (7)C 6-14 aryloxy-carbonyl,

[0354] (8) Select 1 to 3 from C. 1-6Alkyl substituents of 5- to 14-membered aromatic heterocyclic carbonyl groups,

[0355] (9) A 3- to 14-membered non-aromatic heterocyclic carbonyl group optionally substituted with 1 to 3 substituents selected from the following: oxo, C 1-6 alkyl-carbonyl, C 1-6 alkoxy-carbonyl and C 1-6 alkylsulfonyl,

[0356] (10) Selected from 1 to 3 atoms chosen from halogen atoms, cyano groups, hydroxyl groups, and C 1-6 Alkoxy substituents of single or double-C 1-6 alkyl-carbamoyl,

[0357] (11) Single or di-C 3-10 cycloalkyl-carbamoyl,

[0358] (12) Single or di-C 6-14 aryl-carbamoyl,

[0359] (13)C 1-6 alkylsulfonyl,

[0360] (14)C 3-10 Cycloalkylsulfonyl,

[0361] (15) C atoms that are substituted with 1 to 3 halogen atoms by choice 6-14 arylsulfonyl,

[0362] (16) Select 1 to 3 from C. 1-6 Alkyl substituents of heterocyclic groups - sulfonyl groups,

[0363] (17) Mono- or di-C 1-6 alkyl-aminosulfonyl, or

[0364] (18)C 1-6 alkyl-carbonyl-carbonyl;

[0365] R 2 It is C 3-6 Cycloalkyl or 3 to 6-membered saturated monocyclic nonaromatic heterocyclic groups, each optionally substituted by 1 to 3 substituents selected from the following:

[0366] (1) Deuterium,

[0367] (2) Halogen atoms,

[0368] (3) Hydroxyl group,

[0369] (4) Selected from 1 to 3 atoms chosen from halogen atoms and C 6-14 Aryl substituents substituted C 1-6 alkyl,

[0370] (5)C 3-10 cycloalkyl,

[0371] (6) Randomly select C 3-10 Cycloalkyl-substituted C 1-6 Alkoxy

[0372] (7) C16 cells substituted with 1 to 3 substituents selected from the following groups. 6-14 Aryl group: halogen atom, cyano group, C group optionally substituted with 1 to 3 halogen atoms 1-6 Alkyl groups, C atoms optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy and hydroxyl groups

[0373] (8)C 6-14 aryloxy,

[0374] (9) Tri-C 1-6 Alkylsilyloxy,

[0375] (10) Select 1 to 3 atoms chosen from halogen atoms, C 1-6 Alkyl and C 1-6 Alkoxy substituents substituted with 5 to 14 membered aromatic heterocyclic groups, and

[0376] (11)C 6-14 aryl-carbonyl;

[0377] R 3 It is C 1-6 Alkyl, mono- or di-C 1-6 Alkylamino.

[0378] [Compound I-6]

[0379] Compound (I), which is the compound described above [8].

[0380] [Compound I-7]

[0381] Compound (I), wherein R 1 yes

[0382] (1) Hydrogen atom,

[0383] (2) C16 cells substituted with 1 to 7 substituents selected from the following groups. 1-6 Alkyl-carbonyl: (i) halogen atom, (ii) cyano, (iii) hydroxyl, (iv) cyclopropyl, (v) C 1-6 Alkoxy, (vi) phenyl, (vii) phenoxy, (viii) pyrazolyl, thiazolyl, pyrimidinyl or pyridazinyl, each optionally substituted with an oxo group, and (ix) optionally substituted with one to three groups selected from C 1-6 Alkyl substituents of pyrazolyloxy groups, (x)C 1-6Alkyl-carbonyl, (xi)C 1-6 Alkoxy-carbonyl, (xii)C 1-6 Alkyl-carbonyloxy group, (xiii)C 1-6 alkylsulfonyl, (xiv) mono- or di-C 1-6 Alkylamino, (xv)C 1-6 Alkyl-carbonylamino, (xvi)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino,

[0384] (3) Cyclopropylcarbonyl, cyclobutyricyl, cyclopentanecarbonyl, or cyclohexylcarbonyl, each optionally composed of 1 to 3 atoms selected from halogen, cyano, hydroxyl, oxo, and C atoms. 1-6 Alkyl substituents,

[0385] (4) C atoms optionally substituted with 1 to 6 substituents selected from deuterium, halogen atoms and phenyl groups 1-6 alkoxy-carbonyl,

[0386] (5) Select 1 to 3 from C. 1-6 Alkyl substituents replace the cyclopropyloxycarbonyl group.

[0387] (6) A phenyl carbonyl group optionally substituted with 1 to 3 substituents selected from halogen atoms and phenyl groups,

[0388] (7) Phenoxycarbonyl,

[0389] (8) furanylcarbonyl, thiophenylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl or pyridylcarbonyl, each optionally surrounded by 1 to 3 carbon atoms. 1-6 Alkyl substitution,

[0390] (9) Azahexacyclic butylcarbonyl, oxacyclobutylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl or morpholinylcarbonyl, each optionally selected from 1 to 3 oxo, C 1-6 alkyl-carbonyl, C 1-6 alkoxy-carbonyl and C 1-6 Substitution of alkyl sulfonyl groups,

[0391] (10) Selected from 1 to 3 atoms chosen from halogen atoms, cyano groups, hydroxyl groups, and C 1-6 Alkoxy substituents of single or double-C 1-6 alkyl-carbamoyl,

[0392] (11) Cyclopropylcarbamoyl,

[0393] (12) Phenencarbamoyl group,

[0394] (13)C 1-6 alkylsulfonyl,

[0395] (14) Cyclopropylsulfonyl group,

[0396] (15) A benzenesulfonyl group optionally substituted with 1 to 3 halogen atoms

[0397] (16) Thiophenesulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridinylsulfonyl, or dihydrochromenylsulfonyl, each optionally surrounded by 1 to 3 carbon atoms. 1-6 Alkyl substitution,

[0398] (17) dimethylaminosulfonyl, or

[0399] (18)C 1-6 alkyl-carbonyl-carbonyl;

[0400] R 2 It is cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, piperidinyl, or dioxyl, each optionally substituted by 1 to 3 substituents selected from the following:

[0401] (1) Deuterium,

[0402] (2) Halogen atoms,

[0403] (3) Hydroxyl group,

[0404] (4) C14 atoms optionally substituted with 1 to 3 substituents selected from halogen atoms and phenyl groups 1-6 alkyl,

[0405] (5) Cyclohexyl,

[0406] (6) C substituted with cyclopropyl group by choice 1-6 Alkoxy

[0407] (7) A phenyl group optionally substituted with 1 to 3 substituents selected from the following: halogen atom, cyano group, C group optionally substituted with 1 to 3 halogen atoms. 1-6 Alkyl groups, C atoms optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy and hydroxyl groups

[0408] (8) Phenoxy,

[0409] (9) Tri-C 1-6 Alkylsilyloxy,

[0410] (10) pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl, or isoquinolinyl, each optionally composed of 1 to 3 atoms selected from halogen atoms, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups, and

[0411] (11) Benzoyl group;

[0412] R3 It is C 1-6 Alkyl, mono- or di-C 1-6 Alkylamino.

[0413] [Compound I-8]

[0414] Compound (I), which is the compound described above [9].

[0415] [Compound I-9]

[0416] Compound (I), which is the compound described above

[10] .

[0417] [Compound I-10]

[0418] Compound (I), wherein R 1 It is C 1-6 alkoxy-carbonyl;

[0419] R 2 It is a cyclohexyl group optionally substituted with a phenyl group; and

[0420] R 3 It is C 1-6 alkyl.

[0421] [Compound I-11]

[0422] Compound (I), wherein R 1 C is optionally substituted with a hydroxyl group 1-6 alkyl-carbonyl;

[0423] R 2 It is a cyclohexyl group optionally substituted with a phenyl group, wherein the phenyl group is optionally substituted with 1 to 3 halogen atoms;

[0424] R 3 It is C 1-6 alkyl.

[0425] [Compound I-12]

[0426] Compound (I), wherein R 1 Is it single or double-C? 1-6 alkyl-carbamoyl;

[0427] R 2 It is optional to be C 1-6 Alkyl-substituted cyclohexyl groups;

[0428] R 3 It is C 1-6 alkyl.

[0429] Specific examples of compound (I) include the compounds of Examples 1-372 below, wherein, preferably

[0430] (2R,3S)-N-ethyl-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)-3-((methanesulfonyl)amino)piperidine-1-carboxamide (Example 2),

[0431] N-((2R,3S)-1-acetyl-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (Example 4),

[0432] (2R,3S)-3-((methanesulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylic acid methyl ester (Example 5),

[0433] N-((2R,3S)-1-acetyl-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (Example 8),

[0434] (2R,3S)-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-((methanesulfonyl)amino)piperidine-1-carboxylic acid methyl ester (Example 11),

[0435] N-((2R,3S)-1-acetyl-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (Example 14),

[0436] N-((2R,3S)-1-(cyclopropylcarbonyl)-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (Example 16),

[0437] N-((2R,3S)-1-acetyl-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (Example 19)

[0438] (2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)-3-((methanesulfonyl)amino)piperidine-1-carboxylic acid methyl ester (Example 20),

[0439] N-((2R,3S)-1-acetyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (Example 22),

[0440] N-((2R,3S)-1-acetyl-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (Example 24),

[0441] N-((2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)-1-ethanolylpiperidin-3-yl)methanesulfonamide (Example 25),

[0442] N-((2R,3S)-1-(cyclopropylcarbonyl)-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (Example 28),

[0443] (2R,3S)-3-((dimethylaminosulfonyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)piperidin-1-carboxylic acid isopropyl ester (Example 29),

[0444] (2R,3S)-N-ethyl-3-((methanesulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxamide (Example 30),

[0445] N-((2R,3S)-1-(cyclopropylcarbonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (Example 31),

[0446] (2R,3S)-3-((methanesulfonyl)amino)-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidine-1-carboxylic acid methyl ester (Example 32),

[0447] N-((2R,3S)-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (Example 7),

[0448] N-((2R,3S)-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (Example 13),

[0449] N-(2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide (Example 15), and

[0450] N-((2R,3S)-1-ethanolacyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (Example 340).

[0451] As a salt of the compound represented by formula (I), a pharmaceutically usable salt is preferred. Examples of such salts include: salts formed with inorganic bases, salts formed with organic bases, salts formed with inorganic acids, salts formed with organic acids, salts formed with basic or acidic amino acids, and so on.

[0452] Preferred examples of salts that form with inorganic bases include: alkali metal salts, such as sodium salts, potassium salts, etc.; alkaline earth metal salts, such as calcium salts, magnesium salts, etc.; aluminum salts, ammonium salts, etc.

[0453] Preferred examples of salts formed with organic bases include salts formed with the following organic bases: trimethylamine, triethylamine, pyridine, methylpyridine, ethanolamine, diethanolamine, triethanolamine, aminobutanetriol [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, etc.

[0454] Preferred examples of salts formed with inorganic acids include salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.

[0455] Preferred examples of salts formed with organic acids include those formed with the following organic acids: formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.

[0456] Preferred examples of salts formed with basic amino acids include salts formed with the following basic amino acids: arginine, lysine, ornithine, etc.

[0457] Preferred examples of salts formed with acidic amino acids include salts formed with the following acidic amino acids: aspartic acid, glutamic acid, etc.

[0458] Compound (I) can be used in the form of a prodrug. A prodrug of compound (I) refers to a compound that can be converted into compound (I) of the present invention in an organism under physiological conditions due to reactions such as enzymes and gastric acid. That is, a compound that can be converted into compound (I) of the present invention through oxidation, reduction, hydrolysis, etc., depending on the type of enzyme; and a compound that can be converted into compound (I) of the present invention through hydrolysis, etc., due to gastric acid, etc., etc.

[0459] The prodrug of compound (I) may be: a compound obtained by acylation, alkylation, or phosphorylation of the amino group in compound (I) (e.g., compounds obtained by acylation, alanineylation, pentanoylation, (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)methoxycarbonylation, tetrahydrofuranylation, pyrrolidinyl methylation, neopentanoyloxy methylation, or tert-butylation of the amino group in compound (I); a compound obtained by acylation, alkylation, phosphorylation, or borylation of the hydroxyl group in compound (I) (e.g., compounds obtained by acetylation, browning, or hydroxylation of the hydroxyl group in compound (I)). Compounds obtained by palmitoylation, propionylation, neopentanoylation, succinylation, fumarate acylation, alanine acylation, or dimethylaminomethyl carbonylation, etc.; compounds obtained by esterification or amidation of the carboxyl group in compound (I) (e.g., compounds obtained by ethyl esterification, phenyl esterification, carboxymethyl esterification, dimethylaminomethyl esterification, neopentanoyloxymethyl esterification, ethoxycarbonyloxyethyl esterification, phthaloyl esterification, (5-methyl-2-oxo-1,3-dioxacyclopenten-4-yl)methyl esterification, cyclohexyloxycarbonylethyl esterification, and formamideation, etc.), etc. Any of these compounds can be prepared from compound (I) using methods known per se.

[0460] The prodrug of compound (I) may also be a compound that can be converted into compound (I) under physiological conditions, for example, those described in the following literature: IYAKUHIN no KAIHATSU (Development of Pharmaceuticals), Vol.7, Design of Molecules, pp.163-198, Published by HIROKAWASHOTEN (1990).

[0461] In this specification, the prodrug may form a salt, which may be one of the salts exemplified by the salts of the compounds represented by formula (I) above.

[0462] Isotopes can be used (e.g., 3 H, 13 C 14 C 18 F, 35 S, 125 I) and other labeled compounds (I).

[0463] Isotope-labeled or substituted compounds (I) can be used, for example, as tracers for positron emission tomography (PET) (PET tracers), and therefore, it can be used in fields such as medical diagnostics.

[0464] Furthermore, compound (I) can be a hydrate or a nonhydrate, a nonsolvent (e.g., a dehydrate), or a solvate (e.g., a hydrate).

[0465] Compound (I) also includes a deuterium inversion form, in which, 1 H transforms into 2 H(D).

[0466] Furthermore, compound (I) can be a pharmaceutically acceptable cocrystal or cocrystal salt. A cocrystal or cocrystal salt is a crystalline substance composed of two or more specific solids at room temperature, each solid having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). Cocrystals or cocrystal salts can be prepared using known co-crystallization methods.

[0467] The compound (I) or its precursor drug (hereinafter, sometimes simply referred to as the compound of the present invention) has low toxicity and can be used directly as a medicament for the prevention or treatment of various diseases mentioned below in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, monkeys), or mixed with a pharmaceutically acceptable carrier, etc., to form a pharmaceutical composition (also referred to as a drug).

[0468] As pharmaceutically viable carriers, a variety of organic or inorganic carrier substances commonly used as pharmaceutical materials can be used. For solid dosage forms, these carriers can be used as excipients, lubricants, binders, and disintegrants; for liquid dosage forms, they can be used as solvents, solubilizers, suspending agents, isotonic agents, buffers, and soothing agents; and so on; and as needed, pharmaceutical additives, such as preservatives, antioxidants, colorants, sweeteners, etc., can be added.

[0469] Preferred examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, gelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl cellulose, gum arabic, amylopectin, light anhydrous silicate, synthetic aluminum silicate, and magnesium aluminum silicate.

[0470] Preferred examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica.

[0471] Preferred examples of binders include gelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, amylopectin, hydroxypropylcellulose, hydroxypropyl methylcellulose, and polyvinylpyrrolidone.

[0472] Preferred examples of disintegrants include lactose, sucrose, starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, sodium carboxymethyl starch, light anhydrous silicate, and low-substituted hydroxypropyl cellulose.

[0473] Preferred examples of solvents include: water for injection, physiological saline, Ringer's solution, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil.

[0474] Preferred examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, triaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate.

[0475] Preferred examples of suspending agents include surfactants, such as stearoyl triethanolamine, sodium lauryl sulfonate, lauryl aminopropionate, lecithin, benzalkonium chloride, benzyl chloride, glyceryl monostearate, etc.; hydrophilic polymers, such as poly(vinyl alcohol), polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, etc.; polysorbates; and polyoxyethylene hydrogenated castor oil.

[0476] Preferred examples of isotonic agents include sodium chloride, glycerol, D-mannitol, D-sorbitol, and glucose, among others.

[0477] Preferred examples of buffers include buffers containing phosphates, acetates, carbonates, citrates, etc.

[0478] Preferred examples of placebos include benzyl alcohol.

[0479] Preferred examples of preservatives include parabens, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid.

[0480] Preferred examples of antioxidants include sulfites and ascorbic acid salts.

[0481] Preferred examples of colorants include: water-soluble edible tar pigments (e.g., food colorings, such as food colorings Red 2 and 3, food colorings Yellow 4 and 5, food colorings Blue 1 and 2, etc.), water-insoluble lake pigments (e.g., aluminum salts of the above-mentioned water-soluble edible tar pigments), natural dyes (e.g., beta-carotene, chlorophyll, iron oxide red), etc.

[0482] Preferred examples of sweeteners include sodium saccharin, dipotassium glycyrrhizate, aspartame, and sage.

[0483] Examples of dosage forms for the aforementioned pharmaceutical compositions include: oral formulations, such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets), capsules (including soft capsules, microcapsules), granules, powders, lozenges, syrups, emulsions, suspensions, films (e.g., orally disintegrating films), etc.; parenteral formulations, such as injections (e.g., subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, intravenous infusion), topical formulations (e.g., epidermal formulations, ointments), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal formulations, pulmonary formulations (inhalers), eye drops, etc., which can be safely administered orally or parenterally (e.g., topically, rectally, or intravenously).

[0484] These formulations can be controlled-release formulations (e.g., sustained-release microcapsules), such as immediate-release formulations, sustained-release formulations, and so on.

[0485] Pharmaceutical compositions can be prepared according to methods commonly used in the field of pharmaceutical formulation, such as those described in Japanese Pharmacopoeia, etc.

[0486] The content of the compound of the present invention in the pharmaceutical composition of the present invention varies depending on the dosage form, the dosage of the compound of the present invention, etc., for example, from about 0.1 to 100 wt%.

[0487] When preparing oral formulations, coating may be used when necessary to mask taste, enteric properties, or persistence.

[0488] Examples of coating base materials include: sugar coating base materials, water-soluble film coating base materials, enteric film coating base materials, and sustained-release film coating base materials.

[0489] For the coating base, sucrose is used, and one or more base materials selected from talc, precipitated calcium carbonate, gelatin, gum arabic, amylopectin, gallopa wax, etc. can be further combined.

[0490] Examples of water-soluble film coating base materials include: cellulose polymers, such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, etc.; synthetic polymers, such as polyvinyl acetal diethylaminoethyl ester, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone, etc.; and polysaccharides, such as amylopectin, etc.

[0491] Examples of enteric film coating base materials include: cellulose polymers, such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, etc.; acrylic polymers, such as methacrylic acid copolymer L [Eudragit L (trademark name)], methacrylic acid copolymer LD [Eudragit L-30D55 ​​(trademark name)], methacrylic acid copolymer S [Eudragit S (trademark name)], etc.; and naturally occurring substances, such as film, etc.

[0492] Examples of sustained-release film coating base materials include: cellulose polymers, such as ethyl cellulose, etc.; and acrylic polymers, such as aminoalkyl methacrylate copolymer RS ​​[Eudragit RS (trademark name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trademark name)], etc.

[0493] Two or more of the aforementioned coating base materials can be used in a mixture in appropriate proportions. Additionally, during coating, for example, light-shielding agents such as titanium dioxide, red iron oxide, etc., can be used.

[0494] Because the compounds of this invention have low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and few side effects, they can be used as preventive or therapeutic agents or diagnostic agents for various diseases in mammals (e.g., humans, cattle, horses, dogs, cats, monkeys, mice, rats).

[0495] Appetite peptide type II receptors are involved in many biological functions. Thus, we can hypothesize that these receptors play a role in various disease processes in humans or other species. The compounds of this invention can be used to treat, prevent, or improve the risk of one or more symptoms or diseases of various neurological and psychiatric disorders associated with one or more or more appetite peptide type II receptors. These symptoms and diseases are: narcolepsy, spontaneous somnolence, hypersomnia, sleep aphasia, narcolepsy syndrome with narcolepsy symptoms, and narcolepsy syndrome with daytime sleepiness (e.g., Kleine). Levin syndrome, severe depression with somnolence, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, facial nerve nucleus hypoplasia, pulmonary hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, acute disseminated encephalomyelitis, acute infectious polyneuritis, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy, coma, loss of consciousness, obesity (e.g., malignant mastocytosis), Exogenous obesity, hyperpancreatic obesity, protoplasmic hyperplasia obesity, pituitary fat hyperplasia, protoplasmic hypoplasia obesity, hypothyroidism obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, diet-related obesity, hypogonadism obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, altered consciousness (e.g., coma), etc., side effects and complications of anesthesia, sleep disorders, sleep problems, insomnia, intermittent sleep, nocturnal myoclonus, REM sleep apnea, jet lag syndrome, time lag syndrome Sleep disorders, including those associated with combination therapies, alternating work schedules, sleep disturbances, night terrors, depression, major depressive disorder, somnambulism, enuresis, Alzheimer's disease, circadian rhythm disorders, fibromyalgia, symptoms caused by poor sleep quality, binge eating, compulsive eating disorders, obesity-related disorders, hypertension, diabetes, elevated plasma insulin levels and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, cancer, osteoarthritis, obstructive sleep apnea, gallstones, heart disease, abnormal heartbeats, and arrhythmias. Myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disease, sudden death, polycystic ovary syndrome, craniopharingioma, Prader-Willi syndrome, Froelich's syndrome, growth hormone deficiency, normal-mutant short stature, Turner's syndrome, childhood acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, decreased male gonadal function, sexual and reproductive dysfunction, such as female hirsutism, fetal defects associated with maternal obesity, gastrointestinal motility disorders.For example, obesity-related gastroesophageal reflux, obesity-related hypoventilation syndrome (Pickwick syndrome), respiratory diseases such as asthma, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, the risk of secondary consequences of obesity such as a reduced risk of left ventricular hypertrophy, migraines, headaches, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweats, diseases of the reproductive / urinary system, diseases related to sexual function or fertility, symptoms of depression, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclic psychosis, acute stress disorder, agoraphobia, generalized psychosis, etc. Sexual anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorder, acute neurological and psychiatric disorders, such as brain defects after cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic nerve injury, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, cognitive impairment, muscle spasms, tremor, epilepsy, disorders related to muscle rigidity, mental confusion, amnesia, age-related cognitive decline, schizophrenia, paranoia, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, drug-induced Parkinson's syndrome, Jill-Do La Tourette's syndrome, chorea, myoclonus, spasticity, restless legs syndrome, dystonia, movement disorders, attention deficit hyperactivity disorder (ADHD), behavioral disorders, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, arthralgia, toothache, sudden falls, and traumatic brain injury (TBI).

[0496] In particular, the compounds of the present invention can be used as therapeutic or preventive agents for narcolepsy, spontaneous narcolepsy, somnolence, sleep-apnea syndrome, narcolepsy syndrome with narcolepsy symptoms, narcolepsy syndrome with daytime sleepiness (e.g., Parkinson's disease, acute infectious polyneuritis and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, altered consciousness (e.g., coma, etc.), anesthetic side effects and complications, etc., or as antagonists of anesthetics.

[0497] The dosage of the compounds of the present invention varies depending on the patient, route of administration, targeted disease, symptoms, etc. For example, when the compounds of the present invention are administered orally or parenterally to adult patients, the dosage is, for example, approximately 0.01 to 100 mg / kg body weight per dose, preferably 0.1 to 50 mg / kg body weight per dose, and more preferably 0.5 to 20 mg / kg body weight per dose. Preferably, this amount is administered in the form of 1 to 3 doses per day.

[0498] The compounds of this invention can be used in combination with other drugs (hereinafter referred to as synergistic drugs). The combination of the compounds of this invention with synergistic drugs can achieve the following excellent effects, for example:

[0499] (1) Compared with administering the compound of the present invention alone or in combination with other drugs, the dosage can be reduced.

[0500] (2) Depending on the patient's condition (mild, severe, etc.), a combination drug with the compound of the present invention can be selected.

[0501] (3) By selecting concomitant drugs with different effects and mechanisms of action than the compounds of this invention, a longer course of treatment can be established.

[0502] (4) By selecting drugs with different effects and mechanisms of action than the compounds of the present invention, sustained therapeutic effects can be designed.

[0503] (5) Synergistic effects can be obtained by using the compounds of the present invention in combination with drugs, etc.

[0504] In this specification, the compounds of the present invention used in combination with other drugs are referred to as "the combination drugs of the present invention".

[0505] When using the combination drugs of the present invention, there are no restrictions on the timing of administration of the compounds of the present invention and the combined drugs. The patient may be given the compounds of the present invention or their pharmaceutical compositions and the combined drugs or their pharmaceutical compositions simultaneously, or they may be administered at different times. The dosage of the combined drugs may be determined based on clinically used dosages and may be appropriately selected according to the patient being treated, the route of administration, the disease, the combination, etc.

[0506] There are no particular limitations on the administration mode of the combination drugs and concurrent drugs of the present invention, as long as the compounds of the present invention and concurrent drugs are administered together at the same time. Examples of such administration modes include the following:

[0507] (1) administering a single formulation obtained by simultaneously processing the compound of the present invention and the medicament thereof; (2) administering two formulations of the compound of the present invention and the medicament thereof prepared separately via the same route of administration; (3) administering two formulations of the compound of the present invention and the medicament thereof prepared separately via the same route of administration in an alternating manner; (4) administering two formulations of the compound of the present invention and the medicament thereof prepared separately via different routes of administration; (5) administering two formulations of the compound of the present invention and the medicament thereof prepared separately via different routes of administration in an alternating manner (e.g., administering in the order of the compound of the present invention and the medicament thereof, or in the reverse order); etc.

[0508] The dosage of the concurrent drugs can be appropriately determined based on the dosage used in clinical situations. The mixing ratio of the compounds of the present invention and the concurrent drugs can be appropriately determined according to the patient being treated, the route of administration, the targeted disease, the symptoms, the combination drugs, etc.

[0509] For example, based on the entire formulation, the content of the compound of the present invention in the combination drug of the present invention varies depending on the formulation form, and is generally from about 0.01 to about 100 wt%, preferably from about 0.1 to about 50 wt%, and more preferably from about 0.5 to about 20 wt%.

[0510] Based on the entire formulation, and the content of the drug in the combination drug of the present invention varies depending on the form of the formulation, it is generally from about 0.01 to about 100 wt%, preferably from about 0.1 to about 50 wt%, and more preferably from about 0.5 to about 20 wt%.

[0511] The content of additives (e.g., carriers, etc.) in the combination drug of the present invention varies depending on the formulation, and is typically from about 1 to about 99.99 wt%, preferably from about 10 to about 90 wt%, based on the formulation.

[0512] When the compounds of the present invention are formulated independently and in combination with pharmaceuticals into a formulation, similar amounts can be used.

[0513] Examples of combined medications include, but are not limited to, the following: Medications for treating narcolepsy (e.g., methylphenidate, amphetamine, pemeridine, phenelzine, protriptyline, sodium oxybutyrate, modafinil, caffeine); Anti-obesity drugs (amphetamine, benzphenamine, bromocriptine, bupropion, amphetamine, exenatide, fenfluramine, triiodothyronine, liraglutide, chlorpheniramine, deoxyephedrine, octreotide, octreotide, orlistat, benzoylmorpholine, benzoylmorpholine, phenmethoxyline, phenbutylamine, Qnexa (registered trademark), phenacetin. Alkylamines, pramlinide, hexahydrodeoxyephedrine, recombinant leptin, sibutramine, topiramate, zimeridine, zonisamide, lorcaserin, metformin), acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, zanapezil, idebenone, tacrine), antidementia agents (e.g., memantine), inhibitors of β-amyloid production, secretion, accumulation, aggregation and / or deposition, β-secretase inhibitors (e.g., 6... -(4-Biphenyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene, 6-(4-biphenyl)methoxy-2-(N,N-dimethylamino)methyltetrahydronaphthalene, 6-(4-biphenyl)methoxy-2-(N,N-dipropylamino)methyltetrahydronaphthalene, 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)methoxytetrahydronaphthalene, 6-(4-biphenyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetrahydronaphthalene, 2-[2-(N,N-dimethylamino)ethyl]-6 -(4'-methylbiphenyl-4-yl)methoxytetrahydronaphthalene, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetrahydronaphthalene, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene, 6-[4-(1,3-benzodioxane-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetrahydronaphthalene,[N-Dimethylamino]ethyl]tetrahydronaphthalene, its optical form, its salt and its hydrate, OM99-2(WO01 / 00663)), γ-secretase inhibitors, β-amyloid aggregation inhibitors (e.g., PTI-00703, ALZHEMED(NC-531), PPI-368 (National Publication of International Patent Application No. 11-514333), PPI-558 (National Publication of International Patent Application No. 11-514333), PPI-558 (National Publication of International Patent Application No. 11-514333), PPI-558). No. 2001-500852), SKF-74652 (Biochem.J.(1999), 340(1), 283-289), β-amyloid vaccine, β-amyloid depressant enzyme, etc., brain function enhancers (e.g., piracetam, ergot bromonic ester), Parkinson's disease treatment drugs [(e.g., dopamine receptor agonists (e.g., L-DOPA, bromocriptine, pergolide, talipexole, pramipexole, cabergoline)]. Amyotrophic lateral sclerosis (ALS) treatments include: amantadine, monoamine oxidase (MAO) inhibitors (e.g., propyne, selegiline, remacemide, riluzole), anticholinergic agents (e.g., trihexyphenidyl, biperidone), COMT inhibitors (e.g., entacapone), medications for ALS (e.g., riluzole, etc.), neurotrophic factors, and medications for treating abnormal behaviors associated with progressive dementia, confusion, etc. For example, sedatives, anxiolytics, cell programmed death inhibitors (e.g., CPI-1189, IDN-6556, CEP-1347), neuronal differentiation (regeneration promoters (e.g., leteprinim, xaliproden; SR-57746-A), SB-216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-penta] [Methyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isodihydroindole, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isodihydroindole, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxacyclopentenyl[4,[5-F] Isoindole, and its optically active forms, salts or hydrates), nonsteroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, indomethacin, etc.), steroid drugs (dexamethasone, diethylstilbestrol, cortisone acetate, etc.), disease-modifying antirheumatic drugs (DMARDs), anticytokine drugs (e.g., TNF inhibitors, MAP kinase inhibitors), treatments for incontinence and urinary frequency (e.g., flavoxate hydrochloride, hydroxybutyrate hydrochloride, propivapine hydrochloride), phosphodiesterase inhibitors (e.g., sildenafil (citrate)), dopamine agonists (e.g., apomorphine), antiarrhythmic drugs (e.g., bradycardia), sex hormones or their derivatives (e.g., progesterone, estradiol, phenylestradiol), treatments for osteoporosis (e.g., alfacalcidol, calcitriol, calcitonin, calcitonin histone). Salmon), estriol, eprafenone, pamidronate disodium, alendronate sodium hydrate, incardron disodium), parathyroid hormone (PTH), calcium receptor antagonists, medications for insomnia (e.g., benzodiazepines, non-benzodiazepines, melatonin agonists, appetite peptide receptor antagonists), medications for schizophrenia (e.g., typical antipsychotics, such as haloperidol, etc.; atypical antipsychotics, such as clozapine, olanzapine, risperidone, aripiprazole, etc.; drugs acting on metabotropic synaptic receptors or ion channel conjugated synaptic receptors; phosphodiesterase inhibitors), benzodiazepines (Librium, diazepam, loratadine potassium, chlordiazepoxide, clonazepam, alprazolam, etc.), L-type calcium channel inhibitors (pregabalin) Tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (flupentixol maleate, fluoxetine hydrochloride, citalopram hydrobromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-norepinephrine reuptake inhibitors (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), norepinephrine reuptake inhibitors (reboxetine mesylate, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT, 1A Agonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT 2A Antagonists, 5-HT 2AReverse agonists, 5-HT3 antagonists (cyanemazine, etc.), cardiac non-selective β inhibitors (propranolol hydrochloride, metoprolol hydrochloride, etc.), histamine H1 antagonists (hydroxyzine hydrochloride, etc.), CRF antagonists, other anxiolytics (tranexamic acid, etc.), tachykinin antagonists (MK-869, saredutant, etc.), drugs acting on metabolite synolate receptors, CCK antagonists, β3-adrenergic antagonists (amibegron hydrochloride, etc.), GAT-1 inhibitors (tiagabine hydrochloride, etc.), N-type calcium channel inhibitors, carbonic anhydrase II inhibitors, NMDA glycine partial agonists, NMDA antagonists (metamethasone, etc.). Targeted therapies include: benzodiazepine receptor agonists, antidiuretic hormone antagonists, antidiuretic hormone V1b antagonists, antidiuretic hormone V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, niacin receptor agonists, thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenylethylhydrazine sulfate, transphenylcyclopropane sulfate, moclobemide, etc.), COMT inhibitors (entacapone, etc.), medications for bipolar disorder (lithium carbonate, sodium valproate, levamisole, riluzole, felbamate, etc.), cannabinoid CB1 antagonists (rimonaban, etc.), FAAH inhibitors, sodium channel inhibitors, etc. Anti-ADHD medications (methylphenidate hydrochloride, ephedrine hydrochloride, etc.), medications for alcoholism, autism, chronic fatigue syndrome, spasms, fibromyalgia syndrome, headaches, smoking cessation, myasthenia gravis, cerebral infarction, mania, drowsiness, pain, dysphoria, autonomic nervous system dysfunction, male and female sexual dysfunction, migraines, pathological gamblers, restless legs syndrome, substance addiction, alcohol-related syndromes, irritable bowel syndrome. Treatments include medications for ALS (riluzole, etc., neurotrophic factors, etc.), medications for lipid disorders such as cholesterol-lowering drugs (statins (pravastatin sodium, atorvastatin, sivastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthase inhibitors), medications for abnormal behavior or dementia-induced apathy (sedatives, anti-anxiety drugs, etc.), anti-obesity drugs, medications for diabetes, medications for diabetic complications, medications for hypertension, medications for hypotension, diuretics, chemotherapy agents, immunotherapy agents, antithrombotic agents, anticancer agents, etc.

[0514] Two or more of the above-mentioned drugs can be used in a mixture in appropriate proportions.

[0515] When the compounds of the present invention are applied to each of the above-mentioned diseases, they can also be used in combination with biological agents (e.g., antibody drugs, nucleic acids or nucleic acid derivatives, aptamer drugs, vaccine preparations), or in combination with gene therapy methods, etc., as combination therapy, or in combination with treatment methods in the field of mental illness that do not use drugs.

[0516] Examples of antibody and vaccine formulations include: vaccines against angiotensin II, vaccines against CETP, CETP antibodies, antibodies against TNFα and other cytokines, amyloid-β vaccines, type 1 diabetes vaccines (e.g., Peptor's DIAPEP-277), anti-HIV antibodies and HIV vaccines, as well as antibodies or vaccines against cytokines, renin-angiotensinase and its products, antibodies or vaccines against enzymes or proteins involved in lipid metabolism, antibodies or vaccines related to enzymes and proteins involved in blood coagulation or fibrinolysis, antibodies or vaccines against proteins involved in glucose metabolism or insulin resistance, and so on. Additionally, they can be used in combination with growth factor-related biologics, such as GH, IGF, etc.

[0517] Examples of gene therapy methods include: treatments using genes related to cytokines, renin-angiotensinase and its products, G proteins, G protein conjugate receptors and their phosphorylases; treatments using DNA decoys (e.g., NFκB decoys, etc.); treatments using antisense genes; treatments using genes related to enzymes or proteins involved in lipid metabolism (e.g., genes related to the metabolism, excretion or absorption of cholesterol or triglycerides or HDL-cholesterol or blood phospholipids); treatments using genes related to enzymes or proteins involved in the formation of blood vessels involved in peripheral vascular occlusion (e.g., growth factors, such as HGF, VEGF, etc.); treatments using genes related to proteins involved in glucose metabolism or insulin resistance, antisense cytokines (e.g., TNF, etc.); and so on.

[0518] Examples of non-pharmacological treatments in the field of psychiatry include: modified electroconvulsive therapy, deep brain stimulation therapy, repetitive transcranial magnetic stimulation therapy, and psychotherapy including cognitive behavioral therapy, among others.

[0519] It can also be used in combination with various organ regeneration methods, such as heart regeneration, kidney regeneration, pancreas regeneration, blood vessel regeneration, etc., or in combination with cell transplantation therapy using bone marrow cells (bone marrow-derived mononuclear cells, bone marrow-derived stem cells), or in combination with tissue-designed artificial organs (e.g., artificial blood vessels, cardiomyocyte layers).

[0520] The compounds of the present invention can be administered orally, parenterally (e.g., intramuscular, intraperitoneal, intravenous, arterial, intraventricular, intracisional, or intravenous infusion; subcutaneous injection; or implantation), or via local routes such as inhalation sprays, intratracheal, nasal, vaginal, rectal, sublingual, subcutaneous, transdermal, and ocular drops. Therefore, they contain pharmaceutically acceptable, non-toxic carriers, adjuvants, and excipients suitable for each route of administration. In addition to treating homeothermic animals, such as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc., the compounds of the present invention can be effectively used in humans.

[0521] Unit dosage forms of pharmaceutical compositions for administering the compounds of the present invention can be suitably obtained and can be prepared by any method well known in the pharmaceutical industry. All methods involve the step of mixing the active ingredient with one or more carriers constituting the adjuvant component. Typically, a pharmaceutical composition can be prepared by uniformly and completely mixing the active ingredient with a liquid carrier or a ground solid carrier, or both, and then molding the product into a desired dosage form as needed. In a pharmaceutical composition, the amount of active compound included is sufficient to produce the desired effect for the course or symptoms of a disease. The term "composition" as used herein encompasses products including a specified amount of a particular component, and all products are obtained directly or indirectly from a combination of specified amounts of the particular component.

[0522] Orally administered pharmaceutical compositions can be prepared according to any method known in the art related to the preparation of pharmaceutical compositions. To provide a formulation with pharmaceutically high quality and a good taste, such compositions may contain one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives. Tablets contain an active ingredient mixed with a pharmaceutically acceptable, non-toxic excipient suitable for tablet preparation. These excipients may be, for example, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, sodium phosphate, etc.; granulating and disintegrants such as corn starch, alginic acid, etc.; binders such as starch, gelatin, gum arabic, etc.; lubricants such as magnesium stearate, stearic acid, talc, etc. Tablets may be uncoated tablets, or they may be coated using known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a prolonged duration of action. Compositions for oral use can also be provided in hard capsule form, in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate, and kaolin), or in soft capsule form, in which the active ingredient is mixed with an aqueous or oil medium (e.g., peanut oil, liquid paraffin, and olive oil). Aqueous suspensions contain a mixture of the active substance and excipients suitable for preparing the suspension. Oily suspensions can be formulated by suspending the active ingredient in a suitable oil. Oil-in-water emulsions can also be used. Dispersible powders and granules suitable for preparing aqueous suspensions (with added water) can provide a mixture of the active ingredient with a dispersant or wetting agent, a suspending agent, and one or more preservatives. Pharmaceutical compositions of the compounds of the present invention can be in the form of sterile injectable aqueous suspensions or oily suspensions. The compounds of the present invention can also be administered in the form of suppositories for rectal administration. For topical use, creams, ointments, gels, solutions, suspensions, etc., containing the compounds of the present invention can be used. The compounds of the present invention can also be formulated for inhalation administration. The compounds of the present invention can also be administered via transdermal membranes prepared according to methods known in the art.

[0523] Various methods for preparing the compound (I) of the present invention or its salt (hereinafter simply referred to as compound (I)) have been investigated, and representative examples are shown in the following reaction route 1. In the explanation of the following preparation method, the starting compound and its reaction products can form a salt that does not hinder the reaction.

[0524] For example, compound (I) is prepared by the method shown in reaction route 1 below.

[0525] (Reaction Route 1)

[0526]

[0527] Among them, R 5 It was R 3 The substituted carbonyl or sulfonyl group, and other symbols as described above.

[0528] For the starting compound (II), for example, a purchased compound, or a compound that is known by way of preparation, or a compound prepared by a method similar to its preparation method (e.g., Organic Letters 2008, V10(13), 2701-2704, etc.) can be used.

[0529] Step 1 can be performed by methods already known or similar. For example, alkylation reactions can be used (e.g., SRSandler and W. Karo, Organic Functional Group Preparations I, 2nd ed., Academic Press, 1983, Chapter 13), etc.

[0530] For step 2, for example, methods that are already known can be used (e.g., Journal of Organic Chemistry, 77(16), 6908-6916; 2012, etc.), etc.

[0531] Step 3 shows the reaction of compound (IV) with sulfonyl chloride, acyl chloride or isocyanate in the presence of a base to prepare compound (V).

[0532] For the base, organic bases (e.g., triethylamine, pyridine, diethylisopropylamine, sodium methoxide, sodium ethoxide, etc.), inorganic bases (e.g., sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, sodium hydride, metallic sodium, etc.) are used. The amount of base used per 1 mol of compound (IV) is typically 1 to 10 mol, preferably 1 to 3 mol. For the type of base, organic bases are preferred, particularly triethylamine, pyridine, diethylisopropylamine, etc., with pyridine being especially preferred.

[0533] Preferably, the reaction can be carried out in a solvent. Suitable solvents include hydrocarbons (e.g., pentane, hexane, cyclohexane, benzene, toluene, etc.), ethers (e.g., diethyl ether, tetrahydrofuran, dioxane, etc.), amides (e.g., N,N-dimethylformamide, hexamethylphosphotriamide, etc.), halogenated hydrocarbons (e.g., dichloromethane, chloroform, etc.), sulfoxides (e.g., dimethyl sulfoxide, etc.), ureas (e.g., 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidine), etc. When the above-mentioned organic base is a liquid (e.g., triethylamine, pyridine, diethylisopropylamine, etc.), it can also be used as a solvent. These solvents can be used alone, or two or more of these solvents can be mixed in suitable proportions and used. The amount of solvent used per 1g of compound (IV) is typically 1 to 100 ml, preferably 5 to 20 ml. The reaction temperature is typically from -20°C to the boiling point of the solvent used in the reaction, preferably 0°C to 60°C. The reaction time varies depending on the type and amount of alkali used, ranging from 10 minutes to 3 days, preferably from 1 hour to 24 hours.

[0534] For example, step 4 can be performed according to methods that are already known (e.g., Organic Letters 2011, V13(10), 2564-2567, etc.).

[0535] For example, step 5 can be performed using a known method (e.g., WO 2011119541 A1, etc.).

[0536] Step 6 can be performed using methods that are already known (e.g., SRSandler and W. Karo, Organic Functional Group Preparations II, 2nd ed., Academic Press, 1989, Chapter 6, etc.).

[0537] In the resulting compound (VII), functional groups within the molecule can be transformed into target functional groups through combinations of previously known chemical reactions. Examples of such chemical reactions include oxidation, reduction, alkylation, acylation, ureation, hydrolysis, amination, esterification, aryl coupling, deprotection, and so on.

[0538] In the above preparation method, when the raw material compound has amino, carboxyl, hydroxyl, carbonyl or thiol groups as substituents, the protecting groups commonly used in peptide chemistry can be incorporated into these groups, and after the reaction, the protecting groups can be removed as needed to obtain the target compound.

[0539] Examples of protecting groups for amino groups include: formyl group, C... 1-6alkyl-carbonyl, C 1-6 Alkoxy-carbonyl, benzoyl, C 7-10 Aryl alkyl-carbonyl (e.g., benzyl carbonyl), C 7-14 Arylalkoxy-carbonyl (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), triphenylmethyl, phthaloyl, N,N-dimethylaminomethylene, substituted silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 Alkenyl (e.g., 1-allyl), etc. These groups can have one to three atoms selected from halogen atoms, C, etc. 1-6 Substitution of alkoxy and nitro groups.

[0540] Examples of protecting groups for carboxyl groups include: C 1-6 Alkyl, C 7-10 Aryl (e.g., benzyl), phenyl, triphenylmethyl, substituted silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 Alkenyl (e.g., 1-allyl), etc. These groups can have one to three atoms selected from halogen atoms, C, etc. 1-6 Substitution of alkoxy and nitro groups.

[0541] Examples of protecting groups for hydroxyl groups include: C 1-6 Alkyl, phenyl, triphenylmethyl, C 7-10 Aryl (e.g., benzyl), formyl, C 1-6 Alkyl-carbonyl, benzoyl, C 7-10 Arylalkyl-carbonyl (e.g., benzylcarbonyl), 2-tetrahydropyranyl, 2-tetrahydrofuranyl, substituted silyl (e.g., trimethylsilyl, triethylsilyl, dimethylphenylsilyl, tert-butyldimethylsilyl, tert-butyldiethylsilyl), C 2-6 Alkenyl (e.g., 1-allyl), etc. These groups can have one to three atoms selected from halogen atoms, C, etc. 1-6 Alkyl, C 1-6 Substitution of alkoxy and nitro groups.

[0542] Examples of carbonyl protecting groups include: cyclic acetals (e.g., 1,3-dioxane), acyclic acetals (e.g., di-C... 1-6 Alkyl acetals, etc.

[0543] Examples of protecting groups for thiol groups include: C 1-6 Alkyl, phenyl, triphenylmethyl, C 7-10 Aryl alkyl (e.g., benzyl), C 1-6Alkyl-carbonyl, benzoyl, C 7-10 Aryl alkyl-carbonyl (e.g., benzyl carbonyl), C 1-6 Alkoxy-carbonyl, C 6-14 Aryloxy-carbonyl (e.g., phenoxycarbonyl), C 7-14 Aryl alkoxy-carbonyl (e.g., benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl), 2-tetrahydropyranyl, C 1-6 Alkylamino-carbonyl (e.g., methylaminocarbonyl, ethylaminocarbonyl), etc. These groups can have one to three atoms selected from halogen atoms, C... 1-6 Alkyl, C 1-6 Substitution of alkoxy and nitro groups.

[0544] The protecting group can be removed using a known deprotection reaction.

[0545] The compound (I) obtained by the above preparation method can be separated and purified using known methods, such as solvent extraction, liquid conversion, phase transfer, crystallization, recrystallization, chromatography, etc.

[0546] When compound (I) includes optical isomers, stereoisomers, regioisomers, or rotational isomers, these compounds are also included within the scope of compound (I), and their individual products can be obtained using known synthetic and separation methods. For example, when an optical isomer is present in compound (I), the optical isomers resolved from that compound are also included within the scope of compound (I).

[0547] In this paper, the optical isomers can be prepared using methods that are already known.

[0548] Compound (I) can be a crystal.

[0549] Crystals of compound (I) can be prepared by crystallizing compound (I) using known crystallization methods (hereinafter, sometimes abbreviated as crystals of the present invention).

[0550] The crystals of the present invention have superior physicochemical properties (e.g., melting point, solubility, stability) and biological characteristics (e.g., pharmacokinetic properties (absorption, distribution, metabolism, excretion), effect expression), and are therefore very suitable for use as medicines. [Example]

[0551] The present invention will now be explained in detail with reference to the embodiments, experimental embodiments, and formulation embodiments. However, these embodiments do not limit the present invention, and modifications may be made within the scope of the present invention.

[0552] In the examples below, "room temperature" is typically from about 10°C to about 35°C. Unless otherwise stated, the proportions of the mixed solvents are volume-mixed proportions, and % refers to wt%, unless otherwise stated.

[0553] Unless otherwise specified, in these examples, column chromatography elution is performed by observing TLC (thin-layer chromatography). During the TLC observation, Merck's 60F... 254 The solvent used as the eluent in TLC plates and column chromatography is used as the eluent, and a UV detector is used for detection. In silica gel column chromatography, NH refers to silica gel bonded with aminopropylsilane, and Diol refers to silica gel bonded with 3-(2,3-dihydroxypropoxy)propylsilane. In preparative HPLC (high performance liquid chromatography), C18 refers to silica gel bonded with octadecyl groups. The eluent ratio is a volume-mixing ratio unless otherwise specified.

[0554] In the following embodiments, the following abbreviations are used.

[0555] THF: Tetrahydrofuran, DMSO: Dimethyl sulfoxide, DME: 1,2-Dimethoxyethane, IPE: Isopropyl ether, PdCl 2( dppf)∶1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride, NMP∶1-methyl-2-pyrrolidone, MPa∶megapascal, psi∶psi, CDCl3∶deuterated chloroform, DMSO-d6∶deuterated dimethyl sulfoxide

[0556] 1 1H NMR (proton nuclear magnetic resonance) is measured using Fourier transform NMR. For analysis 1 ¹H NMR, using ACD / SpecManager (trademark name) software, etc. Sometimes, very light proton peaks of hydroxyl, amino, etc., are not described.

[0557] MS (mass spectrometry) was determined by LC / MS (liquid chromatography-mass spectrometry). As an ionization method, ESI (electrospray ionization) or APCI (atmospheric pressure chemical ionization) was used. The data represent the measured values. Molecular ion peaks are usually observed, and fragment ion peaks are sometimes observed. In the case of salts, peaks of free molecular ion or fragment ion peaks are usually observed. Powder X-ray diffraction peaks refer to peaks measured at room temperature using Cu Kα-rays as the radiation source, using Ultima IV (Rigaku Corporation, Japan). Measurement conditions are as follows.

[0558] Voltage / Current: 40kV / 50mA

[0559] Scanning speed: 6 degrees / minute

[0560] 2θ scan range: 2-35 degrees

[0561] The crystallinity of the examples was calculated using powder X-ray diffraction using the Hermans method.

[0562] Example 1

[0563] N-(cis-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0564] A) 3-Bromo-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)pyridine

[0565] At room temperature, cis-4-isopropylcyclohexanol (19.91 g) was added to a suspension of 60% sodium hydride (7.00 g) in THF (80 mL). The reaction mixture was stirred overnight at room temperature, and 3-bromo-2-(bromomethyl)pyridine (17.56 g) was added to the reaction mixture, which was then stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by NH4Cl chromatography to give the title compound (17.30 g).

[0566] MS, measured values: 312.2, 314.2.

[0567] B)N-(2-(((cis-4-isopropylcyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

[0568] A mixture of 3-bromo-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)pyridine (3.0 g), methanesulfonamide (1.097 g), di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (0.408 g), tris(dibenzylacetone)dipalladium(0) (0.440 g), cesium carbonate (4.70 g), and THF (40 mL) was stirred at 120 °C for 20 minutes under heating and microwave irradiation. The reaction mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (2.310 g).

[0569] MS, measured value: 327.3.

[0570] C)N-(cis-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0571] A mixture of N-(2-(((cis-4-isopropylcyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide (2.285 g), platinum oxide (0.079 g), methanol (15 mL), and acetic acid (15 mL) was stirred overnight at 50 °C under a hydrogen atmosphere of 0.6 MPa. The mixture was filtered, and the filtrate was neutralized with a saturated aqueous sodium bicarbonate solution at 0 °C and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by NH4Cl chromatography to give the title compound (1.630 g).

[0572] 1 H NMR(300MHz, CDCl3)δ0.78-0.90(6H,m),0.96-1.15(1H,m),1.20-1.48(8H,m),1. 48-1.77(9H,m),1.79-1.90(2H,m),1.91-2.03(1H,m),2.67(1H,td,J=11.8,2.8H z),2.86(1H,ddd,J=7.9,4.5,1.9Hz),3.04(1H,dt,J=11.4,2.4Hz),3.33(1H,dd, J=9.4,7.9Hz),3.46(2H,dd,J=9.4,4.5Hz),3.59(1H,brs),5.36(1H,d,J=8.3Hz).

[0573] Example 2

[0574] (2R,3S)-N-ethyl-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)-3-((methanesulfonyl)amino)piperidine-1-carboxamide

[0575] At room temperature, a solution of N-(cis-2-(((cis-4-isopropylcyclohexyl)oxy)succinic acid (579 mg) in ethanol (4 mL) was added to a solution of N-(cis-2-(((cis-4-isopropylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (498 mg) in ethanol (4 mL), and the solution was left to stand overnight. The resulting solid was collected by filtration and washed with acetonitrile to give a solid (270 mg). Ethyl isocyanate (14.83 mg) was added to a solution of the obtained solid (100 mg) and triethylamine (0.078 mL) in THF (2 mL) at 0 °C, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give the title compound (54 mg).

[0576] 1 H NMR(300MHz, CDCl3)δ0.86(6H,d,J=6.8Hz),1.20-1.25(1H,m),1.34-1.53(5H,m),1.5 6-1.71(8H,m),1.71-1.81(1H,m),1.89(2H,d,J=13.4Hz),2.82(1H,td,J=12.7,2.7Hz) ,3.00(3H,s),3.25(2H,qd,J=7.2,5.4Hz),3.48-3.61(3H,m),3.66-3.79(1H,m),3.87( 1H,dd,J=9.3,7.8Hz), 4.44-4.56(1H,m), 4.66(1H,t,J=4.9Hz), 5.73(1H,d,J=7.7Hz).

[0577] Example 3

[0578] N-((2R,3S)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0579] A) 3-Bromo-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyridine

[0580] At 0 °C, 17.29 g of 60% sodium hydride was added to a THF (300 mL) solution of cis-4-phenylcyclohexanol (50.8 g), and the mixture was stirred for 30 min. 72.3 g of 3-bromo-2-(bromomethyl)pyridine was added to the reaction mixture, and the mixture was stirred overnight at room temperature. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (84.43 g).

[0581] MS, measured values: 346.0, 348.0.

[0582] B)N-(2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

[0583] At room temperature, di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (9.32 g), tris(dibenzylacetone)palladium(0) (10.05 g), cesium carbonate (53.6 g), and methanesulfonamide (12.53 g) were added to a DME mixture of 3-bromo-2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyridine (38 g) in 450 mL, and the reaction mixture was stirred at 100 °C for 5 hours under a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give a pale orange solid, which was recrystallized from ethyl acetate / hexane to give the title compound (17.19 g).

[0584] MS, measured value: 361.2.

[0585] C)N-((2R,3S)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0586] A mixture of N-(2-(((cis-4-phenylcyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide (6.48 g), 5% rhodium / carbon (7.40 g), and ethanol / acetic acid (9:1) solution (222.22 mL) was stirred for 23.5 h under a hydrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, and the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate, washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. At 60 °C, a solution of ethyl acetate (48 mL) of (+)-mandelic acid (2.82 g) in ethyl acetate (20 mL) was added to the obtained residue (6.80 g), and the mixture was stirred at the same temperature for 1 h. At 50 °C, seed crystals were added to the reaction mixture, and the mixture was gradually cooled to room temperature and stirred overnight at room temperature. The salt was collected by filtration and washed with a mixed solvent of ethyl acetate / IPE (2:3). The solid was recrystallized using a mixed solvent of ethyl acetate and acetonitrile (1:1). The obtained crystals were dissolved in an aqueous solution of ethyl acetate and 10% potassium carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.09 g).

[0587] 1H NMR(300MHz, CDCl3) δ1.47-1.86(10H,m),1.92-2.08(3H,m),2.53(1H,tt,J=11.4,3.7Hz),2.69(1H,td,J=11.6,2.8Hz),2.86-2.94(1H,m), 2.98(3H,s),3.02-3.12(1H,m),3.32-3.42(1H,m),3.51(1H,dd,J=9.3,4.4Hz),3.57-3.68(2H,m),5.38(1H,d,J=7.2Hz),7.13-7.37(5H,m).

[0588] Example 4

[0589] N-((2R,3S)-1-acetyl-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0590] The reaction mixture of N-((2R,3S)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (220 mg), pyridine (4 mL), and acetic anhydride (1 mL) was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue (ethyl acetate / hexane) was purified by NH silica gel column chromatography to give the title compound (249 mg).

[0591] 1 H NMR (300MHz, CDCl3) δ1.48-2.65(15H,m),2.94-3.16(4H,m),3.43-5.20(7H,m),5.31-6.22(1H,m),7.13-7.36(5H,m).

[0592] Example 5

[0593] (1) (2R,3S)-3-((methanesulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylic acid methyl ester

[0594] At room temperature, methyl chloroformate (0.024 mL) was added to a reaction mixture of N-((2R,3S)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (58 mg), triethylamine (0.044 mL), and THF (3 mL). The mixture was stirred overnight in a calcium chloride tube under dry air. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (64 mg).

[0595] 1 H NMR (300MHz, CDCl3) δ1.48-1.58(2H,m),1.59-1.67(2H,m),1.68-1.89(6H ,m),2.01-2.12(3H,m),2.47-2.61(1H,m),2.73-2.88(1H,m),2.99(3H,s), 3.53-3.63(2H,m),3.64-3.69(1H,m),3.70-3.77(3H,m),4.00-4.10(1H,m ),4.48-4.73(1H,m),6.00(1H,brs),7.14-7.26(3H,m),7.27-7.35(2H,m).

[0596] (2)(2R,3S)-3-((methanesulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylic acid methyl ester

[0597] At room temperature, methyl chloroformate (337 mg) and triethylamine (0.622 mL) were added to a THF (25 mL) solution of N-((2R,3S)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (1.09 g), and the mixture was stirred over the weekend. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in heated ethanol (3 mL), and the solution was stirred at room temperature for 10 minutes. After crystals began to precipitate, water (3 mL) was added to the solution, and the mixture was stirred overnight. The crystals were collected by filtration to give crystals of the title compound (1.023 g).

[0598] X-ray powder diffraction patterns of the obtained crystals were prepared using Ultima IV containing Cu Kα rays.

[0599] The powder X-ray diffraction pattern of the obtained crystal has characteristic peaks at the following diffraction angles (2θ): 8.8°, 11.0°, 13.4°, 15.3°, 17.6°, 19.2°, 20.4° and 23.4°.

[0600] Example 6

[0601] N-(cis-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide acetate

[0602] A) 3-Bromo-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridine

[0603] A solution of cis-4-(3,5-difluorophenyl)cyclohexanol (1.91 g) in THF (40 mL) was cooled to 0 °C, and 60% sodium hydride (0.720 g) was added. The mixture was stirred for 2 hours at room temperature in a calcium chloride tube under dry air. 3-Bromo-2-(bromomethyl)pyridine (2.416 g) was added to the reaction mixture, and the mixture was stirred for 30 minutes at room temperature, followed by stirring at 70 °C for 3 hours. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (3.33 g).

[0604] MS, measured values: 382.0, 384.0.

[0605] B)N-(2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

[0606] A mixture of 3-bromo-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridine (3.3 g), methanesulfonamide (0.985 g), di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (0.440 g), tris(dibenzylacetone)dipalladium(0) (0.395 g), cesium carbonate (4.22 g), and DME (40 mL) was heated under reflux at 95 °C in a nitrogen atmosphere for 6 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (3.20 g).

[0607] MS, measured value: 397.2.

[0608] C)N-(cis-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide acetate

[0609] A mixture of N-(2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide (1.95 g), 5% rhodium / carbon (2.025 g), ethanol (45 mL), and acetic acid (5.0 mL) was stirred at room temperature under a hydrogen atmosphere for 6 hours. The mixture was filtered, toluene was added to the filtrate, and the mixture was concentrated under reduced pressure. The residue was washed with IPE to give the title compound (1.5045 g).

[0610] MS, measured value: 403.2.

[0611] Example 7

[0612] N-((2R,3S)-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0613] N-(cis-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide acetate (1.15 g) was dissolved in ethyl acetate, and the mixture was alkalized with 1 mol / L aqueous sodium hydroxide solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Using HPLC (column: CHIRALPAK AD (LF001), 50 mm ID × 500 mmL, manufactured by Daicel Corporation, mobile phase: hexane / 2-propanol / diethylamine = 700 / 300 / 1), 295.5 mg of the fraction with the shortest retention time was separated from the residue (0.976 g) to obtain the title compound (0.143 g).

[0614] 1 H NMR (300MHz, CDCl3) δ1.45-1.59(3H,m),1.60-1.77(6H,m),1.81-1.89(1H,m),1.89-2.04(2H, m),2.52(1H,tt,J=11.1,4.0Hz),2.64-2.76(1H,m),2.90(1H,ddd,J=8.1,4.4,1.9Hz),2.94-3 .01(3H,m),3.07(1H,dt,J=11.5,2.4Hz),3.30-3.42(1H,m),3.46-3.55(1H,m),3.56-3.67(2H ,m),3.71-3.79(1H,m),5.35(1H,d,J=8.0Hz),6.61(1H,tt,J=8.9,2.3Hz),6.69-6.79(2H,m).

[0615] Example 8

[0616] N-((2R,3S)-1-acetyl-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0617] At room temperature, acetyl chloride (0.068 mL) was added to a THF solution of N-((2R,3S)-2-(((cis-4-(3,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (200 mg) and triethylamine (0.138 mL), and the mixture was stirred in a calcium chloride tube under dry air for 30 minutes. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (218 mg).

[0618] 1 H NMR(300MHz, CDCl3)δ1.52(1H,brs),1.58-1.88(7H,m),1.97-2.25(6H,m),2.44-2.66(1H,m),2.92-3.14(4H,m),3.39-3.75(4.5 H,m),3.84-4.08(1H,m),4.38(0.5H,brs),5.11(1H,brs),5.24-6.18(1H,m),6.62(1H,tt,J=9.0,2.3Hz),6.76(2H,d,J=6.8Hz).

[0619] Example 9

[0620] N-(cis-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0621] A) 8-(2,5-difluorophenyl)-1,4-dioxaspiro[4,5]dec-7-ene

[0622] At room temperature, tetrakis(triphenylphosphine)palladium (0) (1.002 g) was added to a mixture of (2,5-difluorophenyl)boronic acid (4.11 g), 1,4-dioxanespiro[4.5]dec-7-en-8-yltrifluoromethanesulfonate (5 g), sodium carbonate (7.35 g), and lithium chloride (0.037 g) in DME (60 mL) - water (15.00 mL). The mixture was heated overnight under reflux at 100 °C in a nitrogen atmosphere. At room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (3.582 g).

[0623] MS, measured value: 253.0.

[0624] B)8-(2,5-difluorophenyl)-1,4-dioxane[4,5]decane

[0625] At room temperature, 10% palladium / carbon (337 mg) was added to a 15 mL ethanol solution of 800 mg of 8-(2,5-difluorophenyl)-1,4-dioxaspiro[4,5]dec-7-ene. The mixture was stirred for 1 hour at room temperature under a hydrogen atmosphere. The mixture was filtered, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (754 mg).

[0626] MS, measured value: 255.0.

[0627] C)4-(2,5-Difluorophenyl)cyclohexanone

[0628] At room temperature, 2 mol / L hydrochloric acid (30 mL) was added to a solution of 4.15 g of 8-(2,5-difluorophenyl)-1,4-dioxaspiro[4.5]decane in 30 mL of acetone. The mixture was stirred at 60 °C for 2 hours. Ethyl acetate was added, and the reaction mixture was partitioned. The organic layer was washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (3.32 g).

[0629] MS, measured value: 211.0.

[0630] D) cis-4-(2,5-difluorophenyl)cyclohexanol

[0631] At -78°C, a 1 mol / L THF solution (46.0 mL) of tris(sec-butyl)borohydride was added to a THF solution (150 mL) of 3.32 g of 4-(2,5-difluorophenyl)cyclohexanone. The mixture was stirred at 0°C for 3 hours. At 0°C, 30% hydrogen peroxide solution was added dropwise to the mixture, and the mixture was stirred for 5 minutes. Acetone (22 mL), water (52 mL), and 30% hydrogen peroxide solution (22 mL) were added sequentially to the reaction mixture, and the mixture was stirred for 5 minutes and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (2.85 g).

[0632] 1 H NMR (300MHz, CDCl3) δ1.31 (1H,d,J=2.3Hz), 1.64-1.99 (8H,m), 2.75-2.98 (1H,m), 4.07-4.23 (1H,m), 6.74-7.06 (3H,m).

[0633] E)3-Bromo-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridine

[0634] A solution of cis-4-(2,5-difluorophenyl)cyclohexanol (2.85 g) in THF (60 mL) was cooled to 0 °C, and 60% sodium hydride (1.074 g) was added. The mixture was stirred in a calcium chloride tube at room temperature under dry air for 2 hours. 3-Bromo-2-(chloromethyl)pyridine (3.60 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes, then at 70 °C for 3 hours. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (4.33 g).

[0635] MS, measured values: 382.0, 383.9.

[0636] F)N-(2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

[0637] At room temperature, tris(dibenzylacetone)dipalladium(0) (1.037 g) was added to a DME (65 mL) mixture of 3-bromo-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridine (4.33 g), methanesulfonamide (1.293 g), di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (0.962 g) and cesium carbonate (5.54 g). The mixture was heated under reflux at 100 °C in a nitrogen atmosphere for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (3.95 g).

[0638] MS, measured value: 397.1.

[0639] G)N-(cis-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0640] At room temperature, 5% rhodium / carbon (3.90 g) was added to a mixed solution of N-(2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide (3.76 g) in ethanol (99 mL) and acetic acid (11.00 mL). The mixture was stirred at room temperature under a hydrogen atmosphere for 11 hours. The mixture was filtered, and the solvent was evaporated under reduced pressure. After washing with IPE-methanol, the residue was suspended in a saturated aqueous solution of sodium bicarbonate, and the suspension was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (2.015 g).

[0641] 1 H NMR (300MHz, CDCl3) δ1.44-1.65(7H,m),1.69-1.82(3H,m),2.02(3H,d,J=1 3.3Hz),2.59-2.75(1H,m),2.80-2.94(2H,m),2.96-3.00(3H,m),3.08(1H, dt,J=11.5,2.4Hz),3.31-3.42(1H,m),3.51(1H,dd,J=9.3,4.4Hz),3.62(2 H, d, J = 2.7Hz), 5.37 (1H, d, J = 6.1Hz), 6.73-6.87 (1H, m), 6.89-7.02 (2H, m).

[0642] Example 10

[0643] N-((2R,3S)-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0644] N-(cis-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide was separated by HPLC (column: CHIRALPAK AD (LF001), 50 mm ID × 500 mm L, manufactured by Daicel Corporation; mobile phase: hexane / 2-propanol / diethylamine = 700 / 300 / 1), and the fraction with the short retention time was obtained as the title compound (0.718 g).

[0645] 1H NMR (300MHz, CDCl3) δ1.48-1.65(6H,m),1.70-1.83(4H,m),1.93-2.12(3H,m),2.70(1H,td,J=11.6,2.8Hz),2.80-2.95(2H,m),2.98(3H,s),3 .09(1H,dt,J=11.5,2.2Hz),3.30-3.43(1H,m),3.48-3.55(1H,m),3.5 9-3.70(2H,m),5.30-5.60(1H,m),6.76-6.87(1H,m)6.88-7.04(2H,m).

[0646] Example 11

[0647] (2R,3S)-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)-3-((methanesulfonyl)amino)piperidine-1-carboxylic acid methyl ester

[0648] At room temperature, methyl chloroformate (0.115 mL) was added to a THF solution of N-((2R,3S)-2-(((cis-4-(2,5-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (300 mg) and triethylamine (0.207 mL), and the mixture was stirred for 1 hour. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (329 mg).

[0649] 1 H NMR (300MHz, CDCl3) δ1.50-1.56(1H,m),1.59-1.91(8H,m),2.03(1H,brs),2.08(2H,brs),2.70-2.95(2H,m),3.01(3H,s) ,3.53-3.71(3H,m),3.73(3H,s),3.84-4.08(2H,m),4.63(1H,brs),5.96(1H,brs),6.77-6.88(1H,m),6.89-7.06(2H,m).

[0650] Example 12

[0651] N-(cis-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0652] A) cis-4-(2,6-difluorophenyl)cyclohexanol

[0653] At -78°C, a 1 mol / L THF solution (37.0 mL) of lithium tris(sec-butyl)borohydride was added to a THF solution of 2.71 g of 4-(2,6-difluorophenyl)cyclohexanone (120 mL). The mixture was heated to 0°C over 3 hours. At 0°C, acetone, water, and 30% hydrogen peroxide solution were added dropwise to the mixture, which was stirred for 5 minutes and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (2.69 g).

[0654] 1 H NMR(300MHz, CDCl3)δ1.40(1H,d,J=4.5Hz),1.56-1.74(4H,m),1.84-2.01(2H,m),2.25(2H,d, J=14.0Hz),3.02(1H,tt,J=12.6,3.3Hz),4.13(1H,brs),6.73-6.92(2H,m),7.01-7.20(1H,m).

[0655] B) 3-Bromo-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)pyridine

[0656] A solution of cis-4-(2,6-difluorophenyl)cyclohexanol (2.69 g) in THF (60 mL) was cooled to 0 °C, and 60% sodium hydride (1.014 g) was added. The mixture was stirred in a calcium chloride tube under dry air for 2 hours. 3-Bromo-2-(chloromethyl)pyridine (3.40 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes, then at 70 °C overnight. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (3.96 g).

[0657] MS, measured values: 382.0, 384.0.

[0658] C)N-(2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

[0659] A mixture of 3-bromo-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)pyridine (3.96 g), methanesulfonamide (1.183 g), di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (0.880 g), tris(dibenzylacetone)dipalladium(0) (0.949 g), cesium carbonate (5.06 g), and DME (60 mL) was heated under reflux at 100 °C in a nitrogen atmosphere for 6 hours. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (3.76 g).

[0660] MS, measured value: 397.1.

[0661] D)N-(cis-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0662] A mixture of N-(2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide (3.76 g), 5% rhodium / carbon (3.90 g), ethanol (99 mL), and acetic acid (11.0 mL) was stirred at room temperature under a hydrogen atmosphere for 9 hours. The mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was washed with IPE. The obtained solid was dissolved in a saturated aqueous solution of sodium bicarbonate, neutralized, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by NH4 silica gel chromatography to give the title compound (1.84 g).

[0663] 1 H NMR (300MHz, CDCl3) δ1.40-1.80(8H,m),1.92-2.22(5H,m),2.71(1H,td,J=11.7,2.6Hz),2.89-3.13(6H,m) ,3.35-3.44(1H,m),3.45-3.53(1H,m),3.63(2H,brs),5.40(1H,brs),6.69-6.94(2H,m),7.01-7.22(1H,m).

[0664] Example 13

[0665] N-((2R,3S)-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0666] N-(cis-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (1800 mg) was separated by HPLC (column: CHIRALPAK AD (LF001), 50 mm ID × 500 mm L, manufactured by Daicel Corporation; mobile phase: hexane / 2-propanol / diethylamine = 800 / 200 / 1), and the fraction with the short retention time was obtained as the title compound (593.2 mg).

[0667] 1 H NMR (300MHz, CDCl3) δ1.51 (4H, dd, J = 9.8, 4.2Hz), 1.65-1.82 (4H, m), 1.93-2.28 (5H, m), 2.71 (1H, td, J = 11.6, 2.8Hz), 2.85-3. 13(6H,m),3.31-3.44(1H,m),3.44-3.51(1H,m),3.63(2H,brs),5.40(1H,brs),6.70-6.94(2H,m),7.10(1H,tt,J=8.3,6.4Hz).

[0668] Example 14

[0669] N-((2R,3S)-1-acetyl-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0670] At room temperature, acetic anhydride (0.036 mL) was added to a pyridine (2.0 mL) solution of N-((2R,3S)-2-(((cis-4-(2,6-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (51.9 mg), and the mixture was stirred in a calcium chloride tube under dry air for 30 minutes. Toluene was added to the mixture, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (53.1 mg).

[0671] 1 H NMR (300MHz, CDCl3) δ1.56-1.65(3H,m),1.68-2.24(11H,m),2.60-3.35(5H,m),3.44-3.81(4H,m),3.82-3.95(1H, m), 4.26-4.66 (1H, m), 4.98-5.47 (1H, m), 5.72 (1H, d, J = 8.3Hz), 6.82 (2H, t, J = 8.5Hz), 7.11 (1H, tt, J = 8.3, 6.3Hz).

[0672] Example 15

[0673] N-(2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

[0674] A) 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene

[0675] At room temperature, tetrakis(triphenylphosphine)palladium (0) (2.005 g) was added to a mixture of (3-fluorophenyl)boronic acid (7.28 g), 1,4-dioxanespiro[4.5]dec-7-en-8-yltrifluoromethanesulfonate (10 g), sodium carbonate (7.35 g), and lithium chloride (0.147 g) in DME (150 mL) - water (30.0 mL). The mixture was heated under reflux at 100 °C in a nitrogen atmosphere for 3 hours. At room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (5.13 g).

[0676] MS, measured value: 235.0.

[0677] B) 8-(3-fluorophenyl)-1,4-dioxane[4.5]decane

[0678] At room temperature, 10% palladium / carbon (1.090 g) was added to an ethanol (30 mL) solution of 2.40 g of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The mixture was filtered, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (1.900 g).

[0679] MS, measured value: 237.0.

[0680] C) 4-(3-Fluorophenyl)cyclohexanone

[0681] At room temperature, 6 mol / L hydrochloric acid (3 mL) was added to a solution of 3.96 g of 8-(3-fluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene in 30 mL of acetone. The mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure. Saturated brine was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (3.01 g).

[0682] MS, measured value: 193.1.

[0683] D) cis-4-(3-fluorophenyl)cyclohexanol

[0684] At -78°C, a 1 mol / L THF solution (3.95 mL) of lithium tris(sec-butyl)borohydride was added to 4-(3-fluorophenyl)cyclohexanone (380 mg) / THF (15 mL). The mixture was stirred at 0°C for 2 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (325 mg).

[0685] 1 H NMR(300MHz, CDCl3)δ1.31(1H,s),1.60-1.76(4H,m),1.77-1.98(4H,m),2.45-2.62(1 H,m),4.10-4.18(1H,m),6.82-6.97(2H,m),7.01(1H,d,J=7.6Hz),7.18-7.26(1H,m).

[0686] E)3-Bromo-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyridine

[0687] A solution of cis-4-(3-difluorophenyl)cyclohexanol (1.0 g) in THF (20 mL) was cooled to 0 °C, and 60% sodium hydride (0.412 g) was added. The mixture was stirred in a calcium chloride tube under dry air for 1 hour. 3-Bromo-2-(chloromethyl)pyridine (1.382 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours, then at 70 °C for 2.5 hours. A saturated aqueous solution of ammonium chloride was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (1.580 g).

[0688] MS, measured values: 363.9, 365.9.

[0689] F)N-(2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

[0690] At room temperature, tris(dibenzylacetone)dipalladium(0) (0.289 g) was added to a DME (20 mL) solution of 3-bromo-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyridine (1.15 g), methanesulfonamide (0.601 g), di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (0.134 g) and cesium carbonate (2.057 g). The mixture was stirred at 120 °C for 2 hours under microwave irradiation. The reaction mixture was filtered through diatomaceous earth, the filtrate was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (1.100 g).

[0691] MS, measured value: 379.0.

[0692] G)N-((2R,3S)-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0693] At room temperature, 5% rhodium / carbon (3.07 g) was added to a mixed solution of N-(2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide (2.82 g) in ethanol (40 mL) and acetic acid (2.105 mL). The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in a saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was separated by HPLC (column: CHIRALPAK AD (AF003), 50 mm ID × 500 mm L, manufactured by Daicel Corporation, mobile phase: hexane / 2-propanol / diethylamine = 650 / 350 / 1), and the fraction with the shortest retention time was obtained as the title compound (1.040 g).

[0694] 1H NMR(300MHz, CDCl3) δ1.50-1.76(10H,m),1.92-2.07(3H,m),2.54(1H,tt,J=11.4,4.0Hz) ,2.69(1H,td,J=11.7,2.7Hz),2.90(1H,ddd,J=8.0,4.3,2.1Hz),2.97(3H,s),3.07(1H,d t,J=11.5,2.4Hz),3.29-3.42(1H,m),3.49-3.54(1H,m),3.49-3.54(1H,m),3.56-3.66(2 H,m),5.38(1H,d,J=7.6Hz),6.82-6.95(2H,m),6.99(1H,d,J=7.6Hz),7.18-7.26(1H,m).

[0695] Example 16

[0696] N-((2R,3S)-1-(cyclopropylcarbonyl)-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0697] At room temperature, cyclopropylcarbonyl chloride (0.028 mL) was added to a solution of N-((2R,3S)-2-(((cis-4-(3-fluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (60 mg), triethylamine (0.043 mL), and the mixture was stirred for 1 hour. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (59.3 mg).

[0698] 1 H NMR (300MHz, CDCl3) δ0.80 (2H, dd, J = 7.8, 3.6Hz), 0.92-1.05 (2H, m), 1.52 (1H, d,J=2.3Hz),1.59-2.25(12H,m),2.54(1H,dt,J=15.0,7.7Hz),2.92-3.20(4H,m ),3.43-3.73(3H,m),4.00(1H,t,J=9.1Hz),4.50(1H,brs),4.65-5.23(1H,m), 5.42-6.37(1H,m),6.81-6.97(2H,m),7.01(1H,d,J=7.6Hz),7.19-7.26(1H,m).

[0699] Example 17

[0700] N-(cis-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0701] A) 8-(2,3-difluorophenyl)-1,4-dioxane[4.5]dec-7-ene

[0702] To a DME / water (4:1) (250 mL) solution of 2,4-dioxane[4.5]dec-7-en-8-yltrifluoromethanesulfonate (20.0 g), 2,3-difluorophenylboronic acid (16.45 g), lithium chloride (1.0 g), and sodium carbonate (29.8 g) were added. Tetra(triphenylphosphine)palladium (0) (6.42 g) was added, and the reaction mixture was stirred under reflux for 16 hours. The reaction mixture was diluted with ethyl acetate and filtered through diatomaceous earth. The filtrate was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (11.0 g).

[0703] 1 H NMR(400MHz,DMSO-d6)δ1.80(2H,t,J=6.4Hz),2.38(2H,s),2.50(2H,brs),3.93( 4H,s),5.88(1H,s),7.12-7.19(1H,m),7.25-7.34(1H,m),7.41(1H,t,J=7.6Hz).

[0704] B)8-(2,3-difluorophenyl)-1,4-dioxane[4.5]decane

[0705] A solution of 10.0 g of 8-(2,3-difluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene in ethanol (500 mL) was degassed with an argon stream for 15 minutes, and 10% palladium / carbon (1 g) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 2 hours. The reaction mixture was filtered through diatomaceous earth, and the residue was washed with ethanol. The filtrate was concentrated under reduced pressure to give the title compound (8.0 g).

[0706] 1 H NMR (400MHz, DMSO-d6) δ1.61-1.78(8H,m),2.90-2.93(1H,m),3.89(4H,s),7.11-7.18(1H,m),7.21(1H,m),7.40(1H,t,J=8.1Hz).

[0707] C)4-(2,3-difluorophenyl)cyclohexanone

[0708] At 0 °C, concentrated sulfuric acid (6.4 mL) was added to a THF / water (1:1) (100 mL) solution of 8-(2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decane (8.0 g), and the mixture was stirred at room temperature for 16 hours. An aqueous solution of sodium carbonate was added to the reaction mixture at 0 °C, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (6.0 g).

[0709] 1 H NMR (400MHz, DMSO-d6) δ1.87-1.98(2H,m),2.03-2.07(2H,m),2.26-2.29(2H,m),2.59-2. 67(2H,m),3.35-3.44(1H,m),7.14-7.22(1H,m),7.25-7.31(1H,m),7.41(1H,t,J=7.7Hz).

[0710] D) cis-4-(2,3-difluorophenyl)cyclohexanol

[0711] At -78°C, a 1 mol / L THF solution (21.43 mL) of lithium tris(sec-butyl)borohydride was added to a 20 mL THF solution of 3.0 g of 4-(2,3-difluorophenyl)cyclohexanone, and the mixture was stirred at the same temperature for 30 min. The reaction mixture was gradually heated to 0°C and stirred at 0°C for 2 h. At 0°C, water and a 1 mol / L aqueous sodium hydroxide solution were added dropwise to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (1.3 g).

[0712] 1 H NMR(400MHz,DMSO-d6)δ1.49-1.59(4H,m),1.73-1.77(2H,m),1.82-1.91(2H,m ),2.80-2.86(1H,m),3.90-3.91(1H,m),4.38-4.39(1H,m),7.12-7.26(3H,m).

[0713] E)3-Bromo-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)pyridine

[0714] At 0 °C, 60% sodium hydride (610 mg) was added to a THF (5 mL) solution of cis-4-(2,3-difluorophenyl)cyclohexanol (1.3 g), and the mixture was stirred under reflux for 2 hours. At room temperature, a THF (5 mL) solution of 3-bromo-2-(bromomethyl)pyridine (2.31 g) was slowly added to the reaction mixture, and the mixture was stirred under reflux for 4 hours. Water was added to the reaction mixture, which was then neutralized with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (810 mg).

[0715] 1 H NMR(400MHz,DMSO-d6)δ1.52-1.60(4H,m),1.75-1.85(2H,m),2.00-2.03(2H,m),2.86-2.92(1H,m),3.78(1H,s),4.60(2 H,s),7.10-7.20(2H,m),7.22-7.26(1H,m),7.32-7.35(1H,m),8.10(1H,dd,J=8.1,1.1Hz),8.55(1H,dd,J=4.5,1.2Hz).

[0716] F)N-(2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

[0717] To a solution of 800 mg of 3-bromo-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)pyridine in dioxane (5 mL), methanesulfonamide (345 mg) and cesium carbonate (1.02 g) were added. The reaction mixture was purged with argon for 20 min, and di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (178 mg) and tris(dibenzylacetone)dipalladium (0) (192 mg) were added. The mixture was sealed and stirred at 120 °C for 4 h under argon atmosphere. The reaction mixture was filtered through diatomaceous earth, and the residue was washed with ethyl acetate. The filtrate was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (620 mg).

[0718] 1H NMR(400MHz,DMSO-d6)δ1.53-1.61(4H,m),1.70-1.76(2H,m),1.99-2.05(2H,m),2.87-2.93(1H,m),3.10(3H,s),3.79(1H,brs) ,4.75(2H,s),7.10-7.15(2H,m),7.22-7.24(1H,m),7.37-7.41(1H,m),7.79(1H,d,J=8.0Hz),8.37-8.38(1H,m),9.11(1H,brs).

[0719] G)N-(cis-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0720] Platinum oxide (60 mg) was added to a methanol / acetic acid (10:1) (66 mL) solution of N-(2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide (600 mg). The reaction mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere at 40 psi. The reaction mixture was filtered through diatomaceous earth, and the residue was washed with methanol. The filtrate was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by NH4Cl column chromatography to give the title compound (400 mg).

[0721] 1 H NMR(400MHz,DMSO-d6)δ1.35-1.38(1H,m),1.50-1.56(5H,m),1.68-1.98(7H,m),2.54-2.57(1H,m),2.84-2.90(3H,m) ,2.93(3H,s),3.36-3.40(2H,m),3.51(1H,brs),3.59(1H,brs),6.72(1H,brs),7.11-7.18(2H,m),7.19-7.26(1H,m).

[0722] Example 18

[0723] N-((2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0724] N-(cis-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (3.5 g) was separated by HPLC (column: CHIRALPAK AD (LF001), 50 mm ID × 500 mm L, manufactured by Daicel Corporation, mobile phase: hexane / 2-propanol / diethylamine = 700 / 100 / 1), and the fraction with the short retention time was obtained as the title compound (1.57 g).

[0725] 1 H NMR (300MHz, CDCl3) δ1.48-1.64(6H,m),1.70-1.86(3H,m),2.69(1H,td,J=11.7,2.7Hz),2.85-1.96(2H,m),2.97-3.00( 3H,m), 3.07(1H,dt,J=11.5,2.4Hz), 3.28-3.56(3H,m), 3.63(2H,d,J=2.7Hz), 5.38(1H,dt,J=8.3Hz), 6.90-7.06(3H,m).

[0726] Example 19

[0727] N-((2R,3S)-1-acetyl-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0728] At room temperature, acetyl chloride (0.079 mL) and triethylamine (0.208 mL) were added to a THF (15 mL) solution of N-((2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (300 mg), and the mixture was stirred at the same temperature for 4 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of ammonium chloride and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (315 mg).

[0729] 1 H NMR (300MHz, CDCl3) δ1.59-1.90(8H,m),1.95-2.24(6H,m),2.79-4.43(10H,m),4.48-6.25(2H,m),6.87-7.16(3H,m).

[0730] Example 20

[0731] (2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)-3-((methanesulfonyl)amino)piperidine-1-carboxylic acid methyl ester

[0732] At room temperature, methyl chloroformate (18 mg) and triethylamine (38 mg) were added to a THF (5 mL) solution of N-((2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (50 mg), and the mixture was stirred overnight at the same temperature. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (52 mg).

[0733] 1 H NMR (300MHz, CDCl3) δ1.51-2.12(12H,m),2.74-2.86(1H,m),2.87-2.98(1H,m),3.00(3H,s),3.54-3.65(2H, m),3.68(1H,t,J=2.5Hz),3.72(3H,s),3.90-4.07(2H,m),4.64(1H,brs),6.02(1H,brs),6.86-7.16(3H,m).

[0734] Example 21

[0735] N-((2R,3S)-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0736] A) 8-(2,3,6-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene

[0737] At room temperature, PdCl2 (dppf) (0.275 g) was added to a mixed solution of 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborphane-2-yl)-1,4-dioxaspiro[4.5]dec-7-ene (1 g), 2-bromo-1,3,4-trifluorobenzene (1.189 g), and sodium bicarbonate (0.631 g) in DME (15 mL) and water (3.00 mL). The mixture was heated overnight under reflux at 100 °C in a nitrogen atmosphere. The mixture was filtered through diatomaceous earth, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (0.970 g).

[0738] MS, measured value: 271.0.

[0739] B)8-(2,3,6-trifluorophenyl)-1,4-dioxane[4.5]decane

[0740] At room temperature, 10% palladium / carbon (2.73 g) was added to an ethanol (60 mL) solution of 6.94 g of 8-(2,3,6-trifluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene. The mixture was stirred at room temperature under a hydrogen atmosphere for 7 hours. The mixture was filtered, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (4.23 g).

[0741] MS, measured value: 273.0.

[0742] C)4-(2,3,6-trifluorophenyl)cyclohexanone

[0743] At room temperature, 6 mol / L hydrochloric acid (7.95 mL) was added to a mixture of 6.49 g of 8-(2,3,6-trifluorophenyl)-1,4-dioxaspiro[4.5]decane in 100 mL of acetone and 20 mL of water. The mixture was stirred at 70 °C for 1 hour. The solvent was evaporated under reduced pressure, saturated brine was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give the title compound (5.24 g).

[0744] MS, measured value: 229.1.

[0745] D) cis-4-(2,3,6-trifluorophenyl)cyclohexanol

[0746] At -78°C, a 1 mol / L THF solution (22.67 mL) of lithium tris(sec-butyl)borohydride was added to a 50 mL THF solution of 3.98 g of 4-(2,3,6-trifluorophenyl)cyclohexanone. The mixture was stirred at -78°C for 1 hour under a nitrogen atmosphere. At -78°C, 30% hydrogen peroxide solution was added dropwise to the mixture, which was then heated to room temperature and stirred for 5 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (3.66 g).

[0747] 1H NMR (300MHz, CDCl3) δ1.39(1H,d,J=3.0Hz),1.54(1H,d,J=2.7Hz),1.58-1.74(3H,m),1.84-1.98(2H,m),2.15-2.37(2 H,m),3.02(1H,tt,J=12.6,3.3Hz),4.11-4.19(1H,m),6.76(1H,tdd,J=9.5,4.2,2.3Hz),6.95(1H,qd,J=9.1,4.9Hz).

[0748] E)3-Bromo-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)pyridine

[0749] A solution of cis-4-(2,3,6-trifluorophenyl)cyclohexanol (3.66 g) in THF (100 mL) was cooled to 0 °C, and 60% sodium hydride (1.272 g) was added. The mixture was stirred in a calcium chloride tube at room temperature under dry air for 10 min. 3-Bromo-2-(chloromethyl)pyridine (4.92 g) was added to the reaction mixture, and the mixture was stirred at 70 °C for 3 h. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (3.73 g).

[0750] MS, measured values: 401.0, 403.0.

[0751] F)N-(2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

[0752] At room temperature, tris(dibenzylacetone)dipalladium(0) (0.915 g) was added to a DME (100 mL) mixture of 3-bromo-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)pyridine (4.0 g), methanesulfonamide (1.901 g), di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (0.424 g) and cesium carbonate (6.51 g). The mixture was heated overnight under reflux at 100 °C in a nitrogen atmosphere. The reaction mixture was filtered through diatomaceous earth, the filtrate was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (3.97 g).

[0753] MS, measured value: 415.2.

[0754] G)N-((2R,3S)-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0755] At room temperature, 5% rhodium / carbon (3.92 g) was added to a mixed solution of N-(2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide (3.95 g) in 100 mL of ethanol and 11.11 mL of acetic acid. The mixture was stirred for 6 hours at room temperature under a hydrogen atmosphere. The mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate-hexane, and the precipitate was collected by filtration. The precipitate was dissolved in a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was separated using HPLC (column: CHIRALPAK AD (AF003), 50 mm ID × 500 mm L, manufactured by Daicel Corporation, mobile phase: hexane / 2-propanol / diethylamine = 700 / 300 / 1), and the fraction with the short retention time was obtained as the title compound (1.02 g).

[0756] 1 H NMR (300MHz, CDCl3) δ1.39-1.85(12H,m),1.89-2.04(2H,m),2.06-2.24(2H,m),2.70(1H,td,J=11.7,2.7Hz),2.92(1H,ddd,J=8.2,4.4,2.1Hz) ,3.00-3.14(2H,m),3.33-3.43(1H,m),3.45-3.55(1H,m),3.63(2H,d,J =2.3Hz),5.37(1H,brs),6.68-6.80(1H,m),6.94(1H,qd,J=9.1,4.9Hz).

[0757] Example 22

[0758] N-((2R,3S)-1-acetyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0759] Acetyl chloride (0.303 mL) was added to a THF (15 mL) solution of N-((2R,3S)-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (900 mg) and triethylamine (0.893 mL), and the mixture was stirred for 1 hour. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (920 mg).

[0760] 1 H NMR (300MHz, CDCl3) δ1.45-1.57(3H,m),1.58-1.69(3H,m),1.74-2.10(6H,m),2.18(2H,s),2.97-3.06(4H,m),3.06-3.30(1H,m),3.5 1-3.79(4H,m),3.81-3.96(1H,m),4.24-4.64(1H,m),4.98-5.28(1H,m),5.67(1H,d,J=8.7Hz),6.68-6.82(1H,m),6.88-7.03(1H,m).

[0761] Example 23

[0762] N-((2R,3S)-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0763] A) cis-4-(2-(trifluoromethyl)phenyl)cyclohexanol

[0764] At -78°C, a 1 mol / L THF solution (13.74 mL) of lithium tris(sec-butyl)borohydride was added dropwise over 4 minutes to a THF solution of 2.56 g of 4-(2-(trifluoromethyl)phenyl)cyclohexanone (50 mL). The mixture was stirred at -78°C for 2 hours and then at 0°C overnight. At 0°C, acetone, water, and 30% hydrogen peroxide solution were added dropwise to the mixture, and the mixture was stirred at room temperature for 1 hour and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (2.13 g).

[0765] 1H NMR (300MHz, CDCl3) δ1.31 (1H, d, J = 2.3Hz), 1.58-1.79 (4H, m), 1.83-2.01 (4H, m) ,2.95(1H,t,J=11.2Hz),4.14-4.25(1H,m),7.22-7.31(1H,m),7.46-7.65(3H,m).

[0766] B) 3-Bromo-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)pyridine

[0767] At 0 °C, a solution of 1.0 mol / L potassium hexamethyldisilazide in methyl tert-butyl ether (57.5 mL) was added to a THF (150 mL) solution of cis-4-(2-(trifluoromethyl)phenyl)cyclohexanol (9.36 g), and the mixture was stirred for 30 min. 3-Bromo-2-(bromomethyl)pyridine (19.26 g) was added to the reaction mixture, and the mixture was stirred in a calcium chloride tube at 60 °C for 5 h under dry air. At room temperature, potassium carbonate (15.89 g) and 2-mercaptoacetic acid (5.32 mL) were added, and the mixture was stirred overnight. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with a 1 mol / L aqueous solution of sodium hydroxide and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by NH4 silica gel chromatography and silica gel column chromatography to give the title compound (3.87 g).

[0768] MS, measured values: 414.1, 416.1.

[0769] C)N-(2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

[0770] At room temperature, methanesulfonamide (1.066 g), di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (0.159 g), tris(dibenzylacetone)dipalladium(0) (0.171 g), and cesium carbonate (4.57 g) were added to a DME (25 mL) solution of 3-bromo-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)pyridine (3.87 g) at room temperature. The mixture was stirred overnight at 80 °C under a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (3.85 g).

[0771] MS, measured value: 429.2.

[0772] D)N-((2R,3S)-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0773] A mixture of N-(2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide (0.93 g), 5% rhodium / carbon (0.893 g), ethanol (27 mL), and acetic acid (3.00 mL) was stirred for 11 hours at room temperature under a hydrogen atmosphere. The mixture was filtered, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and the organic layer was washed with 1 mol / L aqueous sodium hydroxide solution and saturated brine. The residue was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with IPE and recrystallized from ethanol / hexane to give a white solid (361 mg). The mother liquor was concentrated under reduced pressure. The residue (ethyl acetate / hexane) was purified by NH silica gel chromatography to give a white solid (208 mg). The obtained white solids (361 mg and 208 mg) were combined and separated by HPLC (column: CHIRALPAK AD (LF001), 50 mm ID × 500 mm L, manufactured by Daicel Corporation, mobile phase: hexane / 2-propanol / diethylamine = 900 / 100 / 1), and the fraction with the short retention time was obtained as the title compound (0.257 g).

[0774] 1 H NMR (300MHz, CDCl3) δ1.51 (2H, brs), 1.57-1.88 (8H, m), 2.03 (3H, d, J = 13.0Hz) ,2.71(1H,td,J=12.0,2.8Hz),2.86-2.96(2H,m),2.99(3H,s),3.09(1H,d,J=1 1.0Hz),3.39(1H,dd,J=9.3,7.8Hz),3.54(1H,dd,J=9.5,4.5Hz),3.60-3.69(2 H,m),5.35(1H,d,J=7.6Hz),7.27-7.33(1H,m),7.43-7.54(2H,m),7.61(1H,s).

[0775] Example 24

[0776] N-((2R,3S)-1-acetyl-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0777] At room temperature, acetic anhydride (0.042 mL) was added to a THF solution of N-((2R,3S)-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (97.2 mg) and triethylamine (0.094 mL), and the mixture was stirred overnight in a calcium chloride tube under dry air. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography and NH4Cl column chromatography to give the title compound (87.8 mg).

[0778] 1 H NMR (300MHz, CDCl3) δ1.48-2.31(14H,m),2.50-3.22(5H,m),3.31-3.79(3H,m),3.84-4.06(1H,m),4.30-4.65( 1H,m),5.17(1H,dt,J=9.0,4.4Hz),5.63(1H,brs),6.31(1H,d,J=7.6Hz),7.20-7.29(1H,m),7.47-7.64(3H,m).

[0779] Example 25

[0780] N-((2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)-1-ethanolylpiperidin-3-yl)methanesulfonamide

[0781] At room temperature, 2-chloro-2-oxoethyl acetate (51 mg) was added to a pyridine (2 mL) solution of N-((2R,3S)-2-(((cis-4-(2,3-difluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (100.2 mg). The mixture was stirred overnight in a calcium chloride tube under dry air at the same temperature. At room temperature, 1 mol / L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (2 mL), and at 0 °C, 1.25 mL of 1 mol / L aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour. At room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (104 mg).

[0782] 1 H NMR (300MHz, CDCl3) δ1.58-2.23(11H,m),2.70-3.00(2H,m),3.01(3H,s),3.05-3.37(1H,m),3.4 4-4.00(5H,m),4.01-4.62(3H,m),4.79-5.29(1H,m),5.89(1H,d,J=7.95Hz),6.81-7.15(3H,m).

[0783] Example 26

[0784] N-(cis-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0785] A) 8-(2-methoxyphenyl)-1,4-dioxaspiro[4.5]dec-7-ene

[0786] To a mixture of 1,4-dioxaspiro[4.5]dec-7-en-8-yltrifluoromethanesulfonate (3.00 g), (2-methoxyphenyl)boronic acid (2.37 g), sodium carbonate (4.41 g), and lithium chloride (22 mg) in DME (40 mL) / water (10 mL), tetrakis(triphenylphosphine)palladium (0) (601 mg) was added, and the mixture was stirred at 90 °C for 2 hours under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.60 g).

[0787] MS, measured value: 247.1.

[0788] B) 4-(2-Methoxyphenyl)cyclohexanone

[0789] To a 25 mL ethanol solution of 1.60 g of 8-(2-methoxyphenyl)-1,4-dioxaspiro[4.5]dec-7-ene, 10% palladium / carbon (346 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (at ambient pressure) for 2 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. To a 15 mL acetone solution of the residue, 15 mL of 2 mol / L hydrochloric acid was added, and the mixture was stirred at 60 °C for 2 hours. The reaction mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give the title compound (1.02 g).

[0790] MS, measured value: 205.1.

[0791] C) cis-4-(2-methoxyphenyl)cyclohexanol

[0792] Under a nitrogen atmosphere, at 0 °C, a 1 mol / L THF solution (6.4 mL) of lithium tris(sec-butyl)borohydride was added dropwise to a THF solution of 1.00 g of 4-(2-methoxyphenyl)cyclohexanone (20 mL), and the mixture was stirred at the same temperature for 1 hour. At 0 °C, water and 30% hydrogen peroxide solution were added sequentially to the reaction mixture, and the mixture was stirred at the same temperature for 5 minutes and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (893 mg).

[0793] 1 H NMR(300MHz,DMSO-d6)δ1.36-1.59(4H,m),1.66-1.87(4H,m),2.80-2.95(1H,m),3.7 6(3H,s),3.86-3.94(1H,m),4.22-4.39(1H,m),6.76-7.00(2H,m),7.04-7.27(2H,m).

[0794] D)3-Bromo-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)pyridine

[0795] At 0 °C, 60% sodium hydride (345 mg) was added to a THF (20 mL) solution of cis-4-(2-methoxyphenyl)cyclohexanol (889 mg), and the mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. 3-Bromo-2-(chloromethyl)pyridine (1.16 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 2 hours, then at 70 °C for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (743 mg).

[0796] MS, measured values: 376.0, 378.0.

[0797] E)N-(2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide

[0798] A mixture of 3-bromo-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)pyridine (740 mg), methanesulfonamide (224 mg), di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (100 mg), tris(dibenzylacetone)dipalladium(0) (90 mg), cesium carbonate (961 mg), and DME (10 mL) was heated under reflux in a nitrogen atmosphere for 6 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (723 mg).

[0799] MS, measured value: 391.2.

[0800] F)N-(cis-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0801] To a mixture of N-(2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)pyridin-3-yl)methanesulfonamide (669 mg) in ethanol (9 mL) / acetic acid (1 mL), 5% rhodium / carbon (705 mg) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere (at ambient pressure) for 20 hours. The rhodium / carbon was filtered off, toluene was added, and the solvent was evaporated under reduced pressure. The residue was washed with diisopropyl ether, and the obtained solid was dissolved in ethyl acetate. A saturated aqueous solution of sodium bicarbonate was added, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by NH silica gel column chromatography to give the title compound (123 mg).

[0802] 1 H NMR (300MHz, CDCl3) δ1.48-1.89(9H,m),1.94-2.11(4H,m),2.59-2.76(1H,m),2.84-3.15(6H,m),3.28-3.43(1H,m),3.45 -3.54(1H,m),3.56-3.69(2H,m),3.82(3H,s),5.27-5.54(1H,m),6.81-6.88(1H,m),6.89-6.98(1H,m),7.09-7.24(2H,m).

[0803] Example 27

[0804] N-((2R,3S)-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0805] N-(cis-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (2.0 g) was separated by HPLC (column: CHIRALPAK AD (AF003), 50 mm ID × 500 mm L, manufactured by Daicel Corporation; mobile phase: hexane / 2-propanol / diethylamine = 700 / 300 / 1), and the fraction with the short retention time was obtained as the title compound (783 mg).

[0806] 1 H NMR (300MHz, CDCl3) δ1.45-1.83(9H,m),1.90-2.10(4H,m),2.62-2.76(1H,m),2.86-3.13(6H,m),3.32-3.42(1H,m),3.46 -3.55(1H,m),3.56-3.68(2H,m),3.82(3H,s),5.30-5.51(1H,m),6.82-6.88(1H,m),6.88-6.97(1H,m),7.10-7.24(2H,m).

[0807] Example 28

[0808] N-((2R,3S)-1-(cyclopropylcarbonyl)-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0809] At room temperature, cyclopropylcarbonyl chloride (79 mg) was added to a THF solution of N-((2R,3S)-2-(((cis-4-(2-methoxyphenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (200 mg) and triethylamine (102 mg), and the mixture was stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (227 mg).

[0810] 1 H NMR(300MHz,DMSO-d6)δ0.57-0.87(4H,m),1.31-1.81(10H,m),1.83-2.07(3H, m),2.56-3.07(4H,m),3.10-3.88(8H,m),3.99-5.01(2H,m),6.80-7.39(5H,m).

[0811] Example 29

[0812] cis-3-((dimethylaminosulfonyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)piperidin-1-carboxylic acid isopropyl ester

[0813] A) 4-((3-bromopyridin-2-yl)methoxy)piperidine-1-carboxylic acid tert-butyl ester

[0814] A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (9.63 g) in THF (100 mL) was cooled to 0 °C, and 60% sodium hydride (3.19 g) was added. The mixture was stirred for 20 min. A solution of 3-bromo-2-(bromomethyl)pyridine (10.00 g) in THF (100 mL) was added to the reaction mixture, and the mixture was stirred overnight at room temperature under an argon atmosphere. Water was added to the mixture at 0 °C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (13.12 g).

[0815] MS, measured values: 371.1, 373.1.

[0816] B) 4-((3-((dimethylaminosulfonyl)amino)pyridin-2-yl)methoxy)piperidine-1-carboxylic acid tert-butyl ester

[0817] At room temperature, tris(dibenzylacetone)dipalladium(0) (0.617 g) was added to a DME (50 mL) mixture of 4-((3-bromopyridin-2-yl)methoxy)piperidine-1-carboxylic acid tert-butyl ester (5 g), N,N-dimethylsulfate diamide (2.007 g), di-tert-butyl(2',4',6'-triisopropylbiphenyl-2-yl)phosphine (0.686 g) and cesium carbonate (6.58 g). The mixture was heated under reflux at 100 °C in an argon atmosphere for 20 hours. The reaction mixture was neutralized with 1 mol / L hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / hexane, methanol / ethyl acetate) and NH4 silica gel chromatography (ethyl acetate / hexane) to give the title compound (4.10 g).

[0818] MS, measured value: 415.2.

[0819] C)4-((cis-3-((dimethylaminosulfonyl)amino)piperidin-2-yl)methoxy)piperidin-1-carboxylic acid tert-butyl ester

[0820] At room temperature, 5% rhodium / carbon (3.97 g) was added to a mixed solution of 4-((3-((dimethylaminosulfonyl)amino)pyridin-2-yl)methoxy)piperidine-1-carboxylic acid tert-butyl ester (4.00 g) in ethanol (100 mL) and acetic acid (10.00 mL). The mixture was stirred overnight at room temperature under a hydrogen atmosphere. The mixture was filtered, and the solvent was evaporated under reduced pressure. Ethyl acetate and hexane were added to the residue, and the precipitate was collected by filtration. The obtained solid was dissolved in a saturated aqueous solution of sodium bicarbonate, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.870 g).

[0821] MS, measured value: 421.2.

[0822] D) cis-2-(((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)methyl)-3-((dimethylaminosulfonyl)amino)piperidin-1-carboxylic acid isopropyl ester

[0823] At room temperature, isopropyl chloroformate (29.1 mg) was added to a solution of tert-butyl 4-((cis-3-((dimethylaminosulfonyl)amino)piperidin-2-yl)methoxy)piperidin-1-carboxylic acid (100 mg) and N,N-diisopropylethylamine (0.164 mL) in THF (3 mL), and the mixture was stirred for 2 days. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give the title compound (120 mg).

[0824] MS, measured value: 407.2.

[0825] E) cis-3-((dimethylaminosulfonyl)amino)-2-((piperidin-4-yloxy)methyl)piperidin-1-carboxylic acid isopropyl ester hydrochloride

[0826] At room temperature, 5 mL of 4 mol / L hydrochloric acid-ethyl acetate solution was added to 120 mg of cis-2-(((1-(tert-butoxycarbonyl)piperidin-4-yl)oxy)methyl)-3-((dimethylaminosulfonyl)amino)piperidin-1-carboxylic acid isopropyl ester. The mixture was stirred for 2 hours. The solvent in the mixture was evaporated under reduced pressure to give the title compound (106 mg).

[0827] MS, measured value: 407.2.

[0828] F) cis-3-((dimethylaminosulfonyl)amino)-2-(((1-(pyrimidin-2-yl)piperidin-4-yl)oxy)methyl)piperidin-1-carboxylic acid isopropyl ester

[0829] 2-Chloroprene (41.2 mg) was added to a solution of cis-3-((dimethylaminosulfonyl)amino)-2-((piperidin-4-yloxy)methyl)piperidin-1-carboxylic acid isopropyl ester hydrochloride (106 mg) and cesium carbonate (235 mg) in NMP (2 mL), and the mixture was stirred at 90 °C for 2 hours. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / hexane) to give the title compound (89 mg).

[0830] 1 H NMR (300MHz, CDCl3) δ1.24(3H,s),1.26(3H,s),1.42-1.58(2H,m),1.60-1.66(1H,m),1.67-1.79(2H,m), 1.88-2.00(2H,m),2.00-2.11(1H,m),2.69-2.78(1H,m),2.80(6H,s),3.35-3.54(3H,m),3.62(1H,tt,J=8 .2,3.9Hz),3.70(1H,dd,J=9.7,4.4Hz),3.96(2H,dd,J=9.8,8.3Hz),4.26(2H,dt,J=13.3,5.1Hz),4.46- 4.69 (1H, m), 4.93 (1H, spt, J = 6.2Hz), 5.51 (1H, d, J = 8.0Hz), 6.47 (1H, t, J = 4.7Hz), 8.29 (2H, d, J = 4.5Hz).

[0831] Example 30

[0832] (2R,3S)-N-ethyl-3-((methanesulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxamide

[0833] At 0 °C, ethyl isocyanate (81 mg) was added to a solution of N-[cis-2-(4-phenyl-cyclohexyloxymethyl)-piperidin-3-yl]-methanesulfonamide (280 mg), triethylamine (0.319 mL), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The obtained compound was separated by HPLC (column: CHIRALPAK IC (ME001), 50 mm ID × 500 mm L, manufactured by Daicel Corporation, mobile phase: hexane / 2-propanol = 200 / 800), and the fraction with the longest retention time was obtained as the title compound (153 mg).

[0834] 1 H NMR (300MHz, CDCl3) δ1.14 (3H, t, J = 7.2Hz), 1.56-1.80 (9H, m), 1.98-2.10 ( 3H,m),2.45-2.59(1H,m),2.84(1H,qd,J=12.7,2.8Hz),3.01(3H,s),3.26(2 H,qd,J=7.2,5.3Hz),3.52-3.81(4H,m),3.93(1H,dd,J=9.2,7.7Hz),4.48-4 .59(1H,m),4.70(1H,t,J=5.1Hz),5.74(1H,d,J=7.7Hz),7.14-7.35(5H,m).

[0835] Example 31

[0836] N-((2R,3S)-1-(cyclopropylcarbonyl)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0837] At room temperature, cyclopropylcarbonyl chloride (0.022 mL) was added to a solution of N-((2R,3S)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (58 mg), triethylamine (0.044 mL), and the mixture was stirred overnight in a calcium chloride tube under dry air. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (62 mg).

[0838] 1H NMR(300MHz, CDCl3)δ0.74-0.85(2H,m),0.94-1.05(2H,m),1.58-1.88(10H,m),2.01-2.23(3H,m),2.45-2.63(1H,m),2.92-3 .18(4H,m),3.41-3.77(3H,m),3.89-4.60(2H,m),4.69-5.23(1H,m),5.46-6.39(1H,m),7.13-7.25(3H,m),7.27-7.34(2H,m).

[0839] Example 32

[0840] (2R,3S)-3-((methanesulfonyl)amino)-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidine-1-carboxylic acid methyl ester

[0841] At room temperature, methyl chloroformate (0.018 mL) was added to a THF solution of N-((2R,3S)-2-(((cis-4-(2-(trifluoromethyl)phenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (51.2 mg) and triethylamine (0.049 mL), and the mixture was stirred overnight in a calcium chloride tube under dry air. Water was added to the mixture at room temperature, and the mixture was extracted with ethyl acetate. The residue (ethyl acetate / hexane) was purified by silica gel chromatography to give the title compound (56.3 mg).

[0842] 1 H NMR (300MHz, CDCl3) δ1.55-1.89(9H,m),1.97-2.19(3H,m),2.80(1H,td,J=13.3,3.0Hz),2.88-3.10(4H,m),3.44-3.71 (3H,m),3.72-3.78(3H,m),4.02(2H,t,J=9.1Hz),4.67(1H,brs),6.15(1H,brs),7.19-7.31(1H,m),7.47-7.67(3H,m).

[0843] Example 340

[0844] N-((2R,3S)-1-ethanolacyl-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide

[0845] At room temperature, 2-chloro-2-oxoethyl acetate (49.1 mg) was added to a mixture of N-((2R,3S)-2-(((cis-4-(2,3,6-trifluorophenyl)cyclohexyl)oxy)methyl)piperidin-3-yl)methanesulfonamide (100.8 mg) and pyridine (2.0 mL). The mixture was stirred overnight at room temperature. At room temperature, 1 mol / L hydrochloric acid was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. At 0 °C, 1 mol / L aqueous sodium hydroxide solution was added to a mixture of the residue and methanol (2.0 mL). The mixture was stirred at room temperature for 1 hour. At room temperature, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue (ethyl acetate / hexane) was purified by silica gel column chromatography to give the title compound (108.1 mg).

[0846] 1 H NMR (300MHz, CDCl3) δ1.48-1.68(6H,m),1.85-2.19(6H,m),2.75-3.12(4H,m),3.13-3.89(6H,m),3.93 -4.66(3H,m),4.87-5.16(1H,m),5.40(1H,d,J=8.7Hz),6.66-6.83(1H,m),6.96(1H,qd,J=9.1,4.9Hz).

[0847] The compounds of Examples 33-339 and 341-372 were prepared according to the preparation methods described above, the methods shown in the examples, or similar methods. The prepared example compounds are shown in the table below. In this table, MS values ​​represent measured values.

[0848] [Table 1-1]

[0849]

[0850] [Table 1-2]

[0851]

[0852] [Table 1-3]

[0853]

[0854] [Table 1-4]

[0855]

[0856] [Table 1-5]

[0857]

[0858] [Table 1-6]

[0859]

[0860] [Table 1-7]

[0861]

[0862] [Table 1-8]

[0863]

[0864] [Table 1-9]

[0865]

[0866] [Table 1-10]

[0867]

[0868] [Table 1-11]

[0869]

[0870] [Table 1-12]

[0871]

[0872] [Table 1-13]

[0873]

[0874] [Table 1-14]

[0875]

[0876] [Table 1-15]

[0877]

[0878] [Table 1-16]

[0879]

[0880] [Table 1-17]

[0881]

[0882] [Table 1-18]

[0883]

[0884] [Table 1-19]

[0885]

[0886] [Table 1-20]

[0887]

[0888] [Table 1-21]

[0889]

[0890] [Table 1-22]

[0891]

[0892] [Table 1-23]

[0893]

[0894] [Table 1-24]

[0895]

[0896] [Table 1-25]

[0897]

[0898] [Table 1-26]

[0899]

[0900] [Table 1-27]

[0901]

[0902] [Table 1-28]

[0903]

[0904] [Table 1-29]

[0905]

[0906] [Table 1-30]

[0907]

[0908] [Table 1-31]

[0909]

[0910] [Table 1-32]

[0911]

[0912] [Table 1-33]

[0913]

[0914] [Table 1-34]

[0915]

[0916] [Table 1-35]

[0917]

[0918] [Table 1-36]

[0919]

[0920] [Table 1-37]

[0921]

[0922] [Table 1-38]

[0923]

[0924] [Table 1-39]

[0925]

[0926] [Table 1-40]

[0927]

[0928] [Table 1-41]

[0929]

[0930] [Table 1-42]

[0931]

[0932] [Table 1-43]

[0933]

[0934] [Table 1-44]

[0935]

[0936] [Table 1-45]

[0937]

[0938] [Table 1-46]

[0939]

[0940] [Table 1-47]

[0941]

[0942] [Table 1-48]

[0943]

[0944] [Table 1-49]

[0945]

[0946] [Table 1-50]

[0947]

[0948] [Table 1-51]

[0949]

[0950] [Table 1-52]

[0951]

[0952] [Table 1-53]

[0953]

[0954] [Table 1-54]

[0955]

[0956] [Table 1-55]

[0957]

[0958] [Table 1-56]

[0959]

[0960] [Table 1-57]

[0961]

[0962] [Table 1-58]

[0963]

[0964] [Table 1-59]

[0965]

[0966] [Table 1-60]

[0967]

[0968] [Table 1-61]

[0969]

[0970] [Table 1-62]

[0971]

[0972] Experimental Example 1: Obtaining cells stably expressing human orexin type II receptor

[0973] To obtain cell clones stably expressing human orexin II receptor, human orexin II receptor cDNA was inserted into the pcDNA3.1(+) plasmid vector (Invitrogen), and plasmid DNA (pcDNA3.1(+) / hOX2R) for expressing human orexin II receptor was cloned. The plasmid DNA was introduced into CHO-dhfr cells using electroporation, and limiting dilution was employed, using G418 resistance as a selection marker, to obtain clones expressing human orexin II receptor.

[0974] Experimental Example 2-1: Determination of the agonistic activity of orexin type II receptors

[0975] Chinese hamster ovary (CHO) dhfr cells (hOX2R) strongly expressing human orexin type II receptor were seeded in each well of a black transparent plate (384 wells) (Becton, Dickinson and Company), with 10,000 cells seeded. The cells were cultured for 16 hours at 37°C and 5% CO2 in MEM-alpha (Nikken-Bio Co., Ltd.) medium containing 100 U / ml penicillin, 100 μg / ml streptomycin, 0.5 g / ml G418 (all of which were derived from Invitrogen) and 10% fetal bovine serum (Thermo). After removing the culture medium, 30 μL of test buffer 1 (0.1% bovine serum albumin (Wako Pure Chemical Industries, Ltd.), 1.25 mM probenecid, 10% B2-Quencher, 2.5 μg / mL LFluo-4AM, 10 mM HEPES (DOJINDO)) was added, and the cells were cultured at 37°C and 5% CO2 for 60 minutes. The test compound was dissolved in dimethyl sulfoxide to a concentration of 10 mM, and then diluted with test buffer 2 (20 mM HEPES, Hanks' balanced salt solution (Invitrogen), 0.1% bovine serum albumin). For this reaction, 10 μL of the test compound solution was added, and the fluorescence value of each well was measured every second (excitation wavelength: 488 nm, measurement wavelength: 570 nm) using a TETRA fluorescence imaging reader (FLIPR TETRA; manufactured by Molecular Devices) for 1 minute. The area of ​​fluorescence was used as the intracellular Ca2+. 2+ Concentration indicators were used to determine agonistic activity. Assuming the fluorescence value of wells containing only dilution buffer is 0%, and the fluorescence value of wells containing 10 nM human appetite peptide B (PEPTIDE INSTITUTE, INC.) buffer is 100%, the agonistic activity of the test compounds was calculated. The agonistic activity value (EC) for each compound was calculated. 50 The values ​​for Emax are shown below. Emax, as used herein, represents the value at a concentration of 30 μM when appetite peptide B is converted to a full agonist (maximum agonistic activity: 100%). The results indicate that the compounds of this invention possess agonistic activity against hOX2R.

[0976] [Table 2-1]

[0977]

[0978] [Table 2-2]

[0979]

[0980] [Table 2-3]

[0981]

[0982] Experimental Example 2-2: Determination of the agonistic activity of appetite peptide type II receptors

[0983] CHO cells strongly expressing the human OX2 receptor were seeded in each well of a 384-well black clear-bottomed plate (BD Falcon), at a density of 7,500 cells / well, and incubated at 37°C in a 5% CO2 incubator for one day. After removing the culture medium from the cell plate, 30 μL / well of test buffer A containing a calcium indicator (HBSS (Life Technologies), 20 mM HEPES (Life Technologies), 0.1% BSA (Wako Pure Chemical Industries, Ltd.), 2.5 μg / mL Fluo-4 AM (DOJINDO Chemical), 0.08% Pluronic F127 (DOJINDO Chemical), 1.25 mM probenecid (DOJINDOChemical)) was added. The plate was then incubated at 37°C in a 5% CO2 incubator for 30 minutes, followed by a further 30 minutes at room temperature. The prepared test compound was diluted with 10 μL / well of test buffer B (HBSS, 20 mM HEPES, 0.1% BSA), and the fluorescence value was measured using an FDSS μCELL (Hamamatsu Photonics KK) every 1 second for 1 minute, and then every 2 seconds for 1 minute and 40 seconds. Assuming that the fluorescence value change when DMSO was added instead of the test compound was 0% inhibition, and the fluorescence value change when OX-A (final concentration 10 nM) was 100% inhibition, the activity (%) of the test compound was calculated.

[0984] [Table 2-4]

[0985] 343 150 109 344 290 109 345 21 105 347 260 94 348 9.5 92 350 1600 116 353 1300 100 354 51 104 355 0.44 108 356 21 98 357 84 101 359 1.1 97 360 210 98 362 390 95

[0986] Experimental Example 3: Measuring the Motor Behavior of Mice

[0987] Increased motor behavior, along with increased wakefulness, elevated body temperature, and improved cardiovascular parameters, is a hallmark of arousal. In this experimental embodiment, the arousal effect of an effective treatment for narcolepsy was evaluated by measuring the motor behavior of mice. Male C57BL / 6J mice (6-10 weeks old, Japan CLEA) were used to measure motor behavior (8 mice per group). Infrared light was irradiated from the top of the cage, and a motor behavior measuring instrument (MDC system - Neurosciences Idea) capable of quantifying the number of times mice passed through the irradiation line was used. Specifically, mice were placed in the cage of the device for acclimatization for 4 hours or longer, and the test compound (dose: 30 mg / kg body weight) was administered intraperitoneally. Motor behavior was measured 2 hours after administration. In the test compound group, mice were given a solution of the test compound dissolved in a solvent (composition: 10% DMSO, 10% Cremophor EL (trade name), 20% polyethylene glycol 400 (20% PEG400, 60% water)). On the other hand, in the control group, mice were given the above solvent without the test compound.

[0988] The results are shown in Table 3 below.

[0989] Table 3

[0990]

[0991] As shown in Table 3, the compounds of the present invention can improve the motor behavior of mice.

[0992] In other words, the compounds of the present invention have an awakening effect, indicating that they can effectively treat narcolepsy.

[0993] Formulation Example 1 (Preparation of Capsules)

[0994] 1) Compound of Example 1: 30 mg

[0995] 2) Crystalline cellulose: 10mg

[0996] 3) Lactose: 19mg

[0997] 4) Magnesium stearate: 1 mg

[0998] Total: 60mg

[0999] Mix 1), 2), 3), and 4) and fill the capsules.

[1000] Formulation Example 2 (Preparation of Tablets)

[1001] 1) Compound of Example 1: 30g

[1002] 2) Lactose: 50g

[1003] 3) Corn starch: 15g

[1004] 4) Carboxymethyl cellulose calcium: 44g

[1005] 5) Magnesium stearate: 1g

[1006] 1000 tablets, totaling 140g

[1007] The total amount of 1), 2), 3), and 30g of 4) was stirred together with water, vacuum dried, and sieved. The sieved powder was mixed with 14g of 4) and 1g of 5), and the mixture was pressed using a tablet press. By this method, 1000 tablets were obtained, each containing 30mg of the compound of Example 1.

[1008] [Industrial Applicability]

[1009] The compounds of the present invention have appetite peptide type II receptor agonist activity and are used as preventive or therapeutic agents for narcolepsy.

[1010] This application is based on Japanese Patent Application No. 2016-019834, the entire contents of which are incorporated herein by reference.

Claims

1. A drug comprising a compound or a salt thereof represented by the following formula: in R 1 yes (1) Hydrogen atom, (2) C16 cells substituted with 1 to 7 substituents selected from the following groups. 1-6 Alkyl-carbonyl: (i) halogen atom, (ii) cyano group, (iii) hydroxyl group, (iv) C 3-10 Cycloalkyl, (v)C 1-6 Alkoxy, (vi)C 6-14 Aryl, (vii)C 6-14 aryloxy group, (viii) pyrazolyl, thiazolyl, pyrimidinyl or pyridazinyl, each optionally substituted with an oxygen, (ix) optionally substituted with 1 to 3 carbon atoms. 1-6 Alkyl-substituted pyrazoloxy, (x)C 1-6 Alkyl-carbonyl, (xi)C 1-6 Alkoxy-carbonyl, (xii)C 1-6 Alkyl-carbonyloxy group, (xiii)C 1-6 alkylsulfonyl, (xiv) mono- or di-C 1-6 Alkylamino, (xv)C 1-6 Alkyl-carbonylamino, and (xvi)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino, (3) Select one to three atoms chosen from halogen, cyano, hydroxyl, oxo, and C. 1-6 Alkyl substituents substituted C 3-10 cycloalkyl-carbonyl, (4) Select 1 to 6 atoms chosen from deuterium, halogen atoms and C. 6-14 Aryl substituents substituted C 1-6 alkoxy-carbonyl, (5) Select 1 to 3 from C. 1-6 Alkyl substituents substituted C 3-10 Cycloalkyloxy-carbonyl, (6) Selected from 1 to 3 atoms chosen from halogen atoms and C 6-14 Aryl substituents substituted C 6-14 aryl-carbonyl, (7)C 6-14 aryloxy-carbonyl, (8) furanylcarbonyl, thienylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl, or pyridylcarbonyl, each optionally selected from 1 to 3 C 1-6 Alkyl substituents, (9) Azahexacyclic butylcarbonyl, oxacyclobutylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl or morpholinylcarbonyl, each optionally selected from 1 to 3 oxo, C 1-6 alkyl-carbonyl, C 1-6 alkoxy-carbonyl and C 1-6 Substitution of alkyl sulfonyl groups, (10) Selected from 1 to 3 atoms chosen from halogen atoms, cyano groups, hydroxyl groups, and C 1-6 Alkoxy substituents of single or double-C 1-6 alkyl-carbamoyl, (11) Single or di-C 3-10 cycloalkyl-carbamoyl, (12) Single or di-C 6-14 aryl-carbamoyl, (13)C 1-6 alkylsulfonyl, (14)C 3-10 Cycloalkylsulfonyl, (15) C atoms that are substituted with 1 to 3 halogen atoms by choice 6-14 arylsulfonyl, (16) Thiophenesulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridinylsulfonyl, or dihydrochromenylsulfonyl, each optionally consisting of 1 to 3 selected from C 1-6 Alkyl substituents, (17) Mono- or di-C 1-6 alkyl-aminosulfonyl, or (18)C 1-6 alkyl-carbonyl-carbonyl; R 2 It is C 3-6 Cycloalkyl, pyrrolidinyl, piperidinyl, or dioxyl, each optionally substituted with 1 to 3 substituents selected from the following: (1) Deuterium, (2) Halogen atoms, (3) Hydroxyl group, (4) Selected from 1 to 3 atoms chosen from halogen atoms and C 6-14 Aryl substituents substituted C 1-6 alkyl, (5)C 3-10 cycloalkyl, (6) Randomly select C 3-10 Cycloalkyl-substituted C 1-6 Alkoxy (7) C16 cells substituted with 1 to 3 substituents selected from the following groups. 6-14 Aryl group: halogen atom, cyano group, C group optionally substituted with 1 to 3 halogen atoms 1-6 Alkyl groups, C atoms optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy and hydroxyl groups (8)C 6-14 aryloxy, (9) Tri-C 1-6 Alkylsilyloxy, (10) pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl, or isoquinolinyl, each optionally composed of 1 to 3 atoms selected from halogen atoms, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups, and (11)C 6-14 aryl-carbonyl; and R 3 It is C 1-6 Alkyl, mono- or di-C 1-6 Alkylamino.

2. The drug according to claim 1, wherein R 1 yes (1) Hydrogen atom, (2) C substituted with hydroxyl group by choice 1-6 alkyl-carbonyl, (3) Cyclopropylcarbonyl, (4)C 1-6 alkoxy-carbonyl, or (5) Mono- or di-C 1-6 alkyl-carbamoyl; R 2 yes (A) Cyclohexyl groups optionally substituted with 1 to 3 substituents selected from the following: (1)C 1-6 Alkyl groups, and (2) A phenyl group optionally substituted with 1 to 3 substituents selected from the following: halogen atom, C group optionally substituted with 1 to 3 halogen atoms. 1-6 Alkyl and C 1-6 alkoxy, or (B) Piperidin groups optionally substituted with 1 to 3 pyrimidin groups; R 3 It is C 1-6 Alkyl or di-C 1-6 Alkylamino.

3. The drug according to claim 1, wherein R 1 yes (1) C substituted with hydroxyl group by choice 1-6 alkyl-carbonyl, (2)C 1-6 alkoxy-carbonyl, or (3) Mono- or di-C 1-6 alkyl-carbamoyl; R 2 It is a cyclohexyl group that is optionally substituted by 1 to 3 substituents selected from the following: (1)C 1-6 Alkyl groups, and (2) A phenyl group that is optionally substituted with 1 to 3 halogen atoms; R 3 It is C 1-6 alkyl.

4. The medicament according to claim 1, wherein the compound is (2R,3S)-3-((methanesulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylic acid methyl ester or a salt thereof.

5. The medicament according to any one of claims 1-4, for treating diseases or conditions associated with appetite peptide type II receptor agonists.

6. The medicament according to claim 5, wherein the disease or condition is selected from narcolepsy, somnolence, sleep-apnea syndrome, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, altered consciousness, and side effects and complications caused by anesthesia.

7. The medicament according to claim 5, wherein the disease or condition is selected from narcolepsy, spontaneous somnolence, sleep-apnea syndrome, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, altered consciousness, and side effects and complications due to anesthesia.

8. The medicament according to claim 5, wherein the disease or condition is selected from narcolepsy, somnolence, or sleep apnea syndrome.

9. The medicament according to claim 5, wherein the disease or condition is selected from narcolepsy, spontaneous somnolence, or sleep apnea syndrome.

10. The medicament according to claim 5, wherein the disease or condition is narcolepsy.

11. Use of the compound represented by the following formula or a salt thereof in the preparation of a medicament for treating diseases or conditions associated with the appetite peptide type II receptor, in R 1 yes (1) Hydrogen atom, (2) C16 cells substituted with 1 to 7 substituents selected from the following groups. 1-6 Alkyl-carbonyl: (i) halogen atom, (ii) cyano group, (iii) hydroxyl group, (iv) C 3-10 Cycloalkyl, (v)C 1-6 Alkoxy, (vi)C 6-14 Aryl, (vii)C 6-14 aryloxy group, (viii) pyrazolyl, thiazolyl, pyrimidinyl or pyridazinyl, each optionally substituted with an oxygen, (ix) optionally substituted with 1 to 3 carbon atoms. 1-6 Alkyl-substituted pyrazoloxy, (x)C 1-6 Alkyl-carbonyl, (xi)C 1-6 Alkoxy-carbonyl, (xii)C 1-6 Alkyl-carbonyloxy group, (xiii)C 1-6 alkylsulfonyl, (xiv) mono- or di-C 1-6 Alkylamino, (xv)C 1-6 alkyl-carbonylamino, and (xvi)(C 1-6 Alkyl)(C 1-6 alkyl-carbonyl)amino, (3) Select one to three atoms chosen from halogen, cyano, hydroxyl, oxo, and C. 1-6 Alkyl substituents substituted C 3-10 cycloalkyl-carbonyl, (4) Select 1 to 6 atoms chosen from deuterium, halogen atoms and C. 6-14 Aryl substituents substituted C 1-6 alkoxy-carbonyl, (5) Select 1 to 3 from C. 1-6 Alkyl substituents substituted C 3-10 Cycloalkyloxy-carbonyl, (6) Selected from 1 to 3 atoms chosen from halogen atoms and C 6-14 Aryl substituents substituted C 6-14 aryl-carbonyl, (7)C 6-14 aryloxy-carbonyl, (8) furanylcarbonyl, thienylcarbonyl, pyrazolylcarbonyl, isoxazolylcarbonyl, or pyridylcarbonyl, each optionally selected from 1 to 3 C 1-6 Alkyl substituents, (9) Azahexacyclic butylcarbonyl, oxacyclobutylcarbonyl, pyrrolidinylcarbonyl, tetrahydrofuranylcarbonyl, tetrahydropyranylcarbonyl or morpholinylcarbonyl, each optionally selected from 1 to 3 oxo, C 1-6 alkyl-carbonyl, C 1-6 alkoxy-carbonyl and C 1-6 Substitution of alkyl sulfonyl groups, (10) Selected from 1 to 3 atoms chosen from halogen atoms, cyano groups, hydroxyl groups, and C 1-6 Alkoxy substituents of single or double-C 1-6 alkyl-carbamoyl, (11) Single or di-C 3-10 cycloalkyl-carbamoyl, (12) Single or di-C 6-14 aryl-carbamoyl, (13)C 1-6 alkylsulfonyl, (14)C 3-10 Cycloalkylsulfonyl, (15) C atoms that are substituted with 1 to 3 halogen atoms by choice 6-14 arylsulfonyl, (16) Thiophenesulfonyl, pyrazolylsulfonyl, imidazolylsulfonyl, pyridinylsulfonyl, or dihydrochromenylsulfonyl, each optionally consisting of 1 to 3 selected from C 1-6 Alkyl substituents, (17) Mono- or di-C 1-6 alkyl-aminosulfonyl, or (18)C 1-6 alkyl-carbonyl-carbonyl; R 2 It is C 3-6 Cycloalkyl, pyrrolidinyl, piperidinyl, or dioxyl, each optionally substituted with 1 to 3 substituents selected from the following: (1) Deuterium, (2) Halogen atoms, (3) Hydroxyl group, (4) Selected from 1 to 3 atoms chosen from halogen atoms and C 6-14 Aryl substituents substituted C 1-6 alkyl, (5)C 3-10 cycloalkyl, (6) Randomly select C 3-10 Cycloalkyl-substituted C 1-6 Alkoxy (7) C16 cells substituted with 1 to 3 substituents selected from the following groups. 6-14 Aryl group: halogen atom, cyano group, C group optionally substituted with 1 to 3 halogen atoms 1-6 Alkyl groups, C atoms optionally substituted with 1 to 3 halogen atoms 1-6 alkoxy and hydroxyl groups (8)C 6-14 aryloxy, (9) Tri-C 1-6 Alkylsilyloxy, (10) pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, quinazolinyl, benzothiazolyl, or isoquinolinyl, each optionally composed of 1 to 3 atoms selected from halogen atoms, C 1-6 Alkyl and C 1-6 Substitution of alkoxy groups, and (11)C 6-14 aryl-carbonyl; R 3 It is C 1-6 Alkyl, mono- or di-C 1-6 Alkylamino.

12. The use according to claim 11, wherein R 1 yes (1) Hydrogen atom, (2) C substituted with hydroxyl group by choice 1-6 alkyl-carbonyl, (3) Cyclopropylcarbonyl, (4)C 1-6 alkoxy-carbonyl, or (5) Mono- or di-C 1-6 alkyl-carbamoyl; R 2 yes (A) Cyclohexyl groups optionally substituted with 1 to 3 substituents selected from the following: (1)C 1-6 Alkyl groups, and (2) A phenyl group optionally substituted with 1 to 3 substituents selected from the following: halogen atom, C group optionally substituted with 1 to 3 halogen atoms. 1-6 Alkyl and C 1-6 alkoxy, or (B) Piperidinyl groups optionally substituted with 1 to 3 pyrimidinyl groups; and R 3 It is C 1-6 Alkyl or di-C 1-6 Alkylamino.

13. The use according to claim 11, wherein R 1 yes (1) C substituted with hydroxyl group by choice 1-6 alkyl-carbonyl, (2)C 1-6 alkoxy-carbonyl, or (3) Mono- or di-C 1-6 alkyl-carbamoyl; R 2 It is a cyclohexyl group that is optionally substituted by 1 to 3 substituents selected from the following: (1)C 1-6 Alkyl groups, and (2) A phenyl group optionally substituted with 1 to 3 halogen atoms; and R 3 It is C 1-6 alkyl.

14. The use according to claim 11, wherein the compound is (2R,3S)-3-((methanesulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylic acid methyl ester or a salt thereof.

15. The use according to any one of claims 11-14, wherein the disease or condition is selected from narcolepsy, somnolence, sleep-apnea syndrome, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, altered consciousness, and side effects and complications caused by anesthesia.

16. The use according to any one of claims 11-14, wherein the disease or condition is selected from narcolepsy, spontaneous somnolence, sleep-apnea syndrome, Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, bone loss-related diseases, sepsis, altered consciousness, and side effects and complications due to anesthesia.

17. The use according to claim 15, wherein the disease or condition is selected from narcolepsy, somnolence, sleep aphasia, or side effects and complications caused by anesthesia.

18. The use according to claim 16, wherein the disease or condition is selected from narcolepsy, spontaneous somnolence, sleep aphasia, or side effects and complications caused by anesthesia.

19. The use according to claim 17 or 18, wherein the disease or condition is narcolepsy.

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