heterocyclic compounds

Abstract

To provide a heterocyclic compound having orexin type 2 receptor agonist activity. [Solution] Formula (I): JPEG2026086676000082.jpg3177 [In the formula, each symbol is as described in the specification.] The compound represented by or its salts has orexin type 2 receptor agonist activity and is useful as a prophylactic or therapeutic agent for narcolepsy.

Description

[Technical Field]

[0001] The present invention relates to heterocyclic compounds, particularly heterocyclic compounds having orexin type 2 receptor agonist activity.

[0002] (Background of the invention) Orexin is a neuropeptide specifically produced by certain nerve cells scattered throughout the lateral hypothalamus and surrounding areas of the brain, and consists of two subtypes: orexin A and orexin B. Both orexin A and orexin B are endogenous ligands for orexin receptors, which are G protein-coupled receptors mainly found in the brain, and two subtypes of orexin receptors, type 1 and type 2, are known (Non-Patent Literature 1).

[0003] Orexin-producing nerve cells (orexin nerve cells) are localized near the feeding center, and intracerebroventricular administration of orexin peptides leads to an increase in food intake. Therefore, orexin was initially recognized as a neuropeptide with feeding regulatory effects. Subsequently, it was reported that canine narcolepsy is caused by a gene mutation in the orexin type 2 receptor (Non-Patent Literature 2), and attention has now been drawn to the role of orexin in sleep-wake regulation.

[0004] Studies using transgenic mice with degenerated orexin neurons and double transgenic mice created by crossing these mice with orexin-overexpressing transgenic mice have revealed that narcolepsy-like symptoms appearing due to orexin neuronal degeneration disappear with sustained orexin expression. Similarly, intracerebroventricular administration of orexin peptide to transgenic mice with degenerated orexin neurons also improved narcolepsy-like symptoms (Non-Patent Literature 3). Furthermore, studies using orexin type 2 receptor knockout mice have shown that the orexin type 2 receptor maintains wakefulness. It has been suggested that this is important (Non-Patent Document 4, Non-Patent Document 5). Against this backdrop, it has been suggested that orexin type 2 receptor agonists could be used as treatments for narcolepsy and other sleep disorders that present with hypersomnia (Non-Patent Document 6).

[0005] Furthermore, it has been suggested that peptide agonists that selectively act on orexin type 2 receptors can improve obesity induced by a high-fat diet in mice (Non-Patent Document 7). Furthermore, intracerebroventricular administration of orexin peptide has been suggested to shorten the time required for general anesthesia in rats (Non-Patent Literature 8). Furthermore, it has been suggested that patients with sleep apnea syndrome have low levels of orexin A in their plasma (Non-Patent Document 9). Furthermore, intracerebroventricular administration of orexin peptide has been suggested to improve memory retention in an accelerated aging model mouse (SAMP8) with cognitive impairment (Non-Patent Literature 10). Furthermore, orexin type 2 receptor agonists have been suggested to be potential treatments for heart failure (Patent Document 1, Non-Patent Document 11). Furthermore, it has been suggested that daytime sleepiness in Parkinson's disease patients is caused by the loss of orexin neurons (Non-Patent Literature 12). Furthermore, since orexin controls bone formation and bone loss, it has been suggested that orexin type 2 receptor agonists could be used to treat diseases related to bone loss, such as osteoporosis and rheumatoid arthritis (Patent Document 2). Furthermore, in a septic shock model mouse, continuous peripheral administration of orexin significantly improved mortality, suggesting that orexin receptor agonists are useful for the prevention or treatment of sepsis, severe sepsis, and septic shock (Patent Document 3).

[0006] Therefore, compounds possessing orexin type 2 receptor agonist activity are expected to be useful as therapeutic agents for conditions such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, coma and other disorders of consciousness, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with excessive daytime sleepiness (e.g., Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, and sepsis, as well as as anesthetic antagonists and as preventive or therapeutic agents for side effects and complications of anesthesia.

[0007] On the other hand, as sulfonamide derivatives, formula

[0008] [ka]

[0009] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 4) has been reported.

[0010] Furthermore, the following compounds have been reported to possess orexin type 2 receptor agonist activity. formula

[0011] [ka]

[0012] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 5). formula

[0013] [ka]

[0014] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 6). formula

[0015] [ka]

[0016] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 7).

[0017] formula

[0018] [ka]

[0019] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 8).

[0020] formula

[0021] [ka]

[0022] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 9).

[0023] formula

[0024] [ka]

[0025] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 10).

[0026] formula

[0027] [ka]

[0028] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 11).

[0029] formula

[0030] [ka]

[0031] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 12).

[0032] formula

[0033] [ka]

[0034] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 13).

[0035] formula

[0036] [ka]

[0037] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 14).

[0038] formula

[0039] [ka]

[0040] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 15).

[0041] formula

[0042] [ka]

[0043] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 16).

[0044] However, these compounds are considered insufficient in terms of activity, pharmacokinetics, or safety, and the development of compounds with orexin type 2 receptor agonist activity is still desired. [Prior art documents] [Patent Documents]

[0045] [Patent Document 1] WO 2015 / 073707 A1 [Patent Document 2] WO 2015 / 048091 A1 [Patent Document 3] WO 2015 / 147240 A1 [Patent Document 4] WO 2012 / 137982 A9 [Patent Document 5] WO 2017 / 135306 A1 [Patent Document 6] WO 2018 / 164191 A1 [Patent Document 7] WO 2018 / 164192 A1 [Patent Document 8] WO 2019 / 027003 A1 [Patent Document 9] WO 2019 / 027058 A1 [Patent Document 10] WO 2020 / 004536 A1 [Patent Document 11] WO 2020 / 004537 A1 [Patent Document 12] WO 2020 / 122092 A1 [Patent Document 13] WO 2020 / 122093 A1 [Patent Document 14] WO 2020 / 158958 A1 [Patent Document 15] WO 2020 / 167701 A1 [Patent Document 16] WO 2020 / 167706 A1 [Non-patent literature]

[0046] [Non-Patent Document 1] Cell, Vol. 92, pp. 573-585, 1998. [Non-Patent Document 2] Cell, Vol. 98, pp. 365-376, 1999. [Non-Patent Document 3] Proceedings of the National Academy of Sciences of United States of America, Vol. 101, pp. 4649-4654, 2004. [Non-Patent Document 4] Cell, Vol. 98, pp. 437-451, 1999. [Non-Patent Document 5] Neuron, Vol.38, pp. 715-730, 2003. [Non-Patent Document 6] CNS Drugs, Vol.27, pp. 83-90, 2013. [Non-Patent Document 7] Cell Metabolism, Vol.9, pp. 64-76, 2009. [Non-Patent Document 8] Neuroscience, Vol.121, pp. 855-863, 2003. [Non-Patent Document 9] Respiration, Vol.71, pp. 575-579, 2004. [Non-Patent Document 10] Peptides, Vol.23, pp. 1683-1688, 2002. [Non-Patent Document 11] Journal of the American College of Cardiology, Vol. 66, 2015, Pages 2522-2533. [Non-Patent Document 12] Brain, Vol. 130, pp. 1586-1595, 2007. [Overview of the project] [Problems that the invention aims to solve]

[0047] The present invention aims to provide heterocyclic compounds having orexin type 2 receptor agonist activity. [Means for solving the problem]

[0048] The present inventors have discovered that a compound represented by the following formula (I) or a salt thereof (which may be referred to as compound (I) herein) has orexin type 2 receptor agonist activity, and as a result of further research, have completed the present invention.

[0049] In other words, the present invention relates to the following: [1] Formula:

[0050] [ka] [In the formula, Ring W may be a ring that is further substituted; Ring X may further consist of a 5- or 6-membered aromatic ring; Ring Y may be further substituted with cyclopropyl; Ring Z may be a nitrogen-containing heterocycle that is further substituted; L is a bond, or a methylene group which may be substituted; R may be substituted with C 1-6 Alkyl, possibly substituted C 3-10 Cycloalkyl or optionally substituted diC 1-6 [Indicates an alkylamine.] A compound represented by or a salt thereof. A pharmaceutical product containing the compound or a salt thereof described in [2][1]. [3] The drug described in [2], which is an orexin type 2 receptor agonist. [4] The medicine described in [2], which is a preventive or therapeutic agent for narcolepsy. [Effects of the Invention]

[0051] The compound of the present invention has orexin type 2 receptor agonist activity and is used for the prevention of narcolepsy or It is useful as a therapeutic agent.

[0052] (Detailed description of the invention) The definitions of each substituent used in this specification are described in detail below. Unless otherwise specified, each substituent has the following definitions. In this specification, "halogen atoms" include, for example, fluorine, chlorine, bromine, and iodine. In this specification, "C 1-6Examples of the "alkyl group" 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. In this specification, "C 1-6 alkyl group which may be halogenated" includes, for example, C 1-6 alkyl groups which may have 1 to 7, preferably 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. In this specification, "C 2-6 alkenyl group" includes, for example, ethenyl, 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. In this specification, "C 2-6 alkynyl group" includes, for example, 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. In this specification, "C 3-10Examples of "cycloalkyl groups" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl. In this specification, "C which may be halogenated" 3-10 The "cycloalkyl group" may, for example, have 1 to 7, preferably 1 to 5, halogen atoms. 3-10 Examples include cycloalkyl groups. Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In this specification, "C 3-10 Examples of "cycloalkenyl groups" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. In this specification, "C 6-14 Examples of "aryl groups" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl. In this specification, "C 7-16 Examples of "aralkyl groups" include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0053] In this specification, "C 1-6 Examples of "alkoxy groups" include methoxy, ethoxy, pro. Examples include poxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy. In this specification, "C which may be halogenated" 1-6 The "alkoxy group" may, for example, have 1 to 7, preferably 1 to 5, halogen atoms. 1-6Examples of alkoxy groups include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy, sec-butoxy, pentyloxy, and hexyloxy. In this specification, "C 3-10 Examples of "cycloalkyloxy groups" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy. In this specification, "C 1-6 Examples of alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-butylthio, pentylthio, and hexylthio. In this specification, "C which may be halogenated" 1-6 The alkylthio group may have, for example, 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Alkylthio groups are examples. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio. In this specification, "C 1-6 Examples of alkyl-carbonyl groups include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanol, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanol. In this specification, "C which may be halogenated" 1-6 The alkyl-carbonyl group may have, for example, 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Alkyl-carbonyl groups are examples. Specific examples include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl. In this specification, "C 1-6 Examples of "alkoxy-carbonyl groups" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl. In this specification, "C 6-14 Examples of "aryl-carbonyl groups" include benzoyl, 1-naphthoyl, and 2-naphthoyl. In this specification, "C 7-16 Examples of "aralkyl-carbonyl groups" include phenylacetyl and phenylpropionyl. In this specification, "5- to 14-membered aromatic heterocyclic carbonyl group" refers to, for example, nicotinoyl, isonicotinoyl, tenoyl, and froyl. In this specification, "3- to 14-membered non-aromatic heterocyclic carbonyl group" refers to, for example, morpholinyl carbonyl, piperidinyl carbonyl, and pyrrolidinyl carbonyl.

[0054] In this specification, "mono- or di-C" refers to a single or di-C. 1-6 Examples of alkyl-carbamoyl groups include methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl. In this specification, "mono- or di-C" refers to a single or di-C. 7-16 Examples of "aralkyl-carbamoyl groups" include benzylcarbamoyl and phenethylcarbamoyl. In this specification, "C 1-6 Examples of alkylsulfonyl groups include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl. In this specification, "C which may be halogenated" 1-6 The alkylsulfonyl group may, for example, have 1 to 7, preferably 1 to 5, halogen atoms.1-6 Examples include alkylsulfonyl groups. Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl. In this specification, "C 6-14 Examples of "arylsulfonyl groups" include phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0055] In this specification, "substituents" include, for example, 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 sulfamoyl groups, optionally substituted hydroxyl groups, optionally substituted sulfanyl (SH) groups, and optionally substituted silyl groups. In this specification, "hydrocarbon group" (including "hydrocarbon group" in "optionally substituted hydrocarbon group") means, for example, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 2-6 Alkynyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 An example is the aralkyl group.

[0056] In this specification, "optionally substituted hydrocarbon group" refers, for example, to a hydrocarbon group which may have substituents selected from the following substituent group A. [Substituent group A] (1) Halogen atom, (2) Nitro group, (3) Cyano group, (4) Oxo group, (5) Hydroxyl group, (6) C may be halogenated1-6 Alkoxy group, (7)C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy), (8)C 7-16 Aralkyloxy group (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclic oxy groups (e.g., pyridyloxy), (10) 3- to 14-membered non-aromatic heterocyclic oxy groups (e.g., tetrahydropyranyloxy, morpholinyloxy, piperidinyloxy), (11)C 1-6 Alkyl-carbonyloxy groups (e.g., acetoxy, propanoyloxy), (12)C 6-14 Aryl-carbonyloxy groups (e.g., benzoyloxy, 1-naphthoyloxy, 2-naphthoyloxy), (13)C 1-6 Alkoxy-carbonyloxy groups (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy), (14) mono- or di-C 1-6 Alkyl-carbamoyloxy groups (e.g., methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy, diethylcarbamoyloxy), (15)C 6-14 Aryl-carbamoyloxy groups (e.g., phenylcarbamoyloxy, naphthylcarbamoyloxy), (16) 5- to 14-membered aromatic heterocyclic carbonyloxy groups (e.g., nicotinoyloxy), (17) 3- to 14-membered non-aromatic heterocyclic carbonyloxy groups (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) C which may be halogenated 1-6 Alkyl sulfonyloxy groups (e.g., methyl sulfonyloxy, trifluoromethyl sulfonyloxy), (19)C 1-6 C may be substituted with an alkyl group. 6-14 Aryl sulfonyloxy groups (e.g., phenyl sulfonyloxy, toluene sulfonyloxy), (20) C may be halogenated 1-6 Alkylthio group, (21) 5- to 14-membered aromatic heterocyclic groups, (22) 3- to 14-membered non-aromatic heterocyclic groups, (23) Formyl group, (24) Carboxy group, (25) C may be halogenated 1-6 Alkyl-carbonyl group, (26)C 6-14 Aryl-carbonyl group, (27) 5- to 14-membered aromatic heterocyclic carbonyl group, (28) 3- to 14-membered non-aromatic heterocyclic carbonyl group, (29)C 1-6 Alkoxy-carbonyl group, (30)C 6-14 Aryloxycarbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31)C 7-16 Aralkyloxycarbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), (32) Carbamoyl group, (33) Thiocarbamoyl group, (34) Mono- or di-C 1-6 Alkyl-carbamoyl group, (35)C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), (36) 5- to 14-membered aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl, thienylcarbamoyl), (37) 3- to 14-membered non-aromatic heterocyclic carbamoyl groups (e.g., morpholinyl carbamoyl, piperidinyl carbamoyl), (38) C may be halogenated 1-6 Alkyl sulfonyl group, (39)C 6-14 Aryl sulfonyl group, (40) 5- to 14-membered aromatic heterocyclic sulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl), (41) C which may be halogenated 1-6 Alkyl sulfinyl group, (42)C 6-14 Aryl sulfinyl groups (e.g., phenyl sulfinyl, 1-naphthyl sulfinyl, 2-naphthyl sulfinyl), (43) 5- to 14-membered aromatic heterocyclic sulfinyl groups (e.g., pyridylsulfinyl, thienylsulfinyl), (44) Amino group, (45) Mono- or di-C 1-6 Alkylamino groups (e.g., methylamino, ethylamino, propylamino, isopropylamino, butylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, N-ethyl-N-methylamino), (46) Mono- or di-C 6-14 Arylamino group (e.g., phenylamino), (47) 5- to 14-membered aromatic heterocyclic amino groups (e.g., pyridylamino), (48)C 7-16 Aralkylamino group (e.g., benzylamino), (49) Formylamino group, (50)C 1-6 Alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino), (51)(C 1-6 Alkyl)(C 1-6 Alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), (52)C 6-14 Aryl-carbonylamino groups (e.g., phenylcarbonylamino, naphthylcarbonylamino), (53)C 1-6 Alkoxycarbonylamino groups (e.g., methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, tert-butoxycarbonylamino), (54)C 7-16 Aralkyloxy-carbonylamino group (e.g., benzyloxycarbonylamino), (55)C 1-6Alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), (56)C 1-6 C may be substituted with an alkyl group. 6-14 Aryl sulfonylamino group (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) C which may be halogenated 1-6 alkyl group, (58)C 2-6 Alkenyl group, (59)C 2-6 Alkynyl group, (60)C 3-10 Cycloalkyl groups, (61)C 3-10 Cycloalkenyl group, and (62)C 6-14 Aryl group.

[0057] The number of substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. If there are two or more substituents, each substituent may be the same or different. In this specification, "heterocyclic groups" (including "heterocyclic groups" in "optionally substituted heterocyclic groups") include, for example, (i) aromatic heterocyclic groups, (ii) non-aromatic heterocyclic groups, and (iii) 7- to 10-membered heterobridged ring groups, each containing, in addition to carbon atoms, one to four heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring constituent atoms.

[0058] In this specification, "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") refers to, for example, a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic group containing, in addition to carbon atoms, one to four heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring constituent atoms. Suitable examples of the "aromatic heterocyclic group" include 5 or 6-membered monocyclic aromatic heterocyclic groups such as thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; Benzothiophenyl, benzofuranil, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, phlopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyridinyl, imidazopyridinyl, thienopyridinyl, phlopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thia Examples include 8- to 14-membered condensed polycyclic (preferably 2 or 3-cyclic) aromatic heterocyclic groups such as zolopyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, prinyl, isoquinolyl, quinolyl, phthalazinyl, naphthylidinyl, quinoxalinyl, quinazolinyl, sinnolinyl, carbazolyl, β-carbolinyl, phenantridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxadinyl.

[0059] In this specification, "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") refers to, for example, a 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic group containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring constituent atoms. Suitable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxyranyl, and thirani. 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydroisoxazolyl, piperidinyl, piperadinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridadinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azokanyl, and diazokanyl; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzoisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolidinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzoazepinyl, tetrahydroquinoxalinyl, tetrahydrophenantridinyl, hex Examples include 9- to 14-membered condensed polycyclic (preferably 2 or 3-cyclic) non-aromatic heterocyclic groups such as sahydrophenothiazinyl, hexahydrophenoxadinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrosinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0060] In this specification, preferred examples of a "7- to 10-membered heterocrosslinked ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanil. In this specification, "nitrogen-containing heterocyclic group" refers to a heterocyclic group that contains at least one nitrogen atom as a ring constituent atom. In this specification, examples of the "heterocyclic group which may be substituted" include heterocyclic groups which may have substituents selected from the above-described substituent group A. The number of substituents in the "heterocyclic group which may be substituted" is, for example, 1 to 3. When the number of substituents is 2 or more, each substituent may be the same or different.

[0061] In this specification, examples of the "acyl group" include, for example, "a C which may have 1 to 3 substituents each selected from a halogen atom, an optionally halogenated C 1-6 alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group, C 1-6 alkyl group, C 2-6 alkenyl group, C 3-10 cycloalkyl group, C 3-10 cycloalkenyl group, C 6-14 aryl group, C 7-16 aralkyl group, 5- to 14-membered aromatic heterocyclic group and 3- to 14-membered non-aromatic heterocyclic group, and 1 or 2 substituents selected therefrom", and each may have a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group, a phosphono group. In addition, examples of the "acyl group" also include a hydrocarbon-sulfonyl group, a heterocyclic-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocyclic-sulfinyl group. Here, the hydrocarbon-sulfonyl group means a sulfonyl group to which a hydrocarbon group is bonded, the heterocyclic-sulfonyl group means a sulfonyl group to which a heterocyclic group is bonded, the hydrocarbon-sulfinyl group means a sulfinyl group to which a hydrocarbon group is bonded, and the heterocyclic-sulfinyl group means a sulfinyl group to which a heterocyclic group is bonded. Preferable examples of the "acyl group" include a formyl group, a carboxy group, C 1-6 alkyl-carbonyl group, C 2-6 alkenyl-carbonyl group (e.g., crotonoyl), C 3-10 cycloalkyl-carbonyl group (e.g., cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl), C3-10 Cycloalkenyl-carbonyl group (e.g., 2-cyclohexenecarbonyl), C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group , 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl group, C 6-14 Aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7-16 Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (e.g., pyridylthiocarbamoyl), sulfino group, C 1-6 Alkylsulfinyl group (e.g., methylsulfinyl, ethylsulfinyl), sulfo group, C1-6 Alkyl sulfonyl group, C 6-14 Aryl sulfonyl group, phosphono group, mono- or di-C 1-6 Examples include alkylphosphono groups (e.g., dimethylphosphono, diethylphosphono, diisopropylphosphono, dibutylphosphono).

[0062] In this specification, "optionally substituted amino group" means, for example, "a group which may each have one to three substituents selected from substituent group A, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkyl sulfonyl group and C 6-14 An example is an amino group which may have one or two substituents selected from arylsulfonyl groups. Preferred examples of optionally substituted amino groups include amino groups, mono- or di-(which may be halogenated) C 1-6 Alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 Alkenylamino group (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino groups (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino group (e.g., phenylamino), mono- or di-C 7-16Aralkylamino group (e.g., benzylamino, dibenzylamino), mono- or di-(may be halogenated C) 1-6 Alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C 6-14 Aryl-carbonylamino groups (e.g., benzoylamino), mono- or di-C 7-16 Aralkyl-carbonylamino groups (e.g., benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclic carbonylamino groups (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclic carbonylamino groups (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 Alkoxycarbonylamino groups (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino groups (e.g., pyridylamino), carbamoylamino groups, (mono- or di-C) 1-6 Alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), (mono- or G-C 7-16 Aalkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C 1-6 Alkylsulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), C 6-14 Aryl sulfonylamino group (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 Alkyl-carbonyl)amino group (e.g., N-acetyl-N-methylamino), (C 1-6 Alkyl)(C 6-14 Examples include aryl-carbonyl)amino groups (e.g., N-benzoyl-N-methylamino).

[0063] In this specification, "optionally substituted carbamoyl group" means, for example, "a group which may each have one to three substituents selected from substituent group A, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl groups and mono- or di-C 7-16 Examples of carbamoyl groups include those having one or two substituents selected from aralkyl-carbamoyl groups. Preferred examples of carbamoyl groups that may be substituted include carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl groups (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl groups (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl groups (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 Examples include aryl-carbonyl-carbamoyl groups (e.g., benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclic carbamoyl groups (e.g., pyridylcarbamoyl).

[0064] In this specification, "a thiocarbamoyl group which may be substituted" means, for example, "a group which may each have one to three substituents selected from substituent group A, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl groups and mono- or di-C 7-16 Examples include thiocarbamoyl groups which may have one or two substituents selected from aralkyl-carbamoyl groups. Preferred examples of substituted thiocarbamoyl groups include thiocarbamoyl groups, mono- or di-C 1-6 Alkyl-thiocarbamoyl groups (e.g., methylthiocarbamoyl, ethylthiocarbamoyl, dimethylthiocarbamoyl, diethylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl groups (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl groups (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl groups (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14 Examples include aryl-carbonyl-thiocarbamoyl groups (e.g., benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (e.g., pyridylthiocarbamoyl).

[0065] In this specification, "optionally substituted sulfamoyl group" means, for example, "a group which may each have one to three substituents selected from substituent group A, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl groups and mono- or di-C 7-16 Examples include sulfamoyl groups which may have one or two substituents selected from aralkyl-carbamoyl groups. Suitable examples of sulfamoyl groups that may be substituted include sulfamoyl groups, mono- or di-C 1-6 Alkyl-sulfamoyl groups (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl sulfamoyl group (e.g., diallyl sulfamoyl), mono- or di-C 3-10 Cycloalkyl-sulfamoyl groups (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl groups (e.g., phenylsulfamoyl), mono- or di-C 7-16 Aralkyl sulfamoyl groups (e.g., benzyl sulfamoyl, phenethyl sulfamoyl), mono- or di-C 1-6 Alkyl-carbonyl-sulfamoyl groups (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C 6-14 Examples include aryl-carbonyl-sulfamoyl groups (e.g., benzoylsulfamoyl) and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (e.g., pyridylsulfamoyl).

[0066] In this specification, "optionally substituted hydroxyl group" means, for example, "C which may each have one to three substituents selected from substituent group A."1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Aryl-carbonyl group, C 7-16 Aralkyl-carbonyl group, 5- to 14-membered aromatic heterocyclic carbonyl group, 3- to 14-membered non-aromatic heterocyclic carbonyl group, C 1-6 Alkoxy-carbonyl groups, 5- to 14-membered aromatic heterocyclic groups, carbamoyl groups, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkyl sulfonyl group and C 6-14 Examples include hydroxyl groups which may have substituents selected from arylsulfonyl groups. Preferred examples of hydroxyl groups that may be substituted include hydroxyl groups, C 1-6 Alkoxy group, C 2-6 Alkenyloxy groups (e.g., allyloxy, 2-butenyloxy, 2-pentenyloxy, 3-hexenyloxy), C 3-10 Cycloalkyloxy group (e.g., cyclohexyloxy), C 6-14 Aryloxy group (e.g., phenoxy, naphthyloxy), C 7-16 Aralkyloxy group (e.g., benzyloxy, phenethyloxy), C 1-6 Alkyl-carbonyloxy groups (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C 6-14 Aryl-carbonyloxy group (e.g., benzoyloxy), C 7-16 Aalkyl-carbonyloxy group (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclic carbonyloxy group (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclic carbonyloxy group (e.g., piperidinylcarbonyloxy), C 1-6Alkoxy-carbonyloxy groups (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy groups (e.g., pyridyloxy), carbamoyloxy groups, C 1-6 Alkyl-carbamoyloxy group (e.g., methylcarbamoyloxy), C 7-16 Aralkyl-carbamoyloxy group (e.g., benzylcarbamoyloxy), C 1-6 Alkyl sulfonyloxy group (e.g., methyl sulfonyloxy, ethyl sulfonyloxy), C 6-14 Examples include aryl sulfonyloxy groups (e.g., phenylsulfonyloxy).

[0067] In this specification, "optionally substituted sulfanyl group" means, for example, "a group which may each have one to three substituents selected from substituent group A, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group, C 7-16 Aralkyl group, C 1-6 Alkyl-carbonyl group, C 6-14 Examples include sulfanyl groups and halogenated sulfanyl groups, which may have substituents selected from an aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group. Suitable examples of substituted sulfanyl groups include sulfanyl(-SH) groups and C 1-6 Alkylthio group, C 2-6 Alkenylthio groups (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 Cycloalkylthio group (e.g., cyclohexylthio), C 6-14 Arylthio group (e.g., phenylthio, naphthylthio), C 7-16 Aralkylthio group (e.g., benzylthio, phenethylthio), C 1-6 Alkyl-carbonylthio group (e.g., acetylthio, propionylthio, butyrylthio, isobutylylthio, pivaloylthio), C 6-14Examples include aryl-carbonylthio groups (e.g., benzoylthio), 5- to 14-membered aromatic heterocyclic thio groups (e.g., pyridylthio), and halogenated thio groups (e.g., pentafluorothio).

[0068] In this specification, "optionally substituted silyl group" means, for example, "a group which may each have one to three substituents selected from substituent group A, C 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl group and C 7-16 Examples include silyl groups which may have one to three substituents selected from the aralkyl group. A suitable example of a silyl group that may be substituted is tri-C 1-6 Examples include alkylsilyl groups (e.g., trimethylsilyl, tert-butyl(dimethyl)silyl).

[0069] In this specification, "hydrocarbon ring" means, for example, C 6-14 Aromatic hydrocarbon ring, C 3-10 Cycloalkanes, C 3-10 Cycloalkenes are one example. In this specification, "C 6-14 Examples of aromatic hydrocarbon rings include benzene and naphthalene. In this specification, "C 3-10 Examples of "cycloalkanes" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. In this specification, "C 3-10 Examples of "cycloalkenes" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene. In this specification, "heterocycle" refers to, for example, aromatic heterocycles and non-aromatic heterocycles that contain, in addition to carbon atoms, one to four heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms as ring constituent atoms.

[0070] In this specification, "aromatic heterocycle" refers to, for example, a 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycle containing, in addition to carbon atoms, one to four heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring constituent atoms. Preferred examples of the "aromatic heterocycle" include 5 or 6-membered monocyclic aromatic heterocycles such as thiophene, furan, pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, triazole, tetrazole, and triazine; Benzothiophene, benzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzotriazole, imidazopyridine, thienopyridine, flopyridine, pyrrolopyridine, pyrazolopyridine, o Examples include 8- to 14-membered condensed polycyclic (preferably 2 or 3-cyclic) aromatic heterocycles such as xazolopyridine, thiazolopyridine, imidazopyridine, imidazopyrimidine, thienopyrimidine, phlopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxatiin, indole, isoindole, 1H-indazole, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carbolin, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0071] In this specification, "non-aromatic heterocycle" refers to, for example, a 3 to 14-membered (preferably 4 to 10-membered) non-aromatic heterocycle containing, in addition to carbon atoms, 1 to 4 heteroatoms selected from nitrogen, sulfur, and oxygen atoms as ring constituent atoms. Suitable examples of the "non-aromatic heterocycle" include aziridine, oxirane, thiirane, azetidine, oxetane, thiethane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazolline, pyrazolidine, thiazoline, thiazolidin, tetrahydroisothiazole, tetrahydroxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepan, diazepan, azepine, azocan, diazocan, oxepan, and other 3- to 8-membered monocyclic non-aromatic heterocycles; Examples include 9 to 14-membered condensed polycyclic (preferably 2 or 3-cyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzoisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolidine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzoazepine, tetrahydroquinoxaline, tetrahydrophenanthidine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carbolin, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline. In this specification, "nitrogen-containing heterocycle" refers to a heterocycle that contains at least one nitrogen atom as a ring constituent atom. In this specification, examples of the "4- to 6-membered heterocyclic group" include aromatic or non-aromatic 4- to 6-membered heterocyclic groups, specifically, oxetanyl, furyl, pyrazolyl, pyridyl, pyrimidinyl. In this specification, examples of the "ring" include "hydrocarbon ring" and "heterocyclic ring".

[0072] The definitions of each symbol in formula (I) are described in detail below.

[0073] In the formula, ring W represents a ring which may be further substituted.

[0074] Examples of ring W include (1) 3- to 8-membered monocyclic non-aromatic heterocyclic ring (e.g., piperidine), (2) 5- to 6-membered monocyclic aromatic heterocyclic ring (e.g., furan, pyridine) which may be further substituted with 1 to 3 halogen atoms (e.g., fluorine atom), (3)(i) halogen atom (e.g., fluorine atom, chlorine atom), (ii) C 1-6 alkyl group (e.g., methyl) which may be substituted with 1 to 3 C 1-6 alkoxy groups (e.g., methoxy), and (iii) C 1-6 alkoxy group (e.g., methoxy) and may be further substituted with 1 to 3 substituents selected from 6-14 aromatic hydrocarbon ring (e.g., benzene), or (4) C 3-10 cycloalkane (e.g., cyclobutane, cyclopentane, cyclohexane) is preferred.

[0075] Among them, as ring W, C aromatic hydrocarbon ring (e.g., benzene) which may be further substituted with 1 to 3 halogen atoms (e.g., fluorine atom) is preferred. 6-14 Especially, as ring W, C​​ C 6-14 Aromatic hydrocarbon rings (e.g., benzene) are preferred.

[0076] Ring X represents a 5- or 6-membered aromatic ring, which may be further substituted.

[0077] As for ring X, (1)(i) Halogen atoms (e.g., fluorine atom, chlorine atom), (ii) C which may be halogenated 1-6 Alkyl groups (e.g., methyl, difluoromethyl), and (iii) C 1-6 Alkoxy groups (e.g., methoxy) A benzene ring which may be further substituted with one to three substituents selected from, or (2) 1 to 3 C 1-6 A 5- or 6-membered monocyclic aromatic heterocycle (e.g., thiophene, thiazole, pyridine) which may be further substituted with alkyl groups (e.g., methyl). It is preferable.

[0078] In particular, as for ring X, (i) Halogen atoms (e.g., fluorine atoms), and (ii) C 1-6 Alkyl groups (e.g., methyl), A benzene ring which may be further substituted with one to three substituents selected from the above is preferred.

[0079] Ring Y represents a cyclopropane that may be further substituted.

[0080] As for ring Y, (i) Halogen atoms (e.g., fluorine atoms), (ii) cyano group, and (iii) C 1-6 Alkyl group (e.g., methyl) Cyclopropane is preferred, which may be further substituted with one to three substituents selected from the following.

[0081] Among them, as the ring Y, a cyclopropane which may be further substituted with 1 to 3 halogen atoms (e.g., fluorine atom) is preferable.

[0082] The ring Z represents a nitrogen-containing heterocyclic ring which may be further substituted.

[0083] As the ring Z, (i) a halogen atom (e.g., fluorine atom), (ii) a hydroxy group, (iii) a C 1-6 alkyl group (e.g., methyl), and (iv) a C 1-6 alkoxy group (e.g., methoxy) A 3- to 14-membered nitrogen-containing heterocyclic ring (e.g., azetidine, pyrrolidine, piperidine, morpholine, azepane, azabicyclo[3.1.0]hexane, azaspiro[3.3]heptane, azabicyclo[3.2.0]heptane, azabicyclo[3.2.1]octane, oxazepane, octahydrocyclopenta[c]pyrrole) which may be further substituted with 1 to 3 substituents selected from the above is preferable.

[0084] Among them, as the ring Z, a 3- to 14-membered nitrogen-containing heterocyclic ring (e.g., azetidine, pyrrolidine, piperidine, azepane, 1-6 a oxazepane, octahydrocyclopenta[c]pyrrole) which may be further substituted with 1 to 3 substituents selected from a halogen atom (e.g., fluorine atom), a hydroxy group and a C alkyl group (e.g., methyl) is preferable.

[0085] L represents a bond or a methylene group which may be substituted.

[0086] As L, a bond or a methylene group is preferable.

[0087] R represents a C 1-6 alkyl group which may be substituted, a C3-10 Cycloalkyl groups, or optionally substituted diC 1-6 It shows an alkylamine group.

[0088] As for R, (1)(i) Halogen atoms (e.g., fluorine atoms, bromine atoms), and (ii) C 1-6 Alkoxy (e.g., methoxy) C may be substituted with one to three substituents selected from the following. 1-6 Alkyl groups (e.g., methyl, ethyl), (2) C 3-10 Cycloalkyl groups (e.g., cyclopropyl), or (3) C 1-6 Alkylamino group (e.g., dimethylamino) It is preferable.

[0089] In particular, R is (1) C 1-6 Alkyl groups (e.g., methyl, ethyl), or (2) Di C 1-6 Alkylamino group (e.g., dimethylamino) It is preferable.

[0090] Compound (I) is preferably an optically active compound, and preferably a compound having the stereostructure represented by the following formula (I') in the ring Y portion.

[0091] [ka]

[0092] As for compound (I), Ring W is (1) Monocyclic non-aromatic heterocycles with 3 to 8 members (e.g., piperidine), (2) It may be further substituted with one to three halogen atoms (e.g., fluorine atoms). 6-membered monocyclic aromatic heterocycles (e.g., furan, pyridine), (3)(i) Halogen atoms (e.g., fluorine atom, chlorine atom), (ii) 1 to 3 C 1-6 C may be substituted with an alkoxy group (e.g., methoxy). 1-6 Alkyl alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., methoxy) C may be further substituted with one to three substituents selected from 6-14 Aromatic hydrocarbon rings (e.g., benzene), or (4) C 3-10 Cycloalkanes (e.g., cyclobutane, cyclopentane, cyclohexane) and; Ring X is (1)(i) Halogen atoms (e.g., fluorine atom, chlorine atom), (ii) C which may be halogenated 1-6 Alkyl groups (e.g., methyl, difluoromethyl), and (iii) C 1-6 Alkoxy groups (e.g., methoxy) A benzene ring which may be further substituted with one to three substituents selected from, or (2) 1 to 3 C 1-6 A 5- or 6-membered monocyclic aromatic heterocycle (e.g., thiophene, thiazole, pyridine) which may be further substituted with alkyl groups (e.g., methyl). and; Ring Y is (i) Halogen atoms (e.g., fluorine atoms), (ii) cyano group, and (iii) C 1-6 Alkyl group (e.g., methyl) A cyclopropane which may be further substituted with one to three substituents selected from; Ring Z is (i) Halogen atoms (e.g., fluorine atoms), (ii) Hydroxyl group, (iii) C 1-6 Alkyl alkyl groups (e.g., methyl), and (iv) C 1-6 Alkoxy groups (e.g., methoxy) A 3- to 14-member nitrogen-containing compound which may be further substituted with 1 to 3 substituents selected from Heterocyclic compounds (e.g., azetidine, pyrrolidine, piperidine, morpholine, azepane, azabicyclo[3.1.0]hexane, azaspiro[3.3]heptane, azabicyclo[3.2.0]heptane, azabi These are cyclo[3.2.1]octane, oxazepane, and octahydrocyclopenta[c]pyrrole; L is a bond or a methylene group; and R (1)(i) Halogen atoms (e.g., fluorine atoms, bromine atoms), and (ii) C 1-6 Alkoxy (e.g., methoxy) C may be substituted with one to three substituents selected from the following. 1-6 Alkyl groups (e.g., methyl, ethyl), (2) C 3-10 Cycloalkyl groups (e.g., cyclopropyl), or (3) C 1-6 Alkylamino group (e.g., dimethylamino) A compound that is such as the above is preferred.

[0093] Among them, compound (I) is: The ring W may be further substituted with one to three halogen atoms (e.g., fluorine atoms) C 6-14 It is an aromatic hydrocarbon ring (e.g., benzene); Ring X is (i) Halogen atoms (e.g., fluorine atoms), and (ii) C 1-6 Alkyl groups (e.g., methyl), A benzene ring which may be further substituted with one to three substituents selected from; Ring Y may be further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms). It is clopropane; Ring Z contains a halogen atom (e.g., a fluorine atom), a hydroxyl group, and C1-6 Alkyl alkyl groups (e.g., me A 3- to 14-member molecule which may be further substituted with one to three substituents selected from (Chill). Nitrogen-containing heterocycles (e.g., azetidine, pyrrolidine, piperidine, azepane, oxazepane, etc.) It is kutahydrocyclopenta[c]pyrrole); L is a bond or a methylene group; and R (1) C 1-6 Alkyl groups (e.g., methyl, ethyl), or (2) Di C 1-6 Alkylamino group (e.g., dimethylamino) A compound that is such as the above is preferred.

[0094] Specific examples of compound (I) include the compounds described in Examples 1-12, 14-132, 134-138, 140-230, and 232-320 below.

[0095] The salt of the compound represented by formula (I) is preferably a pharmacokinetically acceptable salt, and examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, and salts with basic or acidic amino acids. Suitable examples of salts with inorganic bases include alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; aluminum salts; and ammonium salts. Suitable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, and the like. Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include salts with 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, and the like. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and the like. Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, and the like.

[0096] The method for producing the compound of the present invention is described below.

[0097] The raw materials and reagents used in each step of the following manufacturing method, as well as the resulting compounds, may each form salts. Examples of such salts include those similar to the salts of the compound represented by formula (I) above.

[0098] If the compounds obtained in each step are free compounds, they can be converted to the desired salt by methods known to the public. Conversely, if the compounds obtained in each step are salts, they can be converted to free compounds or other types of salts of the desired nature by methods known to the public.

[0099] The compounds obtained in each step can be used in subsequent reactions as reaction solutions or as crude products. Alternatively, the compounds obtained in each step can be isolated and / or purified from the reaction mixture by conventional methods such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, and chromatography.

[0100] If the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as is.

[0101] In each step of the reaction, the reaction time may vary depending on the reagents and solvents used, but this is not specifically described. If none is available, the timeframe is usually between 1 minute and 48 hours, preferably between 10 minutes and 8 hours.

[0102] In each step of the reaction, the reaction temperature may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually -78°C to 300°C, preferably -78°C to 150°C.

[0103] In each reaction step, the pressure may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually between 1 atmosphere and 20 atmospheres, preferably between 1 atmosphere and 3 atmospheres.

[0104] In each step of the reaction, a microwave synthesis apparatus such as a Biotage Initiator may be used. The reaction temperature may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually room temperature to 300°C, preferably 50°C to 250°C. The reaction time may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 1 minute to 8 hours.

[0105] In each step of the reaction, unless otherwise specified, 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, of the reagent are used relative to the substrate. When the reagent is used as a catalyst, 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, of the reagent are used relative to the substrate. When the reagent also acts as the reaction solvent, the amount of the reagent equal to the solvent is used.

[0106] Unless otherwise specified, the reactions in each step are carried out without a solvent, or by dissolving or suspending the product in a suitable solvent. Specific examples of solvents include those described in the examples, or the following: Alcohols: methanol, ethanol, tert-butyl alcohol, 2-methoxyethanol, etc. Ethers: diethyl ether, diphenyl ether, tetrahydrofuran, 1,2-dimethoxyethane, etc. Aromatic hydrocarbons: Chlorobenzene, toluene, xylene, etc. Saturated hydrocarbons: cyclohexane, hexane, etc. Amides: N,N-dimethylformamide, N-methylpyrrolidone, etc. Halogenated hydrocarbons: such as dichloromethane and carbon tetrachloride; Nitriles: such as acetonitrile; Sulfoxides: such as dimethyl sulfoxide; Aromatic organic bases: such as pyridine; Acid anhydrides: such as acetic anhydride; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc. Inorganic acids: hydrochloric acid, sulfuric acid, etc. Esters: such as ethyl acetate; Ketones: such as acetone and methyl ethyl ketone; water. The above solvents may be used by mixing two or more in appropriate proportions.

[0107] When a base is used in the reaction of each step, for example, the bases shown below, or the bases described in the examples, may be used. Inorganic bases: sodium hydroxide, magnesium hydroxide, sodium carbonate, calcium carbonate, sodium bicarbonate, etc. Organic bases: triethylamine, diethylamine, pyridine, 4-dimethylaminopyridine, N,N-dimethylaniline, 1,4-diazabicyclo[2.2.2]octane, 1,8-diazabicyclo[5.4.0]-7-undecene, imidazole, piperidine, etc. Metal alkoxides: sodium ethoxide, potassium tert-butoxide, etc. Alkali metal hydrides: such as sodium hydride; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc. Organolithium compounds: such as n-butyllithium.

[0108] When an acid or acidic catalyst is used in the reaction of each step, for example, the acids and acidic catalysts shown below, or the acids and acidic catalysts described in the examples, may be used. Inorganic acids: hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, etc. Organic acids: Acetic acid, trifluoroacetic acid, citric acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc. Lewis acids: Boron trifluoride diethyl ether complex, zinc iodide, anhydrous aluminum chloride, anhydrous zinc chloride, anhydrous iron chloride, etc.

[0109] Unless otherwise specified, the reactions in each step are based on publicly known methods, e.g., Experimental Chemistry Course, 5th Edition, Volumes 13-19 (edited by the Chemical Society of Japan); New Experimental Chemistry Course, Volumes 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (LF Tietze, Th. Eicher, Nankodo); Revised Organic Named Reactions: Their Mechanisms and Key Points (by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volume I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory: A Collection of Standard Experimental Procedures (by Jie Jack Li, Oxford University Press); Comprehensive The process is carried out according to the methods described in Heterocyclic Chemistry III, Vol.1-Vol.14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated under the supervision of Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers Inc.), 1989, or according to the methods described in the examples.

[0110] In each step, the functional group protection or deprotection reaction is carried out by methods known to the extent of the invention, for example, "Protective Groups" published by Wiley-Interscience in 2007. in Organic Synthesis, 4th Ed.” (Theodora The procedure is carried out in accordance with the methods described in "Protecting Groups 3rd Ed." (by PJ Kocienski), published by Thieme in 2004, or in accordance with the methods described in the examples. Examples of protecting groups for hydroxyl groups of alcohols and other substances, or phenolic hydroxyl groups, include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylic acid ester-type protecting groups such as acetate esters; sulfonic acid ester-type protecting groups such as methanesulfonic acid esters; and carbonate ester-type protecting groups such as tert-butyl carbonate. Examples of protecting groups for the carbonyl group of aldehydes include acetal-type protecting groups such as dimethyl acetal, and cyclic acetal-type protecting groups such as 1,3-dioxane. Examples of protecting groups for the carbonyl group of ketones include ketal-type protecting groups such as dimethyl ketal; cyclic ketal-type protecting groups such as 1,3-dioxane; oxime-type protecting groups such as O-methyloxime; and hydrazone-type protecting groups such as N,N-dimethylhydrazone. Examples of protecting groups for carboxyl groups include ester-type protecting groups such as methyl esters, and amide-type protecting groups such as N,N-dimethylamide. Examples of thiol protecting groups include ether-type protecting groups such as benzyl thioether; and ester-type protecting groups such as thioacetic acid esters, thiocarbonates, and thiocarbamates. Examples of protecting groups for amino groups and aromatic heterocycles such as imidazole, pyrrole, and indole include carbamate-type protecting groups such as benzylcarbamate; amide-type protecting groups such as acetamide; alkylamine-type protecting groups such as N-triphenylmethylamine; and sulfonamide-type protecting groups such as methanesulfonamide. The protecting group can be removed using methods known to the extent that acids, bases, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, trialkylsilyl halides (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or reduction methods.

[0111] When reduction reactions are carried out in each step, the reducing agents used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyboron hydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and triacetoxyboron tetramethylammonium hydride; boranes such as boranetetrahydrofuran complexes; Raney nickel; Raney cobalt; hydrogen; formic acid; and triethylsilane. When reducing carbon-carbon double or triple bonds, catalysts such as palladium-carbon or Lindlar catalysts can be used.

[0112] In each step of the oxidation reaction, the oxidizing agents used include peracids such as m-chloroperbenzoic acid (mCPBA), hydrogen peroxide, and tert-butyl hydroperoxide; perchlorates such as tetrabutylammonium perchlorate; chlorates such as sodium chlorate; chlorites such as sodium chlorite; periodates such as sodium periodate; high-valent iodine reagents such as iodosylbenzene; manganese-containing reagents such as manganese dioxide and potassium permanganate; lead compounds such as lead tetraacetate; chromium-containing reagents such as pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), and Jones reagent; halogen compounds such as N-bromosuccinimide (NBS); oxygen; ozone; sulfur trioxide-pyridine complexes; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0113] When radical cyclization reactions are carried out in each step, the radical initiators used include azo compounds such as azobisisobutyronitrile (AIBN); water-soluble radical initiators such as 4-4'-azobis-4-cyanopentanoic acid (ACPA); triethylboron in the presence of air or oxygen; and benzoyl peroxide. In addition, the radical reaction reagents used include tributylstananne, tritrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, and samarium iodide.

[0114] When Wittig reactions are performed in each step, examples of Wittig reagents used include alkylidene phosphoranes. Alkylidene phosphoranes can be prepared by known methods, for example, by reacting a phosphonium salt with a strong base.

[0115] When performing the Horner-Emmons reaction in each step, the reagents used include phosphonoacetate esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate; and bases such as alkali metal hydrides and organolithium compounds.

[0116] In each step of the Friedel-Crafts reaction, the reagents used may include a combination of a Lewis acid and an acid chloride, or a combination of a Lewis acid and an alkylating agent (e.g., alkyl halides, alcohols, olefins, etc.). Alternatively, organic or inorganic acids can be used instead of Lewis acids, and acid anhydrides such as acetic anhydride can be used instead of acid chlorides.

[0117] In each step of the process, when an aromatic nucleophilic substitution reaction is carried out, the reagents used are a nucleophile (e.g., amines, imidazoles, etc.) and a base (e.g., organic bases, etc.).

[0118] In each step, when a nucleophilic addition reaction using a carbanion, a nucleophilic 1,4-addition reaction using a carbanion (Michael addition reaction), or a nucleophilic substitution reaction using a carbanion is performed, the bases used to generate the carbanion include organolithium compounds, metal alkoxides, inorganic bases, and organic bases.

[0119] When the Grignard reaction is carried out in each step, Grignard reagents include aryl magnesium halides such as phenylmagnesium bromide and alkylmagnesium halides such as methylmagnesium bromide. Grignard reagents can be prepared by known methods, for example, by reacting an alkyl halide or aryl halide with metallic magnesium using ether or tetrahydrofuran as a solvent.

[0120] In each step of the Knoevenagel condensation reaction, the reagents used are an active methylene compound sandwiched between two electron-withdrawing groups (e.g., malonic acid, diethyl malonate, malononitrile, etc.) and a base (e.g., organic bases, metal alkoxides, inorganic bases).

[0121] In each step of the Vilsmeier-Haack reaction, phosphoryl chloride and amide derivatives (e.g., N,N-dimethylformamide) are used as reagents.

[0122] In each step of the process, when carrying out azidation reactions of alcohols, alkyl halides, and sulfonic acid esters, the azidating agents used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, and sodium azide. For example, when azidating alcohols, methods include using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undeca-7-ene (DBU), or using trimethylsilyl azide and a Lewis acid.

[0123] When reductive amination reactions are carried out in each step, the reducing agents used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, and formic acid. When the substrate is an amine compound, the carbonyl compounds used include paraformaldehyde, as well as aldehydes such as acetaldehyde and ketones such as cyclohexanone. When the substrate is a carbonyl compound, the amines used include primary amines such as ammonia and methylamine, and secondary amines such as dimethylamine.

[0124] In each step of the process, when the Mitsunobu reaction is carried out, azodicarboxylic acid esters (e.g., diethyl azodicarboxylic acid (DEAD), diisopropyl azodicarboxylic acid (DIAD), etc.) and triphenylphosphine are used as reagents.

[0125] In each step of the process, when esterification, amidation, or urea formation reactions are carried out, the reagents used include acyl halogenated compounds such as acid chlorides and acid bromides; activated carboxylic acids such as acid anhydrides, activated esters, and sulfate esters. Activators of carboxylic acids include carbodiimide-based condensing agents such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCD); triazine-based condensing agents such as 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate ester-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenyl phosphate azide (DPPA); and benzo Triazole-1-yloxytrisdimethylaminophosphonium salt (BOP reagent); 2-chloro-1-methylpyridinium iodide (Mukoyama Reagent); thionyl chloride; lower alkyl halomates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); Examples include sulfuric acid; or combinations thereof. When using carbodiimide coupling agents, additives such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), and dimethylaminopyridine (DMAP) may be added to the reaction.

[0126] When coupling reactions are carried out in each step, the metal catalysts used include palladium compounds such as palladium(II) acetate, tetrakis(triphenylphosphine)palladium(O), dichlorobis(triphenylphosphine)palladium(II), dichlorobis(triethylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(O), and 1,1'-bis(diphenylphosphineno)ferrocenepalladium(II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel(O); rhodium compounds such as tris(triphenylphosphine)rhodium(III) chloride; cobalt compounds; copper compounds such as copper oxide and copper(I) iodide; and platinum compounds. Furthermore, a base may be added to the reaction, and examples of such bases include inorganic bases.

[0127] In each step of the process, when a thiocarbonylation reaction is carried out, phosphorus pentasulfide is typically used as the thiocarbonylating agent. However, in addition to phosphorus pentasulfide, reagents having a 1,3,2,4-dithiadiphosphetane-2,4-disulfide structure, such as 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide (Lawesson reagent), may also be used.

[0128] In each step of the Wohl-Ziegler reaction, halogenating agents used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, and sulfuryl chloride. Furthermore, the reaction can be accelerated by adding heat, light, or radical initiators such as benzoyl peroxide and azobisisobutyronitrile.

[0129] In each step, when halogenation reactions of hydroxyl groups are carried out, the halogenating agents used include hydrohalic acids and acid halides of inorganic acids. Specifically, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., and for bromination, 48% hydrobromic acid, etc., can be used. Alternatively, a method may be used to obtain alkyl halides from alcohols by the reaction of triphenylphosphine with carbon tetrachloride or carbon tetrabromide, etc. Alternatively, a method may be used to synthesize alkyl halides through a two-step reaction in which the alcohol is converted to a sulfonic acid ester and then reacted with lithium bromide, lithium chloride, or sodium iodide.

[0130] When carrying out the Arbuzov reaction in each step, the reagents used include alkyl halides such as ethyl bromoacetate, and phosphites such as triethyl phosphite and tri(isopropyl) phosphite.

[0131] When sulfonate esterification reactions are carried out in each step, examples of sulfonylation agents that can be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, and p-toluenesulfonic anhydride.

[0132] In each step of the hydrolysis reaction, an acid or a base is used as the reagent. Furthermore, when performing acid hydrolysis of tert-butyl esters, formic acid or triethylsilane may be added to reductively trap the by-product tert-butyl cation.

[0133] When a dehydration reaction is carried out in each step, examples of dehydrating agents that can be used include sulfuric acid, phosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, and polyphosphate.

[0134] Of the compounds (3) used in reaction equation 3 described later, compounds (3)-1 and (3)-2 shown in the figure below can be produced from compound (1) by the method shown in reaction equation 1 below. In the formula, R1 C may be substituted 1-6 R indicates an alkyl group. 2 , R 3 and R 4 Each of these is independently a hydrogen atom, a halogen atom, or a substituted C 1-6 This indicates an alkyl group, and all other symbols have the same meaning as above.

[0135] [ka]

[0136] R 1 , R 2 , R 3 and R 4 The "C which may be substituted" shown by 1-6 As for the alkyl group, among the "optionally substituted hydrocarbon groups", the hydrocarbon group is C 1-6 Examples include alkyl groups.

[0137] Compound (1) can be used as a commercially available product, or it can be produced by a method known to the public or a method equivalent thereto.

[0138] Compound (3)-1 can be prepared by the Corey-Chaykovsky reaction of compound (2) and a sulfonium salt in the presence of a base. Examples of sulfonium salts that can be used include trimethylsulfonium iodide. Examples of bases that can be used include inorganic bases, metal alkoxides, and alkali metal hydrides.

[0139] Compound (6) can be produced by a condensation reaction between compound (1) and hydrazine hydrate.

[0140] Compound (3)-2 can be produced by the cyclopropanation reaction of compound (4) and compound (5) in the presence of a metal catalyst. Examples of metal catalysts that can be used include rhodium compounds such as rhodium(II) acetate dimer and ruthenium compounds such as dichloro(p-cymene)ruthenium(II) dimer.

[0141] Compound (3)-2 can also be produced by the cyclopropanation reaction of compound (6) and compound (7) in the presence of an oxidizing agent. Examples of oxidizing agents that can be used include hypervalent iodine compounds such as iodosobenzene and manganese(IV) oxide.

[0142] Of the compounds (3) used in reaction equation 3 described later, compound (3)-3 shown in the figure below can be produced from compound (8) by the method shown in reaction equation 2 below. In the formula, LG 1 and LG 2 Each of these independently represents a leaving group, R 5 C is a hydrogen atom, a halogen atom, or a substituted C 1-6 This indicates an alkyl group, and all other symbols have the same meaning as above.

[0143] [ka]

[0144] LG 1 The "leaving group" shown can be a halogen atom or a halogenated carbon atom. 1-6 Alkyl sulfonyl oxy (e.g., methanesulfonyl oxy, ethanesulfonyl oxy, trifluoromethanesulfonyl oxy), C 1-6 C may be substituted with alkyl. 6-14 Examples include aryl sulfonyloxy compounds (e.g., benzenesulfonyloxy, toluenesulfonyloxy).

[0145] LG 2Examples of "leaving groups" shown include dihydroxyboryl (e.g., dihydroxyboryl, pinacolateboryl), which may be substituted.

[0146] R 5 The "C which may be substituted" shown by 1-6 As for the alkyl group, among the "optionally substituted hydrocarbon groups", the hydrocarbon group is C 1-6 Examples include alkyl groups.

[0147] Compounds (8) and (9) can be used as commercially available products or produced by methods known to the public or similar methods.

[0148] Compound (3)-3 can be produced by the cyclopropanation reaction of compound (10) and compound (5) in the presence of a metal catalyst. Examples of metal catalysts that can be used include rhodium compounds such as rhodium(II) acetate dimer and ruthenium compounds such as dichloro(p-cymene)ruthenium(II) dimer.

[0149] Compound (11) can be produced from compound (3) by the method shown in the following reaction formula 3. In the formula, each symbol has the same meaning as above.

[0150] [ka]

[0151] Compound (15) can be produced from compound (12) by the method shown in the following reaction formula 4. In the formula, LG 3 The symbol indicates a leaving group, P indicates a protecting group, and all other symbols have the same meaning as above.

[0152] [ka]

[0153] LG 3The "leaving group" shown can be a halogen atom or a halogenated carbon atom. 1-6 Alkyl sulfonyl oxy (e.g., methanesulfonyl oxy, ethanesulfonyl oxy, trifluoromethanesulfonyl oxy), C 1-6 C may be substituted with alkyl. 6-14 Examples include aryl sulfonyloxy compounds (e.g., benzenesulfonyloxy, toluenesulfonyloxy).

[0154] Examples of "protecting groups" represented by P include those mentioned above, such as "amino groups and protecting groups for aromatic heterocycles such as imidazole, pyrrole, and indole."

[0155] Compound (12) can be used as a commercially available product, or it can be produced by a method known to the public or a method equivalent thereto.

[0156] Compound (14) can be produced by a sulfonamidate reaction between compound (12) and compound (13). Examples of compound (13) that can be used include sulfonyl chlorides and sulfamoyl chlorides. Compound (13) can be used as a commercially available product or produced by a method known or equivalent.

[0157] Compound (I) can be produced from compound (11) and compound (15) by the method shown in the following reaction formula 5. In the formula, each symbol has the same meaning as above.

[0158] [ka]

[0159] In compound (I) obtained in this manner, the functional groups within the molecule can be converted to desired functional groups by combining known chemical reactions. Examples of such chemical reactions include oxidation reactions, reduction reactions, alkylation reactions, acylation reactions, ureation reactions, hydrolysis reactions, amination reactions, esterification reactions, aryl coupling reactions, and deprotection reactions.

[0160] In the above manufacturing method, if the starting compound has an amino group, carboxyl group, hydroxyl group, carbonyl group, or mercapto group as a substituent, protecting groups commonly used in peptide chemistry, etc., may be introduced to these groups, and the target compound can be obtained by removing the protecting group as needed after the reaction.

[0161] Compound (I) obtained by the above manufacturing method can be isolated and purified by known means, such as solvent extraction, liquid-to-liquid conversion, transsolution, crystallization, recrystallization, chromatography, etc. If compound (I) contains optical isomers, stereoisomers, positional isomers, and rotational isomers, these are also included as compound (I), and each can be obtained individually by known synthesis and separation methods. For example, if compound (I) contains optical isomers, the optical isomers separated from the compound are also included in compound (I). Here, optical isomers can be produced by methods that are already known. Compound (I) may be crystalline. Crystals of compound (I) (hereinafter sometimes abbreviated as "crystals of the present invention") can be produced by applying a known crystallization method to compound (I) and crystallizing it.

[0162] In this specification, the melting point refers to the melting point measured using, for example, a micromelting point analyzer (Yanaco, MP-500D or Buchi, B-545) or a DSC (Differential Scanning Calorimetry) device (METTLER TOLEDO, DSC1). In general, melting points can vary depending on the measuring instrument, measurement conditions, etc. The crystals described herein may exhibit melting points different from those specified herein, as long as they are within the normal margin of error. The crystals of the present invention exhibit excellent physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorption, distribution, metabolism, excretion), and efficacy), making them extremely useful as pharmaceuticals.

[0163] Compound (I) may also be used as a prodrug. A prodrug of compound (I) is a compound that is converted to compound (I) by reactions with enzymes or gastric acid under physiological conditions in the body, that is, a compound that is converted to compound (I) by enzymatic oxidation, reduction, hydrolysis, etc., or a compound that is converted to compound (I) by hydrolysis, etc., with gastric acid, etc. As a prodrug of compound (I), Compounds in which the amino group of compound (I) is acylated, alkylated, or phosphorylated (e.g., compounds in which the amino group of compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated, or tert-butylated); Compounds in which the hydroxyl group of compound (I) is acylated, alkylated, phosphorylated, or borated (e.g., compounds in which the hydroxyl group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumalylated, alanylated, or dimethylaminomethylcarbonylated); Compounds in which the carboxyl group of compound (I) is esterified or amidated (e.g., compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxy Examples include compounds that have been methylated, cyclohexyloxycarbonylethyl esterified, or methylamidated (so-1,3-dioxolene-4-yl). These compounds can be produced from compound (I) by methods known to the public.

[0164] Furthermore, the prodrug of compound (I) may be one that transforms into compound (I) under physiological conditions, as described on pages 163 to 198 of Volume 7, "Development of Pharmaceuticals," published by Hirokawa Shoten in 1990. In this specification, the prodrug may form a salt, and examples of such salts include those represented by the compound shown in formula (I) above. Furthermore, compound (I) is an isotope (e.g., 3 H, 13 C, 14 C, 18 F, 35 S, 125 I) It may also be marked with, etc. Compounds (I) labeled or substituted with isotopes can be used, for example, as tracers (PET tracers) in positron emission tomography (PET), and are useful in fields such as medical diagnosis. Furthermore, compound (I) may be a hydrate, a nonhydrate, a solvate (e.g., an anhydride), or a solvate (e.g., a hydrate). moreover, 1 H 2 Deuterium converters converted to H(D) are also included in compound (I). Furthermore, compound (I) may be a pharmaceutically acceptable cocrystal or cocrystalline salt. Here, a cocrystal or cocrystalline salt means a crystalline substance composed of two or more distinct solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). Cocrystals or cocrystalline salts can be produced according to known cocrystallization methods.

[0165] Compound (I) or its prodrug (hereinafter sometimes simply referred to as the "compound of the present invention") can be used as is, or mixed with a pharmacologically acceptable carrier, etc., to form a pharmaceutical composition (also called a pharmaceutical), which can then be used in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cattle, horses, pigs, monkeys) as a preventive or therapeutic agent for various diseases described later. Herein, pharmacologically acceptable carriers include various organic or inorganic carrier substances commonly used as formulation materials, which are incorporated as excipients, lubricants, binders, and disintegrants in solid formulations; and as solvents, solubilizers, suspending agents, isotonic agents, buffers, and analgesics in liquid formulations. Furthermore, formulation additives such as preservatives, antioxidants, colorants, and sweeteners may be used as needed.

[0166] Suitable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, acacia gum, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate. Suitable examples of lubricants include magnesium stearate, calcium stearate, talc, and colloidal silica. Suitable examples of binders include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable examples of disintegrants include lactose, sucrose, starch, carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose. Suitable examples of solvents include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, and cottonseed oil. Suitable examples of solubilizers include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, and sodium acetate. Suitable examples of suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glyceryl monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; and polysorbates and polyoxyethylene hydrogenated castor oil. Suitable examples of isotonic agents include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose. Suitable examples of buffering agents include buffers such as phosphates, acetates, carbonates, and citrates. A suitable example of an analgesic is benzyl alcohol. Suitable examples of preservatives include para-hydroxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Suitable examples of antioxidants include sulfites and ascorbic acid salts. Suitable examples of colorants include water-soluble food tar dyes (e.g., food colorants such as Food Red No. 2 and 3, Food Yellow No. 4 and 5, Food Blue No. 1 and 2), water-insoluble lake dyes (e.g., aluminum salts of the aforementioned water-soluble food tar dyes), and natural pigments (e.g., β-carotene, chlorophyll, red iron oxide). Suitable examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia.

[0167] Examples of dosage forms for the pharmaceutical composition include oral preparations such as tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), capsules (including soft capsules, microcapsules), pills, granules, powders, lozenges, syrups, liquids, emulsions, suspensions, aerosols, and films (e.g., orally disintegrating films, oral mucosal adhesive films); and parenteral preparations such as injections (e.g., subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drip infusions), topical preparations (e.g., transdermal preparations, ointments, lotions, patches), suppositories (e.g., rectal suppositories, vaginal suppositories), pellets, nasal preparations, pulmonary preparations (inhalants), and eye drops. The compounds and pharmaceuticals of the present invention can be safely administered orally or parenterally (e.g., rectally, intravenously, intraarterially, intramuscularly, subcutaneously, intraorganically, intranasally, intradermally, ophthalmally, intracerebrally, intravaginally, intraperitoneally, within a tumor, proximal to a tumor, etc., and directly to the lesion). These formulations may be controlled-release formulations such as immediate-release formulations or sustained-release formulations (e.g., sustained-release microcapsules).

[0168] Pharmaceutical compositions can be manufactured by methods commonly used in the pharmaceutical technology field, such as those described in the Japanese Pharmacopoeia. The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, the amount of the compound administered, etc., but is, for example, about 0.1 to 100% by weight. When manufacturing oral preparations, coating may be applied as needed for purposes such as masking the taste, enteric coating, or sustained release.

[0169] Examples of coating bases used in coating include sugar coating bases, water-soluble film coating bases, enteric-coated film coating bases, and sustained-release film coatings. A base material is one example. As the sugar coating base, sucrose is used, and one or more of the following may be used in combination: talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. Examples of water-soluble film coating bases include cellulosic polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; synthetic polymers such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], and polyvinylpyrrolidone; and polysaccharides such as pullulan. Examples of enteric-coated film coating bases include cellulosic polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethylcellulose, and cellulose acetate phthalate; acrylic acid polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 ​​(trade name)], and methacrylic acid copolymer S [Eudragit S (trade name)]; and natural products such as shellac. Examples of sustained-release film coating bases include cellulosic polymers such as ethylcellulose; acrylic acid polymers such as aminoalkyl methacrylate copolymer RS ​​[Eudragit RS (trade name)] and ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)]. The above-mentioned coating bases may be used by mixing two or more of them in appropriate proportions. Furthermore, a light-shielding agent such as titanium dioxide or iron(III) oxide may be used during the coating process.

[0170] The compounds of the present invention have low toxicity (e.g., acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and few side effects, and can be used in mammals (e.g., humans, cattle, horses, dogs, cats, monkeys, mice, rats) as preventive or therapeutic agents for various diseases, or as diagnostic agents.

[0171] The compounds of the present invention possess excellent orexin type 2 receptor agonist activity and can treat, prevent, and alleviate the risk of various neurological and psychiatric disorders associated with the orexin type 2 receptor. For example, the compounds of the present invention can be used to treat narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime hypersomnia (e.g., Kleine-Levin syndrome, major depressive disorder with hypersomnia, Lewy body dementia, Parkinson's disease, progressive supranuclear palsy, Prader-Willi syndrome, Moebius syndrome, hypoventilation syndrome, Niemann-Pick disease type C, cerebral contusion, cerebral infarction, brain tumor, muscular dystrophy, multiple sclerosis, etc. Acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen encephalitis, Wernicke encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g., malignant mast cell disease, exogenous obesity, hyperinsulinic obesity, hyperplasma obesity, pituitary obesity, hypoplasma obesity, hypothyroidism, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, diet-induced obesity, hyposexual dysfunction obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, impaired consciousness such as coma, side effects and complications of anesthesia, sleep disturbance, sleep problems, insomnia, intermittent sleep, nocturnal clonic muscle spasms, REM sleep interruption, jet lag, jet lag syndrome, sleep disorders in shift workers, sleep abnormalities, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's twilight, diseases associated with circadian rhythms, fibromyalgia, conditions resulting from poor sleep quality, overeating, obsessive-compulsive eating disorder, obesity-related diseases, hypertension, diabetes, plasma ingestion Children with elevated insulin levels and insulin resistance, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeat, arrhythmia, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovary disease, craniopharyngioma, Florich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, acute lymphoblastic leukemia, and other related conditions. Reduces the risk of syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, male hypogonadism, female hirsutism and other sexual and reproductive dysfunctions, fetal defects associated with gestational obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory disorders such as dyspnea, inflammation such as systemic inflammation of the vascular system, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, and left ventricular hypertrophy. Risks of secondary consequences of obesity, such as causing weight gain, migraines, headaches, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, facial flushing, night sweats, genital / urinary tract disorders, disorders of sexual function or fertility, dysthymia, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymic disorder, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders Acute neurological and psychiatric disorders such as cardiac bypass surgery and post-transplant cerebral malformations, stroke, ischemic stroke, cerebral ischemia, spinal cord injury, head injury, perinatal hypoxia, cardiac arrest, hypoglycemic neuropathy, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injury, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, movement disorders, chronic fatigue It is useful as a preventive and therapeutic agent for various diseases such as syndromes, fatigue, medication-induced Parkinson's syndrome, Gilles de la Tourette syndrome, chorea, myoclonus, tics, restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy, and traumatic brain injury.

[0172] In particular, the compounds of the present invention are useful for the treatment or prevention of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime excessive sleepiness (for example, Parkinson's disease, Guillain-Barré syndrome, and Kleine-Levin syndrome), Alzheimer's disease, obesity, insulin resistance syndrome, heart failure, diseases related to bone loss, sepsis, impaired consciousness such as coma, side effects and complications of anesthesia, and as an anesthetic antagonist.

[0173] The dosage of the compound of the present invention varies depending on the recipient, route of administration, target disease, symptoms, etc., but for example, when administered orally or parenterally to an adult patient, the usual single dose is about 0.01 to 100 mg / kg body weight, preferably 0.1 to 50 mg / kg body weight, and more preferably 0.5 to 20 mg / kg body weight, and it is desirable to administer this amount once to three times a day.

[0174] The compound of the present invention can be used in combination with other drugs (hereinafter abbreviated as "combination drugs"). By combining the compound of the present invention with a co-administered drug, (1) The dosage of the compound of the present invention or the concomitant drug can be reduced compared to when it is administered alone. (2) Depending on the patient's symptoms (mild, severe, etc.), a drug to be used in combination with the compound of the present invention can be selected. (3) By selecting a co-administered drug with a different mechanism of action from the compound of the present invention, the treatment period can be extended. (4) By selecting a co-administered drug with a different mechanism of action from the compound of the present invention, the therapeutic effect can be sustained. (5) By using the compound of the present invention in combination with a co-administered drug, excellent effects such as a synergistic effect can be obtained.

[0175] Hereinafter, the use of the compound of the present invention in combination with a co-administered drug will be referred to as the "combination agent of the present invention." When using the combination agent of the present invention, the timing of administration of the compound of the present invention and the combination drug is not limited. The compound of the present invention or its pharmaceutical composition and the concomitant drug or its pharmaceutical composition may be administered simultaneously to the target patient, or with a time difference. The dosage of the concomitant drug should be in accordance with clinically used dosages and can be appropriately selected depending on the target patient, route of administration, disease, combination, etc. The administration method of the combination agent of the present invention is not particularly limited, and it is sufficient that the compound of the present invention and the combination drug are combined at the time of administration. Examples of such administration methods include: (1) administration of a single formulation obtained by simultaneously formulating the compound of the present invention and the combination drug; (2) simultaneous administration of two formulations obtained by separately formulating the compound of the present invention and the combination drug via the same administration route; (3) administration of two formulations obtained by separately formulating the compound of the present invention and the combination drug via the same administration route with a time difference; (4) simultaneous administration of two formulations obtained by separately formulating the compound of the present invention and the combination drug via different administration routes; and (5) administration of two formulations obtained by separately formulating the compound of the present invention and the combination drug via different administration routes with a time difference (for example, administration in the order of the compound of the present invention; combination drug, or in the reverse order). The dosage of concomitant drugs can be appropriately selected based on clinically used doses. Furthermore, the mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the target patient, route of administration, target disease, symptoms, combination, etc. For example, the content of the compound of the present invention in the combination agent of the present invention varies depending on the form of the formulation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight relative to the total formulation. The content of the concomitant drug in the concomitant formulation of the present invention varies depending on the form of the formulation, but is usually about 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight relative to the total formulation. The content of additives such as carriers in the combination agent of the present invention varies depending on the form of the formulation, but is usually about 1 to 99.99% by weight of the total formulation, preferably about 10 to 90% by weight. Furthermore, the same content may be used when the compound of the present invention and the concomitant drug are formulated separately.

[0176] Examples of concomitant medications include: Narcolepsy medications (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), anti-obesity drugs (amphetamine, benzfetamine, bromocloptin, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, orlistat, fendimethrazine, fendimethrazine, fenmetrazine, phentermine, Qnexa®, phenylpropanolamine, plumrintide, propylhexedrine, recombinant Leptin, sibutramine, topiramate, dimerizine, zonisamide, lorcaserin, metformin), acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, zanapezil, idebenone, tacrine), antidementia agents (e.g., memantine), inhibitors of β-amyloid protein production, secretion, accumulation, aggregation and / or deposition, β-secretase inhibitors (e.g., 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetraline, 6-(4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetraline, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetraline) Lutetralin, 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methylbiphenyl-4-yl)methoxytetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-[4-(1,3-benzodioxol -5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, its optically active derivative, its salt and its hydrate, OM99-2 (International Publication 01 / 00663), γ-secretase inhibitor, β-amyloid protein Aggregation inhibitors (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (JP-Publication No. 11-514333), PPI-558 (JP-Publication No. 2001-500852), SKF-74652 (Biochem.J. (1999), 340(1), 283-289)), β-amyloid vaccines, β-amyloid-degrading enzymes, etc., brain function activators (e.g., aniracetam, Drugs for treating Parkinson's disease (e.g., dopamine receptor agonists (e.g., L-dopa, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine oxidase (MAO) inhibitors (e.g., deprenyl, cergiline, remasemide, riluzole), anticholinergics (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone)), drugs for treating amyotrophic lateral sclerosis (e.g., riluzole, neurotrophic factors), drugs for treating abnormal behavior and wandering associated with the progression of dementia (e.g., sedatives, anxiolytics), apoptosis inhibitors (e.g., CPI-1189, IDN-6556, CEP-1347), and neuronal differentiation and 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-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoin Drin, 6-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]-6,7-dihydro-5H-[1,3]dioxolo[4,5-f]isoindole and its optically active derivatives, salts, and hydrates), nonsteroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroid drugs (dexamethasone). (e.g., Sazon, hexestrol, cortisone acetate), disease-modifying antirheumatic drugs (DMARDs), anti-cytokine drugs (e.g., TNF inhibitors, MAP kinase inhibitors), urinary incontinence / frequent urination treatments (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitors (e.g., sildenafil citrate), dopamine agonists (e.g., apomorphine), antiarrhythmic drugs (e.g., mexiletine), sex hormones or their derivatives. (e.g., progesterone, estradiol, estradiol benzoate), osteoporosis treatments (e.g., alfacalcidol, calcitriol, elcatonin, salmoncalcitonin, estriol, ipriflavone, disodium pamidronate, sodium alendronate hydrate, disodium incadronate), parathyroid hormone (PTH), calcium receptor antagonists, insomnia treatments (e.g., benzodiazepines, non-benzodiazepines; (Pine-type drugs, melatonin agonists, orexin receptor antagonists), antipsychotics for schizophrenia (e.g., typical antipsychotics such as haloperidol; atypical antipsychotics such as clozapine, olanzapine, risperidone, and aripiprazole; drugs that act on metabotropic glutamate receptors or ion channel-coupled glutamate receptors; phosphodiesterase inhibitors), benzodiazepines Antidepressants (chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, clonazepam, alprazolam, etc.), L-type calcium channel inhibitors (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (fluvoxamine maleate, floxetine hydrochloride, citalopram bromide, sertraline hydrochloride, paroxetine hydrochloride) (e.g., escitalopram oxalate), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride), norepinephrine reuptake inhibitors (e.g., reboxetine mesylate), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT1A agonists (e.g., buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride), 5-HT2A antagonists 5-HT2A inverse agonists, 5-HT3 antagonists (such as siamemazine), non-cardiac selective β-blockers (such as propranolol hydrochloride and oxyprenolol hydrochloride), histamine H1 antagonists (such as hydroxyzine hydrochloride), CRF antagonists, other anxiolytics (such as meprobamate), tachykinin antagonists (such as MK-869 and saledutant), drugs acting on metabotropic glutamate receptors, CCK antagonists, β3 adrenergic antagonists (such as amibegron hydrochloride), GAT-1 inhibitors (such as thiagabine hydrochloride), N-type calcium channel inhibitors, type 2 carbonic anhydrase Inhibitors, NMDA glycine site agonists, NMDA antagonists (memantine, etc.), peripheral benzodiazepine receptor agonists, vasopressin antagonists, vasopressin V1b antagonists, vasopressin V1a antagonists, phosphodiesterase inhibitors, opioid antagonists, opioid agonists, uridine, nicotinic acid receptor agonists, thyroid hormones (T3, T4), TSH, TRH, MAO inhibitors (phenelzine sulfate, tranylcypromine sulfate, moclobemide, etc.), bipolar disorder medications (lithium carbonate, sodium valproate, lamotrigine, riluzo). Cannabinoid CB1 antagonists (such as ferbamate), FAAH inhibitors, sodium channel inhibitors, anti-ADHD drugs (such as methylphenidate hydrochloride and methamphetamine hydrochloride), drugs for treating alcohol dependence, drugs for treating autism, drugs for treating chronic fatigue syndrome, drugs for treating convulsions, drugs for treating fibromyalgia, drugs for treating headaches, drugs for smoking cessation, drugs for treating myasthenia gravis, drugs for treating stroke, drugs for treating mania, drugs for treating hypersomnia, drugs for treating pain, drugs for treating mood disorders, drugs for treating autonomic nervous system dysfunction, drugs for treating male and female sexual dysfunction, drugs for treating migraines, drugs for treating pathological gambling, lower limbs Drugs for treating restlessness syndrome, substance dependence, alcohol-related disorders, irritable bowel syndrome, dyslipidemia (such as cholesterol-lowering drugs like statins (pravastatin sodium, atrovastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthesis inhibitors), abnormal behavior drugs or drugs to suppress wandering tendencies due to dementia (sedatives, anxiolytics, etc.), diabetes drugs, drugs for treating diabetic complications, hypertension drugs, hypotension drugs, diuretics, chemotherapy agents, immunotherapy agents, antithrombotic agents, anticancer agents, etc.

[0177] The above-mentioned concomitant drugs may be used in combination of two or more types in appropriate proportions. Furthermore, when applying the compounds of the present invention to the above-mentioned diseases, it is possible to use them in combination with biological agents (e.g., antibody drugs, nucleic acids or nucleic acid derivatives, aptamer drugs, vaccine preparations), as well as in combination with gene therapy and non-pharmacological treatments in the field of psychiatry. Examples of antibody drugs and vaccine preparations include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, TNFα antibodies, antibodies against other cytokines, amyloid-beta vaccine preparations, type 1 diabetes vaccines (e.g., Peptor's DIAPEP-277), anti-HIV antibodies and HIV vaccine preparations, as well as antibodies or vaccine preparations against cytokines, renin-angiotensin system enzymes and their products, antibodies or vaccine preparations against enzymes and proteins involved in blood lipid metabolism, antibodies or vaccines against enzymes and proteins involved in the coagulation and fibrinolysis systems in the blood, and antibodies or vaccine preparations against proteins involved in glucose metabolism and insulin resistance. In addition, combination therapy with biologics related to growth factors such as GH and IGF is also possible. Examples of gene therapies include those using genes related to cytokines, renin-angiotensin system enzymes and their products, G proteins, G protein-coupled receptors and their phosphorylation enzymes; those using DNA decoys such as NFκB decoys; those using antisense; those using genes related to enzymes and proteins involved in blood lipid metabolism (e.g., genes related to the metabolism, excretion, and absorption of cholesterol or triglycerides or HDL-cholesterol or blood phospholipids); those using genes related to enzymes and proteins involved in angiogenesis therapy for peripheral vascular occlusion (e.g., growth factors such as HGF and VEGF); those using genes related to proteins involved in glucose metabolism and insulin resistance; and antisense against cytokines such as TNF. Non-pharmacological treatments in the field of psychiatry include modified electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, and psychotherapy including cognitive behavioral therapy. Furthermore, the compounds of the present invention can be used in combination with various organ regeneration methods such as cardiac regeneration, kidney regeneration, pancreatic regeneration, and blood vessel regeneration, as well as cell transplantation therapy using bone marrow cells (bone marrow mononuclear cells, bone marrow stem cells), and artificial organs using tissue engineering (e.g., artificial blood vessels, myocardial cell sheets). [Examples]

[0178] The present invention will be further described in detail by the following examples, test examples, and formulation examples, but these are not intended to limit the present invention and may be modified without departing from the scope of the present invention. In the following examples, "room temperature" typically refers to approximately 10°C to 35°C. Ratios given for mixed solvents are volume ratios unless otherwise specified. Percentages (%) refer to weight percentages unless otherwise specified. Unless otherwise specified, elution in the column chromatography of the examples was performed under observation by TLC (Thin Layer Chromatography). For TLC observation, a Merck 60 F TLC plate was used. 254 The solvent used was the same solvent used as the elution solvent in column chromatography. A UV detector was used for detection. In silica gel column chromatography, NH indicated aminopropylsilane-bonded silica gel, and DIOL indicated 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel. For preparative HPLC (high-performance liquid chromatography), the column was Boston. Prime C18 (150 mm x 30 mm, 5 μm), Xtimate C18 (100 mm x 30 mm, 3 μm), Gemini NX C18 (150 mm x 30 mm, 5 μm), YMC Triart C18 (250 mm x 50 mm, 7 μm), Exsil plus C18 (150 mm x 50 mm, 5 μm), or Water Xbridge C18 (150 mm x 30 mm, 5 μm) The conditions used included, mobile phase: 0.05% aqueous ammonia / MeCN. When C18 is written, A tadecyl-bonded silica gel was used. Unless otherwise specified, the ratios shown for the elution solvent are volume ratios. 1 For 1H NMR analysis, software such as ACD / SpecManager (product name) was used. Proton peaks that are very gradual, such as those of hydroxyl groups and amino groups, may not be shown. MS was measured by LC / MS. ESI or APCI was used as the ionization method. The data shown are the found values. Typically, molecular ion peaks are observed, but sometimes fragment ions are observed. In the case of salts, typically either the molecular ion peak of the free form or a fragment ion peak is observed. The 6-bromopyridine-2-ol in the examples may exist as the tautomer 6-bromopyridine-2(1H)-one. The following abbreviations are used in the following examples. MS: Mass Spectrum M: Molar concentration N: Normality CDCl3: Deuterated chloroform DMSO-d6: Deuterated Dimethyl Sulfoxide 1 1H NMR: Proton Nuclear Magnetic Resonance LC / MS: Liquid Chromatography Mass Spectrometer ESI: electrospray ionization APCI: atmospheric pressure chemical ionization IPE: Diisopropyl ether IPA: 2-propanol DMF: N,N-dimethylformamide THF: Tetrahydrofuran MeOH: methanol MeCN: Acetonitrile NMP: N-methylpyrrolidone CPME: Cyclopentyl methyl ether DME: 1,2-dimethoxyethane DMSO: Dimethyl sulfoxide DCM: Dichloromethane DCE: Dichloroethane EtOH: Ethanol XPhos Pd G3: (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-bifu [2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate SFC: Supercritical Fluid Chromatography HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOBt: 1-hydroxybenzotriazole EDCI: N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride TEA: Triethylamine DIPEA: N,N-diisopropylethylamine NaH: Sodium hydride Boc: tert-butoxycarbonyl DMAP: 4-dimethylaminopyridine CO2: Carbon dioxide Pd / C: Palladium Carbon

[0179] Example 23 N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide

[0180] A) tert-butyl (S)-3-(methylsulfonamide)pyrrolidine-1-carboxylate tert-butyl (S)-3-aminopyrrolidine-1-carboxylate (4.93 g) and THF (20 mL) To the mixture, add triethylamine (5.53 mL) and methanesulfonic anhydride (4.61 g) at 0 °C and stir at room temperature for 3 hours. Dilute the mixture with ethyl acetate and water at 0 °C, then with ethyl acetate. Extraction was performed. The organic layer was washed with saturated saline solution, dried over sodium sulfate, passed through a silica gel pad, and concentrated under reduced pressure to obtain the title compound (6.39 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.39 (9H, s), 1.69-1.88 (1H, m), 1.97-2.14 (1H, m), 2.94 (3H, s), 3.08 (1H, dd, J = 10.9, 5.6 Hz), 3.14-3.27 (1H, m), 3.28-3.38 (1H, m), 3.43-3.53 (1H, m), 3.80-3.93 (1H, m), 7.34 (1H, s).

[0181] B) (S)-N-(pyrrolidine-3-yl)methanesulfonamide hydrochloride A mixture of tert-butyl (S)-3-(methylsulfonamide)pyrrolidine-1-carboxylate (6.39 g) and 4 M ethyl hydrogen chloride solution (72.5 mL) was stirred overnight at room temperature. To the resulting suspension, heptane (50 mL) was added while stirring, the precipitate was collected, and washed with ethyl acetate. The mixture was dried at 50°C to obtain the title compound (3.71 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.81-1.96 (1H, m), 2.09-2.23 (1H, m), 2.99 (3H, s), 3.05 (1H, dd, J = 12.0, 5.3 Hz), 3.13-3.28 (2H, m), 3.33-3.39 (1H, m), 3.96-4.10 (1H, m), 7.48 (1H, br s), 8.93 (2H, br s).

[0182] C) rac-ethyl (1R,2R)-2-(2-bromophenyl)cyclopropane-1-carboxylate Trimethylsulfoxonium iodide (82.8 g) was gradually added to a mixture of potassium tert-butoxide (42.2 g) and DMSO (400 mL) at room temperature. After stirring at the same temperature for 1 hour, eth Add (E)-3-(2-bromophenyl)acrylate (80.0 g) in DMSO (400 mL) solution, The mixture was then stirred at the same temperature for 12 hours. The mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (34.4 g). Ta. 1 H NMR (400 MHz, CDCl3) δ 1.27-1.36 (4H, m), 1.61-1.67 (1H, m), 1.75-1.83 (1H, m), 2.66-2.75 (1H, m), 4.14-4.28 (2H, m), 6.98-7.05 (1H, m), 7.06-7.13 (1H, m), 7.19-7.26 (1H, m), 7.56 (1H, dd, J = 8.0, 1.2 Hz).

[0183] D) rac-ethyl (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate rac-ethyl (1R,2R)-2-(2-bromophenyl)cyclopropane-1-carboxylate (5.00 g), 2,6-difluorophenylboronic acid (8.80 g), DME (60 mL), and water (50 mL) Xphos Pd G3 (1.57 g) and tripotassium phosphate (11.8 g) were added to the mixture and stirred at 100 °C under a nitrogen atmosphere for 12 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was saturated with After washing with brine, the mixture was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (3.73 g). MS: [M+H] + 303.3.

[0184] E) rac-(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylic acid A mixture of rac-ethyl (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate (3.73 g) and EtOH (40 mL) was mixed with aqueous sodium hydroxide solution (4.93 g / 20 mL) and stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure and diluted with water to 2 M. The pH was adjusted to 4 with hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The compound was concentrated under reduced pressure to obtain the title compound (3.37 g). 1 H NMR (400 MHz, CDCl3) δ 1.30-1.37 (1H, m), 1.40-1.47 (1H, m), 1.70-1.76 (1H, m), 2.39-2.46 (1H, m), 6.94-7.03 (2H, m), 7.15 (1H, t, J = 7.2 Hz), 7.26-7.41 (4H, m)

[0185] F) A mixture of N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide and N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide rac-(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-cal (2.00 g) (S)-N-(pyrrolidine-3-yl)methanesulfonamide hydrochloride (1.46 g) Add DIPEA (3.77 g) to a mixture of HATU (2.91 g) and DMF (15 mL), and leave at room temperature for 12 hours. The mixture was stirred. The mixture was purified by reverse-phase silica gel column chromatography (C18, methanol / water) to obtain the title compound (1.53 g). MS: [M+H] + 421.1.

[0186] G) N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide and N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidine-3-yl A mixture of methanesulfonamide (4.10 g) was analyzed using SFC (column: Phenomenex-Cellulose-2, 250 mm x 50 mm, 10 μm, mobile phase: CO2 / 0.1% aqueous ammonia containing EtOH = 55 / 45 v / v). The fractions were separated, and the fraction with the shortest retention time was concentrated. The residue was dissolved in MeCN (10 mL) and water (50 mL) and freeze-dried. The resulting solid was powdered with petroleum ether / ethyl acetate and then... A compound (1.31 g) was obtained. 1H NMR (400 MHz, CDCl3) δ 1.24-1.32 (1H, m), 1.42-1.52 (1H, m), 1.58-1.72 (1H, m), 1.78-2.10 (1H, m), 2.10-2.30 (1H, m), 2.32-2.43 (1H, m), 2.98 (3H, d, J = 12.0 Hz), 3.27-3.76 (4H, m), 3.94-4.12 (1H, m), 4.67-4.99 (1H, m), 6.91-7.05 (2H, m), 7.14 (1H, d, J = 7.6 Hz), 7.22-7.41 (4H, m).

[0187] Example 24 N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]piperidine-3-yl}methanesulfonamide

[0188] A) tert-butyl (S)-3-(methylsulfonamide)piperidine-1-carboxylate tert-butyl (S)-3-aminopiperidine-1-carboxylate (11.4 g) and THF (50 mL) To the mixture, triethylamine (11.9 mL) and methanesulfonic anhydride (9.92 g) were added at 0 °C, and the mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate and water at 0 °C, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, passed through a silica gel pad, and concentrated under reduced pressure to obtain the title compound (14.9 g). 1 H NMR (300 MHz, CDCl3) δ 1.40-1.80 (12H, m), 1.87-2.01 (1H, m), 3.01 (3H, s), 3.19-3.34 (2H, m), 3.35-3.57 (2H, m), 3.62-3.75 (1H, m), 4.54 (1H, br d, J = 6.0 Hz).

[0189] B) (S)-N-(piperidine-3-yl)methanesulfonamide hydrochloride A mixture of tert-butyl (S)-3-(methylsulfonamide)piperidine-1-carboxylate (14.9 g) and a 4 M hydrogen chloride CPME solution (134 mL) was stirred at room temperature for 3 hours. The CPME was removed by decantation, and the remaining gum-like substance was dried to obtain the title compound (10.0 g). 1 H NMR (300 MHz, DMSO-d6) δ 1.37-2.00 (4H, m), 2.62-2.85 (2H, m), 2.98 (3H, s), 3.04-3.17 (1H, m), 3.20-3.33 (1H, m), 3.47-3.61 (1H, m), 7.45 (1H, d, J = 7.2 Hz), 8.87-9.26 (2H, m).

[0190] C) A mixture of N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]piperidine-3-yl}methanesulfonamide and N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]piperidine-3-yl}methanesulfonamide rac-(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-cal (3.00 g) Pine acid, (S)-N-(piperidine-3-yl)methanesulfonamide hydrochloride (2.35 g) Add DIPEA (5.65 g) to a mixture of HATU (4.37 g) and DMF (30 mL), and leave at room temperature for 12 hours. The mixture was stirred. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (4.93 g). MS: [M+H]+ 435.1.

[0191] D) N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]piperidine-3-yl}methanesulfonamide N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]piperidine-3-yl}methanesulfonamide and N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]piperidine-3-yl A mixture of methanesulfonamide (4.93 g) was subjected to SFC (column: Phenomenex-Cellulose-2, 250 mm x 50 mm, 10 μm, mobile phase: CO2 / 0.1% aqueous ammonia containing EtOH = 55 / 45 v / v) The fractions were separated, and the fraction with the shortest retention time was concentrated. The residue was dissolved in MeCN (10 mL) and water (50 mL), lyophilized, and the title compound (1.56 g) was obtained. 1 H NMR (400 MHz, CDCl3) δ 1.22-1.36 (1H, m), 1.43-1.50 (1H, m), 1.51-1.61 (1H, m), 1.78-2.02 (4H, m), 2.20-2.42 (1H, m), 2.77-3.04 (3H, m), 3.27-3.92 (5H, m), 4.47-4.77 (1H, m), 6.92-7.42 (7H, m).

[0192] Example 25 N-{(4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azepan-4-yl}methanesulfonamide

[0193] A) tert-butyl 4-(methylsulfonamide)azepan-1-carboxylate A mixture of tert-butyl 4-aminoazepan-1-carboxylate (20.0 g) and DCM (180 mL) Add triethylamine (18.9 g) and methanesulfonyl chloride (13.9 g) to the mixture at 0°C. The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with DCM. The organic layer was then saturated with saline solution. After washing, the sample was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (28.5 g). 1 H NMR (400 MHz, CDCl3) δ 1.45 (9H, s), 1.65-2.15 (5H, m), 2.95 (3H, s), 3.06-3.67 (6H, m), 4.64 (1H, d, J = 7.6 Hz).

[0194] B) N-(azepan-4-yl)methanesulfonamide hydrochloride tert-butyl 4-(methylsulfonamide)azepan-1-carboxylate (28.5 g) and 4 M A mixture of hydrogen chloride and dioxane solution (100 mL) was stirred at room temperature for 1 hour. The solvent was then removed under reduced pressure. The compound was removed, and the title compound (23.5 g) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 1.53-2.14 (6H, m), 2.90-3.21 (7H, m), 3.35-3.52 (1H, m), 7.23 (1H, d, J = 6.8 Hz), 9.16 (2H, brs).

[0195] C) A mixture of rac-N-{(4R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azepan-4-yl}methanesulfonamide and rac-N-{(4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azepan-4-yl}methanesulfonamide rac-(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-cal Bonic acid (150 mg), N-(azepan-4-yl)methanesulfonamide hydrochloride (150 mg), DIPEA Add HATU (312 mg) at 0°C to a mixture of (212 mg) and DMF (5.0 mL), and leave at room temperature for 12 hours. The mixture was stirred. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative HPLC (C18, 0.05% ammonia). The compound was purified with water / MeCN and freeze-dried to obtain the title compound (105 mg). MS: [M+H] + 449.3.

[0196] D) N-{(4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azepan-4-yl}methanesulfonamide rac-N-{(4R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopro A mixture (105 mg) of pan-1-carbonyl]azepan-4-yl}methanesulfonamide and rac-N-{(4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropan-1-carbonyl]azepan-4-yl}methanesulfonamide was fractionated by SFC (column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 5 μm, mobile phase: CO2 / 0.1% aqueous ammonia MeOH = 45 / 55 v / v), the fraction with the shortest retention time was concentrated, and the residue was dissolved in MeCN (3.0 mL) and water (3.0 mL), lyophilized, and the crude product (45 mg) was obtained. This was further separated using SFC (column: DAIEL CHIRALPAK IG, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / 0.1% aqueous ammonia IPA = 60 / 40 v / v), and the fraction with the shortest retention time was concentrated. The residue was then processed using MeCN (3.0 The compound (13 mg) was dissolved in water (3.0 mL) and lyophilized to obtain the title compound. 1 H NMR (400 MHz, CDCl3) δ 1.25-1.28 (1H, m), 1.46-1.53 ​​(1H, m), 1.57-2.40 (8H, m), 2.95-2.97 (3H, m), 3.17-3.78 (5H, m), 4.15-4.19 (1H, m), 6.90-7.14 (3H, m), 7.26-7.41 (4H, m).

[0197] Example 195 N-{(3S)-1-[(1R,2R)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane N-1-carbonyl]pyrroridine-3-yl}methanesulfonamide, or N-{(3S)-1-[(1S,2S)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]py Loridine-3-ylmethanesulfonamide

[0198] A) Ethyl (2E)-3-(2-bromo-6-fluorophenyl)propa-2-enoate To a mixture of ethyl 2-diethoxyphosphoryl acetate (64.6 g) and THF (450 mL), 60% NaH (10.6 g) was added at 0 °C. After stirring at room temperature for 15 minutes, 2-bromo-6-fluorobenzaldehyde (45.0 g) was added and the mixture was stirred at the same temperature for 2 hours. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to obtain the title compound (59.8 g). 1 H NMR (400 MHz, CDCl3) δ 1.34 (3H, t, J = 7.2 Hz), 4.28 (2H, q, J = 7.2 Hz), 6.61-6.69 (1H, m), 7.04-7.11 (1H, m), 7.12-7.20 (1H, m), 7.43 (1H, d, J = 8.0 Hz), 7.83 (1H, d, J = 16.4 Hz).

[0199] B) rac-ethyl (1R,2R)-2-(2-bromo-6-fluorophenyl)cyclopropane-1-carboxylate To a mixture of potassium tert-butoxide (14.7 g) and DMSO (250 mL), trimethylsulfoxonium iodide (28.8 g) was added at room temperature. After stirring at the same temperature for 30 minutes, a solution of ethyl (2E)-3-(2-bromo-6-fluorophenyl)propa-2-enoate (29.8 g) in DMSO (250 mL) was added, and the mixture was stirred at the same temperature for a further 6 hours. The reaction was stopped by adding saturated ammonium chloride aqueous solution. The reaction was stopped and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether). The same reaction was carried out in two batches to obtain the title compound (42.2 g). 1H NMR (400 MHz, CDCl3) δ 1.30 (3H, t, J = 7.2 Hz), 1.44-1.52 (1H, m), 1.63-1.74 (1H, m), 1.92-2.02 (1H, m), 2.38-2.48 (1H, m), 4.16-4.28 (2H, m), 6.93-7.00 (1H, m), 7.02-7.11 (1H, m), 7.34-7.39 (1H, m).

[0200] C) rac-ethyl (1R,2R)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate rac-ethyl (1R,2R)-2-(2-bromo-6-fluorophenyl)cyclopropane-1-carboxy A mixture of Rad (15.0 g), 2,6-difluorophenylboronic acid (33.0 g), and DME (100 mL) was mixed with tripotassium phosphate aqueous solution (33.3 g / 100 mL) and Xphos Pd G3 (4.42 g), and stirred at 100 °C for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was saturated. After washing with saline solution, the mixture was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN), lyophilized, and the title compound (2.00 g) was obtained. MS: [M+H] + 321.0.

[0201] D) rel-ethyl (1R,2R)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate rac-ethyl (1R,2R)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopro Pan-1-carboxylate (1.00 g) was fractionated by SFC (column: DAIEL CHIRALCEL OD-H, 250 mm x 30 mm, 5 μm, mobile phase: CO2 / 0.1% aqueous ammonia IPA = 90 / 10 v / v), and the compound with the longer retention time was obtained as the title compound (320 mg). MS: [M+H] + 321.0.

[0202] E) rel-(1R,2R)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylic acid rel-ethyl (1R,2R)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate (320 mg) synthesized in step D), sodium hydroxide aqueous solution (400 mg / A mixture of 1.5 mL of ethyl acetate and 4.5 mL of EtOH was stirred at room temperature for 16 hours. The mixture was adjusted to a pH of 5-6 with 2 M hydrochloric acid, diluted with water, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (330 mg). 1 H NMR (400 MHz, CDCl3) δ 1.15-1.30 (1H,m), 1.34-1.43 (1H, m), 1.64-1.71 (1H, m), 2.35-2.44 (1H, m), 6.94-7.14 (4H, m), 7.25-7.40 (2H, m).

[0203] F) N-{(3S)-1-[(1R,2R)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide, or N-{(3S)-1-[(1S,2S)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl] Pyrrolidine-3-ylmethanesulfonamide (S)-N-(pyrrolidine-3-yl)methanesulfonamide hydrochloride (60.4 mg), rel-(1R,2R)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1- A mixture of carboxylic acid (80.0 mg) and DMF (3 mL) is mixed with HATU (125 mg) and DIPEA (106 mg). The mixture was added and stirred at room temperature for 16 hours. Water was added to stop the reaction, and the mixture was extracted with ethyl acetate. The chamber was washed with saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN), freeze-dried, and the title compound (70.5 mg) was obtained. I got it. 1 H NMR (400 MHz, CDCl3) δ 0.94-1.04 (1H, m), 1.27-1.35 (1H, m), 1.68-2.12 (2H, m), 2.15-2.31 (1H, m), 2.33-2.40 (1H, m), 3.01 (3H, s), 3.38-3.76 (4H, m), 3.97-4.16 (1H, m), 4.45-4.75 (1H, m), 6.96-7.12 (4H, m), 7.27-7.43 (2H, m).

[0204] Example 200 N-{(3S)-1-[(1R,2R)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane N-1-carbonyl]pyrroridine-3-yl}methanesulfonamide, or N-{(3S)-1-[(1S,2S)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]py Loridine-3-ylmethanesulfonamide

[0205] A) Ethyl (2E)-3-(2-bromo-4-fluorophenyl)propa-2-enoate To a mixture of ethyl 2-diethoxyphosphoryl acetate (35.9 g) and THF (250 mL), 60% NaH (5.91 g) was added at 0 °C. After stirring at room temperature for 15 minutes, 2-bromo-4-fluorobenzaldehyde (25.0 g) was added and stirred at the same temperature for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (36.9 g). I got it. 1 H NMR (400 MHz, CDCl3) δ 1.35 (3H, t, J = 7.2 Hz), 4.29 (2H, q, J = 7.2 Hz), 6.34 (1H, d, J = 16.0 Hz), 7.02-7.13 (1H, m), 7.37 (1H, dd, J = 8.0, 2.8 Hz), 7.60 (1H, dd, J = 8.8, 6.0 Hz), 7.99 (1H, d, J = 16.0 Hz).

[0206] B) rac-ethyl (1R,2R)-2-(2-bromo-4-fluorophenyl)cyclopropane-1-carboxylate A mixture of potassium tert-butoxide (18.5 g) and DMSO (150 mL) was mixed with trimethylsulfoxonium iodide (36.2 g) at room temperature. After stirring at the same temperature for 30 minutes, a mixture of ethyl (2E)-3-(2-bromo-4-fluorophenyl)propa-2-enoate (37.4 g) and DMSO (150 mL) was added, and the mixture was stirred at the same temperature for a further 6 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (13.0 g). 1H NMR (400 MHz, CDCl3) δ 1.27-1.32 (4H, m), 1.59-1.66 (1H, m), 1.71-1.81 (1H, m), 2.60-2.68 (1H, m), 4.17-4.25 (2H, m), 6.91-7.04 (2H, m), 7.33 (1H, dd, J = 8.4, 2.8 Hz).

[0207] C) rac-ethyl (1R,2R)-2-[4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropane-1-carboxylate rac-ethyl (1R,2R)-2-(2-bromo-4-fluorophenyl)cyclopropane-1-carboxy A mixture of lat (5.00 g), bis(pinacolato)diborone (6.63 g), and DMSO (50 mL) contains dichloropalladium(II) dichloropalladium (1,1'-bis(diphenylphosphino)ferrocene). Lomethane complex (1.42 g) and potassium acetate (3.42 g) were added, and the mixture was stirred at 100 °C under a nitrogen atmosphere for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (3.96 g). 1 H NMR (400 MHz, CDCl3) δ 1.25-1.35 (16H, m), 1.49-1.58 (1H, m), 1.63-1.76 (1H, m), 3.01-3.19 (1H, m), 4.04-4.28 (2H, m), 6.90-6.96 (1H, m), 6.98-7.05 (1H, m), 7.45 (1H, dd, J = 9.2, 2.8 Hz).

[0208] D) rac-ethyl (1R,2R)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate rac-ethyl (1R,2R)-2-[4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxavorola A mixture of phenyl-2-yl)phenyl-1-carboxylate (3.96 g), 1,3-difluoro-2-iodobenzene (2.84 g), and DME (35 mL) was mixed with Xphos Pd G3 (1.00 g) and tripotassium phosphate (7.55 g), and stirred under a nitrogen atmosphere at 100 °C for 16 hours. The mixture was then dissolved in water. The solution was diluted and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether). The title compound (2.32 g) was obtained. 1 H NMR (400 MHz, CDCl3) δ 1.17-1.26 (4H, m), 1.35-1.41 (1H, m), 1.61-1.68 (1H, m), 2.28-2.37 (1H, m), 3.91-4.08 (2H, m), 6.92-7.02 (3H, m), 7.03-7.09 (1H, m), 7.10-7.16 (1H, m), 7.31-7.39 (1H, m).

[0209] E) rac-(1R,2R)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylic acid A mixture of sodium hydroxide (578 mg), ethOH (20 mL), and water (5 mL) is mixed with rac-eth. (1R,2R)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate (2.32 g) was added and the mixture was stirred at room temperature for 5 hours. The mixture was diluted with water, the pH was adjusted to 5-6 with 2 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the title compound (1.99 g). 1 H NMR (400 MHz, CDCl3) δ 1.25-1.31 (1H, m), 1.38-1.48 (1H, m), 1.58-1.71 (1H, m), 2.29-2.44 (1H, m), 6.97-7.16 (5H, m), 7.30-7.38 (1H, m).

[0210] F) rel-(1R,2R)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylic acid rac-(1R,2R)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1- 500 mg of carboxylic acid was separated by SFC (column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / 0.1% aqueous ammonia MeOH = 80 / 20 v / v), and the solution with the shorter retention time was freeze-dried to obtain the title compound (82.0 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.07-1.21 (1H, m), 1.21-1.33 (1H, m), 1.56-1.69 (1H, m), 1.89-2.04 (1H, m), 7.14-7.30 (5H, m), 7.49-7.58 (1H, m).

[0211] G) N-{(3S)-1-[(1R,2R)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide, or N-{(3S)-1-[(1S,2S)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl] Pyrrolidine-3-ylmethanesulfonamide The rel-(1R,2R)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclo obtained in step F Propane-1-carboxylic acid (30.0 mg), (S)-N-(pyrrolidine-3-yl)methanesulfonamide To a mixture of hydrochloride (20.6 mg) and DMF (1 mL), HATU (39.0 mg) and DIPEA (66.3 mg) were added at 0 °C, and the mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The chamber was dried with sodium sulfate and concentrated under reduced pressure. The residue was separated by preparative HPLC (C18, 0.05%). The compound was purified with Monia water (MeCN), freeze-dried, and the title compound (18.0 mg) was obtained. 1 H NMR (400 MHz, CDCl3) δ 1.17-1.27 (1H, m), 1.40-1.48 (1H, m), 1.52-1.63 (1H, m), 1.80-2.38 (3H, m), 2.98-3.01 (3H, m), 3.28-3.72 (4H, m), 3.92-4.12 (1H, m), 4.50-5.00 (1H, m), 6.94-7.16 (5H, m), 7.30-7.45 (1H, m).

[0212] Example 215 N-{(3R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidine-3-yl}methanesulfonamide, or N-{(3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidine-3-yl}methanesulfonamide

[0213] A) A mixture of tert-butyl {(3R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidine-3-yl}carbamate and tert-butyl {(3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidine-3-yl}carbamate rac-(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-cal Bonic acid (80 mg), tert-butyl N-[(3R)-4,4-difluoro-3-piperidyl]carbamate (83 To a mixture of (mg) and DMF (5 mL), HOBt (39 mg), EDCI (84 mg), and TEA (118 mg) were added and stirred at room temperature for 13 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (200 mg). I obtained it. MS, found: 437.1.

[0214] B) A mixture of N-{(3R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidine-3-yl}methanesulfonamide and N-{(3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidine-3-yl}methanesulfonamide tert-butyl {(3R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl) methyl A mixture of cyclopropan-1-carbonyl]-4,4-difluoropiperidine-3-yl}carbamate and tert-butyl{(3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropan-1-carbonyl]-4,4-difluoropiperidine-3-yl}carbamate (200 mg), A mixture of fluoroacetic acid (3 mL) and DCM (5 mL) was stirred at room temperature for 13 hours. The mixture was concentrated under reduced pressure to obtain a mixture (201 mg) of [(3R)-3-amino-4,4-difluoropiperidine-1-yl][(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate and [(3R)-3-amino-4,4-difluoropiperidine-1-yl][(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate. A mixture of [(3R)-3-amino-4,4-difluoropiperidine-1-yl][(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate and [(3R)-3-amino-4,4-difluoropiperidine-1-yl][(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate (201 mg) and DCM (5 mL) was mixed with methanesulfonyl chloride (68 mg) and TEA (161 mg), and the mixture was stirred at room temperature for 13 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative HPLC (C18, 0.05% ammonia). The compound was purified with water / MeCN and freeze-dried to obtain the title compound (38.9 mg). MS: [M+H] + 471.2.

[0215] C) N-{(3R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidine-3-yl}methanesulfonamide, or N-{(3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl [Bonyl]-4,4-difluoropiperidine-3-yl}methanesulfonamide A mixture of N-{(3R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidine-3-yl}methanesulfonamide (37 mg) was fractionated by SFC (column: DAIEL CHIRALPAK IG, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / 0.1% aqueous ammonia EtOH = 70 / 30 v / v), the fraction with the shorter retention time was concentrated, and the residue was mixed with MeCN (1 mL) and water. The compound was dissolved in (30 mL) and freeze-dried to obtain the title compound (10.6 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.15-1.24 (2H, m), 1.98-2.30 (4H, m), 2.65-3.26 (5H, m), 3.41-3.93 (2H, m), 4.02-4.25 (1H, m), 7.15-7.27 (4H, m), 7.29-7.55 (3H, m), 7.80 (1H, brs).

[0216] Example 216 N-{(3R,4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-fluoropiperidine-3-yl}methanesulfonamide, or N-{(3R,4S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-fluoropiperidine-3-yl}methanesulfonamide

[0217] A) tert-butyl {(3R,4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl) Cyclopropane-1-carbonyl]-4-fluoropiperidine-3-yl}carbamate and tert-butyl {(3R,4S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane A mixture of n-1-carbonyl-4-fluoropiperidine-3-yl carbamate rac-(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-cal A mixture of 100 mg of benzoic acid, 96 mg of tert-butyl N-(3R,4S)-4-fluoro-3-piperidyl]carbamate, and 3 mL of DMF was mixed with 49 mg of HOBt, 105 mg of EDCI, and 148 mg of TEA, and stirred at room temperature for 13 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (215 mg). I obtained it. MS, found: 375.1.

[0218] B) N-{(3R,4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopro A mixture of pan-1-carbonyl]-4-fluoropiperidine-3-yl}methanesulfonamide and N-{(3R,4S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropan-1-carbonyl]-4-fluoropiperidine-3-yl}methanesulfonamide tert-butyl {(3R,4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-fluoropiperidine-3-yl}carbamate and tert-butyl A mixture of {(3R,4S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-fluoropiperidine-3-yl}carbamates (215 mg), truffle A mixture of oelloacetate (3 mL) and DCM (5 mL) was stirred at room temperature for 13 hours. The mixture was concentrated under reduced pressure to obtain [(3R,4S)-3-amino-4-fluoropiperidine-1-yl][(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate and [(3R,4S)-3-amino-4-fluoropiperidine-1-yl][(1S,2S)-2-(2',6'-difluoro[1,1'- Mixture of biphenyl-2-yl cyclopropyl methanone trifluoroacetate (250 mg) I obtained it. [(3R,4S)-3-amino-4-fluoropiperidine-1-yl][(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate and [(3R,4S)-3-amino-4-fluoropiperidine-1-yl][(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2- A mixture of cyclopropyl(yl)methanone trifluoroacetate (250 mg) and DCM (5 mL) To the mixture, add methanesulfonyl chloride (115 mg) and TEA (270 mg), and leave at room temperature until 13:00. The mixture was stirred. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative HPLC (C18, 0.05% ammonia). The compound was purified with water / MeCN and freeze-dried to obtain the title compound (47.2 mg). MS: [M+H] + 453.2.

[0219] C) N-{(3R,4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopro Pan-1-carbonyl]-4-fluoropiperidine-3-yl}methanesulfonamide, or N-{(3R,4S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-fluoropiperidine-3-yl}methanesulfonamide A mixture of N-{(3R,4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-fluoropiperidine-3-yl}methanesulfonamide and N-{(3R,4S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-fluoropiperidine-3-yl}methanesulfonamide (44 mg) was subjected to SFC (column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / 0.1% aqueous ammonia). The compound was separated according to the EtOH content (65 / 35 v / v), the fraction with the shorter retention time was concentrated, and the residue was dissolved in MeCN (1 mL) and water (30 mL), then freeze-dried to obtain the title compound (14.6 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.11-1.23 (2H, m), 1.58-2.05 (3H, m), 2.12-2.26 (1H, m), 2.63-3.24 (5H, m), 3.39-3.81 (2H, m), 3.85-4.15 (1H, m), 4.79-5.01 (1H, m), 7.15-7.27 (4H, m), 7.29-7.55 (4H, m).

[0220] Example 226 N-{4,4-difluoro-1-[2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopro Pan-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide optical isomer

[0221] A) 1-Benzyl-4,4-difluoropyrrolidine-3-yl trifluoromethanesulfonate To a mixture of 1-benzyl-4,4-difluoropyrrolidine-3-ol (1.50 g) and DCM (50 mL), pyridine (2.78 g) and a mixture of trifluoromethanesulfonic anhydride (6.95 g) and DCM (5.0 mL) were added dropwise at -10 °C, and the mixture was stirred at the same temperature for 2 hours. The mixture was poured into water and extracted with DCM. Removed. The organic layer was washed with a 5% citric acid solution and saturated saline solution, then dried with sodium sulfate. The mixture was dried and concentrated under reduced pressure to obtain the title compound (2.00 g). 1 H NMR (400 MHz, CDCl3) δ 2.83-2.88 (1H, m), 2.9-3.01 (1H, m), 3.07-3.16 (1H, m), 3.27-3.31 (1H, m), 3.69 (2H, s), 5.05-5.18 (1H, m), 7.27-7.39 (5H, m).

[0222] B) 4-Azido-1-benzyl-3,3-difluoropyrrolidine 1-Benzyl-4,4-difluoropyrrolidine-3-yl trifluoromethanesulfonate (1.8 To a mixture of (g) and MeCN (30 mL), tetrabutylammonium azide (2.97 g) was added and stirred at 80 °C for 2 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was saturated with sodium chloride. After washing with water, the mixture was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (1.10 g). 1H NMR (400 MHz, CDCl3) δ 2.59-2.64 (1H, m), 2.83-3.16 (3H, m), 3.55-3.72 (2H, m), 3.82-3.98 (1H, m), 7.27-7.37 (5H, m).

[0223] C) rac-N-[(3S)-1-benzyl-4,4-difluoropyrrolidine-3-yl]methanesulfonamide Add triphenylphosphine (2.19 g, 20% purity in the resin) to a mixture of 4-azido-1-benzyl-3,3-difluoropyrrolidine (500 mg), THF (15 mL), and water (2.0 mL), and 70 The mixture was stirred at °C for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain 1-benzyl-4,4-difluoropyrrolidine-3-amine (460 mg). 1-Benzyl-4,4-difluoropyrrolidine-3-amine (860 mg), TEA (820 mg), and DCM Add methanesulfonyl chloride (650 mg) to (10 mL) of the mixture at 0 °C, and leave at room temperature for 1 hour. Stirring was performed. The mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated saline solution and then sulfurized. The mixture was dried over sodium acid and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (1.01 g). 1 H NMR (400 MHz, DMSO-d6) δ 2.32 (1H, t, J = 9.0 Hz), 2.58-2.70 (1H, m), 2.93 (3H, s), 3.10-3.26 (2H, m), 3.49-3.71 (2H, m), 3.90-4.12 (1H, m), 7.23-7.40 (5H, m), 7.80 (1H, d, J = 9.2 Hz).

[0224] D) rel-N-[(3R)-1-benzyl-4,4-difluoropyrrolidine-3-yl]methanesulfonamide rac-N-[(3S)-1-benzyl-4,4-difluoropyrrolidine-3-yl]methanesulfonamide (800 mg) was fractionated by SFC (column: DAIEL CHIRALPAK AD, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / 0.1% aqueous ammonia containing EtOH = 85 / 15 v / v), and the fraction with the longest retention time was concentrated. The residue was dissolved in MeCN (3.0 mL) and water (3.0 mL), lyophilized, and the title compound (368 mg) was obtained. MS: [M+H] + 291.3.

[0225] E) N-{4,4-difluoro-1-[2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide optical isomer rel-N-[(3R)-1-benzyl-4,4-difluoropyrrolidine-3-yl]methane synthesized in step D) A mixture of sulfonamide (368 mg) and 12 M hydrogen chloride (EtOH) solution (5.0 mL) was mixed with 10% Pd / C (50 mg) and stirred at room temperature under a hydrogen atmosphere (15 psi) for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain rel-N-[(3R)-4,4-difluoropyrrolidine-3-yl]methanesulfonamide. I obtained hydrochloride (305 mg). A mixture of rel-(1R,2R)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylic acid (30.0 mg) synthesized in step E) of Example 195 and DMF (2 mL) was mixed with HATU (59 mg), DIPEA (53 mg), and the above rel-N-[(3R)-4,4-difluoropyrrolidine-3-yl]methyl Tansulfonamide hydrochloride (38 mg) was added and the mixture was stirred at room temperature for 14 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN), lyophilized, and the title compound (23.9 mg) was obtained. 1 H NMR (400 MHz, CDCl3) δ 0.09-1.10 (1H, m), 1.32-1.41 (1H, m), 1.62-1.76 (1H, m), 2.30-2.44 (1H, m), 3.06-3.15 (3H, m), 3.20-3.40 (1H, m), 3.63-4.20 (3H, m), 4.20-4.38 (1H, m), 4.85-5.00 (1H, m), 6.95-7.16 (4H, m), 7.27-7.45 (2H, m).

[0226] Example 232 N-{(3S,5R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-5-fluoropiperidine-3-yl}methanesulfonamide

[0227] A) A mixture of ethyl (1R,2R)-2-(2-bromophenyl)cyclopropane-1-carboxylate and ethyl (1S,2S)-2-(2-bromophenyl)cyclopropane-1-carboxylate. Dichloro(p-cymene)ruthenium(II) (dimer) (1.74 g), (S,S)-2,6-bis(4-isop A mixture of ropyrus-2-oxazolin-2-yl)pyridine (1.71 g) and THF (200 mL) is mixed with a mixture of 2-bromostyrene (20.0 g) and THF (100 mL) dropwise at 20 °C under a nitrogen atmosphere. The mixture was heated to 55°C, and ethyl diazoacetate (31.2 g) and toluene (200 g) were added to it. The mixture (mL) was added dropwise under a nitrogen atmosphere over 3 hours. The mixture was stirred at 55 °C for 14 hours. The mixture was cooled and the reaction was stopped with 10% aqueous acetic acid (50 mL). The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was stored in silica gel. The mixture was purified by chromatography (ethyl acetate / petroleum ether), and the title mixture (18.6 g) was obtained. I got it. MS: [M+H] + 268.9.

[0228] B) Ethyl (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1- Carboxylates and ethyl (1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl) Mixture of clopropane-1-carboxylate A mixture of ethyl (1R,2R)-2-(2-bromophenyl)cyclopropane-1-carboxylate and ethyl (1S,2S)-2-(2-bromophenyl)cyclopropane-1-carboxylate (10.0 g) and DME (150 mL) is mixed with 2,6-difluorophenylboronic acid (17.6 g), Xphos Pd G3 (3.15 g), and 1 M tripotassium phosphate aqueous solution (112 mL), and the mixture is incubated at 100 °C under a nitrogen atmosphere for 14 minutes. The mixture was stirred for 14 hours. After cooling to room temperature, 2,6-difluorophenylboronic acid (17.6 g), Xphos Pd G3 (3.15 g), and 1 M tripotassium phosphate aqueous solution (112 mL) were added, and the mixture was stirred for a further 14 hours at 100 °C under a nitrogen atmosphere. The mixture was diluted with water and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether), and further purified by reverse-phase silica gel column chromatography. The compound was purified by matrix (C18, methanol / water) to obtain the title compound (7.52 g). MS: [M+H]+ 303.0.

[0229] C) Ethyl (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1- Carboxylates Ethyl (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate and ethyl (1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclo A mixture of lopropane-1-carboxylate (7.52 g) was fractionated by SFC (column: DAIEL CHIRALPAK IC, 250 mm x 50 mm, 10 μm, mobile phase: CO2 / 0.1% aqueous ammonia IPA = 85 / 15 v / v), and the compound with the longer retention time was obtained as the title compound (6.51 g). MS: [M+H] + 302.9.

[0230] D) (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylic acid A mixture of ethyl (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate (6.51 g) and EtOH (100 mL) is mixed with aqueous sodium hydroxide solution (8.61 g). Add (g / 50 mL) and stir at room temperature for 3 hours. Concentrate the mixture under reduced pressure, dilute with water, and add 4 M salt. The pH was adjusted to 5-6 with acid, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The mixture was concentrated under reduced pressure to obtain the title mixture (5.90 g). MS: [MH] - 272.9.

[0231] E) tert-butyl {(3S,5R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl) Cyclopropane-1-carbonyl]-5-fluoropiperidine-3-yl}carbamate (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbone Acid (40 mg), tert-butyl N-[(3S,5R)-5-fluoro-3-piperidyl]carbamate (35 mg) To a mixture of , and DMF (2 mL), EDCI (42 mg), HOBt (20 mg), and TEA (59 mg) were added and the mixture was stirred at room temperature for 14 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin-layer chromatography (ethyl acetate / petroleum ether) to obtain the title compound (48 mg). MS, found: 375.0.

[0232] F) N-{(3S,5R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopro Pan-1-carbonyl]-5-fluoropiperidine-3-yl}methanesulfonamide tert-butyl {(3S,5R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl) syl A mixture of clopropan-1-carbonyl]-5-fluoropiperidine-3-yl}carbamate (48 mg) and DCM (1 mL) was mixed with trifluoroacetic acid (1 mL) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain [(3S,5R)-3-amino-5-fluoropiperidine-1-yl][(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetic acid I obtained a salt (58 mg). [(3S,5R)-3-amino-5-fluoropiperidine-1-yl][(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate (58 mg) and DCM (5 mL) were mixed with TEA (48 mg) and methanesulfonyl chloride (20 mg) at 0 °C and stirred at room temperature for 3 hours. The mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was separated by preparative HPLC (C18, 0.05% ammonia). The compound was purified with near-water / MeCN and freeze-dried to obtain the title compound (33.0 mg). 1 H NMR (400 MHz, CDCl3) δ 1.23-1.42 (2H, m), 1.87-2.37 (3H, m), 2.40-3.04 (5H, m), 3.25-5.15 (6H, m), 6.87-7.26 (4H, m), 7.28-7.43 (3H, m).

[0233] Example 238 N-2-[(2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]octahydrocyclopenta[c]pyrrole-4-yl}methanesulfonamide optical isomer

[0234] A) rac-tert-butyl (3aR,4S,6aS)-4-[(methanesulfonyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate A mixture of rac-tert-butyl (3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (500 mg) and THF (8 mL) was mixed with methanesulfonyl chloride (301 mg) and TEA (447 mg), and stirred at room temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) and labeled The target compound (664 mg) was obtained. MS, found: 249.0.

[0235] B) rac-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrole-4-yl]methanesulfonamide trifluoroacetate rac-tert-butyl (3aR,4S,6aS)-4-[(methanesulfonyl)amino]hexahydrocyclopeptide A mixture of ¹¹[c]pyrrole-2(1H)-carboxylate (664 mg) and DCM (12 mL) was mixed with trifluoroacetic acid (6 mL) and stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure to obtain the title compound (868 mg). 1 H NMR (400 MHz, DMSO-d6) δ 1.28-1.43 (1H, m), 1.45-1.61 (1H, m), 1.85-2.04 (2H, m), 2.54-2.63 (1H, m), 2.73-2.86 (1H, m), 2.85-2.98 (4H, m), 3.04-3.14 (1H, m), 3.15-3.34 (2H, m), 3.39-3.58 (1H, m), 7.29 (1H, d, J = 6.8 Hz), 8.69-9.05 (2H, m).

[0236] C) rac-N-{(3aR,4S,6aS)-2-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]octahydrocyclopenta[c]pyrrole-4-yl}methanesulfate A mixture of honamide and rac-N-{(3aS,4R,6aR)-2-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]octahydrocyclopenta[c]pyrrole-4-yl}methanesulfonamide rac-(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-cal Bonic acid (43 mg), rac-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrole-4-yl] A mixture of methanesulfonamide trifluoroacetate (50 mg), HATU (63 mg), and DMF (3 mL) was mixed with DIPEA (81 mg) and stirred at room temperature for 12 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN), lyophilized, and labeled. A mixture (4.3 mg) was obtained. MS: [M+H] + 461.2.

[0237] D) N-2-[(2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]octahydrocyclopenta[c]pyrrole-4-yl}methanesulfonamide optical isomer rac-N-{(3aR,4S,6aS)-2-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl) cy Clopropane-1-carbonyl]octahydrocyclopenta[c]pyrrole-4-yl}methanesulfate A mixture (250 mg) of honamide and rac-N-{(3aS,4R,6aR)-2-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]octahydrocyclopenta[c]pyrrole-4-yl}methanesulfonamide was fractionated by SFC (column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / 0.1% aqueous ammonia containing EtOH = 55 / 45 v / v), and the first and second fractions based on retention time were concentrated as a mixture. This was further concentrated by SFC ( The fraction was separated using a DAIEL CHIRALPAK IC column (250 mm x 30 mm, 10 μm) and a mobile phase (CO2 / 0.1% aqueous ammonia with EtOH = 60 / 40 v / v). The fraction with the longer retention time was concentrated. The residue was dissolved in MeCN (10 mL) and water (50 mL), lyophilized, and the title compound (36.7 mg) was obtained. Ta. 1 H NMR (400 MHz, CDCl3) δ 1.39-1.56 (3H, m), 1.60-1.86 (2H, m), 1.99-2.13 (1H, m), 2.18-2.39 (2H, m), 2.45-2.67 (1H, m), 2.68-2.86 (1H, m), 2.87-2.98 (3H, m), 3.32 (1H, dd, J =11.6, 4.4 Hz), 3.45-3.80 (4H, m), 4.24-4.34 (1H, m), 6.88-7.03 (2H, m), 7.12 (1H, d, J =7.6 Hz), 7.21-7.41 (4H, m).

[0238] Example 259 N'-({(2S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)-N,N-dimethyl sulfate diamide

[0239] A) tert-butyl (S)-2-(((N,N-dimethylsulfamoyl)amino)methyl)azetidine-1-carboxylate A mixture of (S)-2-aminomethyl-1-Boc-azetidine (509 mg), DMAP (66.8 mg), TEA (1.14 mL), and THF (12 mL) was mixed with N,N-dimethylsulfamoyl chloride (0.440 mL) at 0 °C and stirred overnight at room temperature. The reaction was stopped by adding saturated sodium bicarbonate aqueous solution at 0 °C and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was analyzed by silica gel column chromatography (ethyl acetate / The compound was purified with hexane to obtain the title compound (498 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.37 (9 H, s), 1.94 - 2.25 (2 H, m), 2.60 - 2.74 (6 H, m), 3.08 (1 H, dt, J = 13.3, 6.7 Hz), 3.24 (1 H, ddd, J = 13.3, 6.3, 4.1 Hz), 3.58 - 3.80 (2 H, m), 4.09 - 4.23 (1 H, m), 7.19 - 7.34 (1 H, m).

[0240] B) N'-({(2S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)-N,N-dimethyl sulfate diamide tert-butyl (S)-2-(((N,N-dimethylsulfamoyl)amino)methyl)azetidine-1-ca Mix ruboxilate (104 mg) and trifluoroacetic acid (0.500 mL) and stir at room temperature for 1 hour. Mixed. The mixture was concentrated under reduced pressure and azeotropically analyzed with toluene. The resulting residue (67.6 mg), (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-cal Mixing 106 mg of bonic acid, 160 mg of HATU, 0.146 mL of TEA, and 2 mL of DMF in a room The mixture was stirred overnight at warm temperature. The reaction was stopped by adding water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was analyzed by silica gel column chromatography (ethyl acetate / hexane) and silica gel column chromatography. The compound was purified with Raffy (NH, ethyl acetate / hexane) to obtain the title compound (140 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.07-1.17 (1H, m), 1.21-1.31 (1H, m), 1.47-1.60 (1H, m), 1.72-1.80 (1H, m), 2.01-2.33 (2H, m), 2.61-2.66 (6H, m), 3.01-3.28 (2H, m) , 3.56-3.74 (1H, m), 3.79-3.91 (1H, m), 4.04-4.18 (1H, m), 7.12-7.61 (8H, m).

[0241] Example 262 N-{(3S,5S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-5-methylpyrrolidine-3-yl}methanesulfonamide

[0242] A) N-[(3S,5S)-5-methylpyrrolidine-3-yl]methanesulfonamide trifluoroacetate A mixture of tert-butyl (2S,4S)-4-amino-2-methylpyrrolidine-1-carboxylate (50 mg), TEA (51 mg), and DCM (5 mL) was mixed with methanesulfonyl chloride (43 mg) at 0 °C and stirred at room temperature for 2 hours. The mixture was poured into ice water and extracted with DCM. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure to obtain tert-butyl (2S,4S)-4-[(methanesulfonyl)amino]-2-methylpyrrolidine-1-carboxylate (83 mg). A mixture of tert-butyl (2S,4S)-4-[(methanesulfonyl)amino]-2-methylpyrrolidine-1-carboxylate (83 mg) and DCM (3 mL) was mixed with trifluoroacetic acid (1 mL) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain the title compound (93 mg). MS: [M+H] + 179.1.

[0243] B) N-{(3S,5S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopro Pan-1-carbonyl]-5-methylpyrrolidine-3-ylmethanesulfonamide N-[(3S,5S)-5-methylpyrrolidine-3-yl]methanesulfonamide trifluoroacetate (93 mg), (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-category A mixture of rubonic acid (87 mg) and DMF (5 mL) was mixed with EDCI (73 mg), HOBt (52 mg), and TEA (129 mg) and stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN), lyophilized, and the title compound (34.2 mg) was obtained. 1H NMR (400 MHz, CDCl3) δ 1.10-1.27 (3H, m), 1.29-1.56 (3H, m), 1.88-1.95 (1H, m), 2.00-2.17 (1H, m), 2.32-2.48 (1H, m), 2.99 (3H, s), 3.33-3.45 (1H, m), 3.61-3.82 (1H, m), 3.95-4.24 (2H, m), 4.42-4.60 (1H, m), 6.92-7.26 (4H, m), 7.27-7.42 (3H, m).

[0244] Example 264 N-{(3S,4R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-methylpyrrolidine-3-yl}methanesulfonamide

[0245] A) N-[(3S,4R)-4-methylpyrrolidine-3-yl]methanesulfonamide trifluoroacetate A mixture of tert-butyl (3S,4R)-3-amino-4-methylpyrrolidine-1-carboxylate (60 mg), TEA (61 mg), and DCM (5 mL) is mixed with methanesulfonyl chloride (51 mg) at 0°C. The mixture was added and stirred at room temperature for 2 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was After washing with saturated saline solution, the solution was dried over sodium sulfate and concentrated under reduced pressure to obtain tert-butyl (3S,4R)-3-[(methanesulfonyl)amino]-4-methylpyrrolidine-1-carboxylate (67 mg). . A mixture of tert-butyl (3S,4R)-3-[(methanesulfonyl)amino]-4-methylpyrrolidine-1-carboxylate (67 mg) and DCM (3 mL) was mixed with trifluoroacetic acid (1 mL) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain the title compound (97 mg). MS: [M+H] +179.1.

[0246] B) N-{(3S,4R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopro Pan-1-carbonyl]-4-methylpyrrolidine-3-ylmethanesulfonamide N-[(3S,4R)-4-methylpyrrolidine-3-yl]methanesulfonamide trifluoroacetate ( 97 mg), (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-ca A mixture of rubonic acid (91 mg) and DMF (5 mL) was mixed with EDCI (76 mg), HOBt (54 mg), and TEA (134 mg) and stirred at room temperature for 16 hours. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN), lyophilized, and the title compound (20.2 mg) was obtained. 1 H NMR (400 MHz, CDCl3) δ 1.10-1.16 (3H, m), 1.24-1.30 (1H, m), 1.43-1.52 (1H, m), 1.61-1.71 (1H, m), 1.93-2.43 (2H, m), 2.84-3.33 (5H, m), 3.41-3.61 (1H, m), 3.66-3.79 (1H, m), 3.83-3.92 (1H, m), 4.45-4.63 (1H, m), 6.92-7.26 (4H, m), 7.29-7.41 (3H, m).

[0247] Example 294 N-{(6S)-4-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-1,4-oxazepan-6-yl}ethanesulfonamide, or N-{(6R)-4-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-1,4-oxazepan-6-yl}ethanesulfonamide

[0248] A) tert-butyl 6-(ethylsulfonamide)-1,4-oxazepan-4-carboxylate 4-Boc-6-amino-1,4-oxazepane (454 mg), DMAP (51.3 mg), TEA (0.878 mL) To a mixture of THF (7 mL), add ethanesulfonyl chloride (0.298 mL) at 0 °C, and allow to cool at room temperature. The mixture was stirred for 2 hours. The reaction was stopped by adding saturated sodium bicarbonate aqueous solution at 0°C, and acetic acid was added. Extraction was performed by chilling. The organic layer was washed with water and saturated saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was analyzed by silica gel column chromatography (ethyl acetate / hexane). The compound was purified to obtain the title compound (501 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.13-1.25 (3H, m), 1.41 (9H, s), 2.91-3.26 (4H, m), 3.48-3.84 (7H, m), 7.22 (1H, br s).

[0249] B) N-(1,4-oxazepan-6-yl)ethanesulfonamide hydrochloride To a mixture of tert-butyl 6-(ethylsulfonamide)-1,4-oxazepane-4-carboxylate (267 mg) and ethyl acetate (2 mL), add 2 M hydrogen chloride CPME solution (4 mL) and prepare at room temperature. The mixture was stirred overnight. The resulting solid was filtered to obtain the title compound (186 mg). 1 H NMR (300 MHz, DMSO-d6) δ 1.20 (3H, t, J = 7.3 Hz), 3.07-3.30 (5H, m), 3.35 (1H, d, J = 3.8 Hz), 3.50-3.64 (1H, m), 3.79-3.95 (4H, m), 7.47 (1H, d, J = 7.9 Hz), 9.46 (2H, br s).

[0250] C) N-{(6S)-4-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-1,4-oxazepan-6-yl}ethanesulfonamide, or N-{(6R)-4-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-1,4-oxazepan-6-yl}ethanesulfonamide (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbone Add HATU (261 mg) at 0°C to a mixture of acid (166 mg), N-(1,4-oxazepan-6-yl)ethanesulfonamide hydrochloride (140 mg), TEA (0.319 mL), and DMF (2 mL), and allow to stand at the same temperature for 3 hours. The mixture was stirred. The reaction was stopped by adding water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate / hexane), and the compound was separated by preparative HPLC (column: DAIEL CHIRALPAK IC, 250 mm x 20 mm, 5 μm, mobile phase: hexane / ethanol / diethylamine = 700 / 300 / 1 v / v / v). The compound with the shorter retention time was obtained as the title compound (94.1 mg). 1H NMR (400 MHz, CDCl3) δ 0.93-1.42 (5H, m), 1.89-2.40 (2H, m), 2.73-3.09 (2H, m), 3.40-3.74 (8H, m), 3.77-4.23 (2H, m),6.84-7.70 (7H, m).

[0251] Example 304 N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide, or N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1- Carbonyl pyrrolidine-3-yl methanesulfonamide

[0252] A) 2,6-difluoro-2'-(1-fluoroethenyl)-1,1'-biphenyl A mixture of 1-bromo-2-(1-fluoroethenyl)benzene (16.2 g), 2,6-difluorophenylboronic acid (63.6 g), DME (150 mL), and water (50 mL) is mixed with Xphos Pd G3 (6.82 g) and Tripotassium phosphate (51.3 g) was added and the mixture was stirred at 100°C for 16 hours. After diluting the mixture with water, Extraction was performed with ethyl acetate. The organic layer was washed with saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to obtain the title compound (4.60 g). 1 H NMR (400 MHz, CDCl3) δ 4.37-4.81 (2H, m), 6.94-7.01 (2H, m), 7.30-7.36 (2H, m), 7.45-7.51 (2H, m), 7.58-7.70 (1H, m).

[0253] B) rac-ethyl (1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorosilicone Clopropane-1-carboxylate 2,6-Difluoro-2'-(1-fluoroethenyl)-1,1'-biphenyl (7.50 g) and DCE (100 mL) To the mixture, rhodium(II) acetate (dimer) (353 mg) was added, and ethyl di A mixture of azoacetate (10.9 g) and DCE (100 mL) was added dropwise at 70 °C over 6 hours. The mixture was stirred at warm temperature for 6 hours. The mixture was concentrated under reduced pressure. Residue was stored in a silica gel column. The crude product was obtained by purification using chromatography (ethyl acetate / petroleum ether). Furthermore, the compound was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN), the fraction with the shorter retention time was concentrated, and lyophilized to obtain the title compound (1.60 g). 1 H NMR (400 MHz, CDCl3) δ 1.22 (3H, t, J = 7.2 Hz), 1.38-1.50 (1H, m), 1.87-1.99 (1H, m), 2.01-2.13 (1H, m), 3.93-4.21 (2H, m), 6.92-7.04 (2H, m), 7.29-7.64 (5H, m).

[0254] C) rel-(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylic acid rac-ethyl (1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylate (800 mg) was fractionated by SFC (column: DAIEL CHIRALPAK IC, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / 0.1% aqueous ammonia EtOH = 80 / 20 v / v) The compound with the longer retention time was obtained as rel-ethyl (1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylate (370 mg). To the mixture of rel-ethyl (1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylate (370 mg), MeOH (2 mL), THF (2 mL), and water (2 mL), sodium hydroxide (462 mg) was added and the mixture was stirred at room temperature for 12 hours. The substance was diluted with water, the pH was adjusted to 5-6 with 2 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was: The mixture was dried over sodium sulfate and concentrated under reduced pressure to obtain the title mixture (330 mg). 1 H NMR (400 MHz, CDCl3) δ 1.44-1.56 (1H, m), 1.58-1.72 (1H, m), 2.00-2.11 (1H, m), 7.17 (2H, t, J = 8.4 Hz), 7.35-7.42 (1H, m), 7.46-7.69 (4H, m), 12.2 (1H, brs).

[0255] D) N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorosil Clopropan-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide, or N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropan-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide The rel-(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-yl synthesized in step C) To a mixture of luorocyclopropane-1-carboxylic acid (50 mg), (S)-N-(pyrrolidine-3-yl)methanesulfonamide hydrochloride (38 mg), and pyridine (2 mL), add EDCI (49 mg). The mixture was stirred at room temperature for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN), lyophilized, and the title compound (36 mg) was obtained. 1 H NMR (400 MHz, CDCl3) δ 1.13-1.30 (1H, m), 1.83-2.34 (4H, m), 2.88-3.02 (3H, m), 3.49-4.14 (5H, m), 4.74-5.83 (1H, m), 6.85-7.07 (2H, m), 7.26-7.43 (4H, m), 7.45-7.50 (1H, m).

[0256] Example 306 N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]piperidine-3-yl}methanesulfonamide, or N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1- Carbonyl piperidine-3-yl methanesulfonamide In step C) of Example 304, a mixture of rel-(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylic acid (50.0 mg), (S)-N-(piperidine-3-yl)methanesulfonamide hydrochloride (38.5 mg), and pyridine (3 mL) was mixed with EDCI (65.6 mg) and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN), lyophilized, and the title compound (28.8 mg) was obtained. . 1 H NMR (400 MHz, CDCl3) δ 1.20-1.32 (1H, m), 1.60-1.73 (2H, m), 1.78-2.10 (3H, m), 2.23-2.67 (1H, m), 2.75-3.04 (3H, m), 3.30-4.11 (5H, m), 4.47 (1H, br d, J = 7.2 Hz), 6.90-7.04 (2H, m), 7.30-7.64 (5H, m).

[0257] Example 318 N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide, or N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl Bonyl pyrrolidine-3-yl methanesulfonamide

[0258] A) Ethyl (2E)-3-(2-bromo-4-methylphenyl)propa-2-enoate A mixture of ethyl 2-diethoxyphosphoryl acetate (7.32 g) and THF (50 mL) contains 60% NaH (1.21 g) was added at 0 °C. After stirring at room temperature for 30 minutes, 2-bromo-4-methylbenzalkonium was added. Add 5.00 g of ethyl 2-diethoxyphosphorylation at room temperature and stir for 2 hours. A mixture of luacetate (7.32 g) and THF (50 mL) is mixed with 60% NaH (400 mg), and the mixture is then prepared. The reaction mixture was added to the compound. After stirring for a further 12 hours at room temperature, the reaction was stopped by adding water at 0°C and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / The compound was purified with petroleum ether to obtain the title compound (6.50 g). 1 H NMR (400 MHz, CDCl3) δ 1.34 (3H, t, J = 7.6 Hz), 2.34 (3H, s), 4.19-4.37 (2H, q, J = 7.2 Hz), 6.35 (1H, d, J = 16.0 Hz), 7.12 (1H, d, J = 8.4Hz), 7.37-7.60 (2H, m), 8.02 (1H, d, J = 16.0 Hz).

[0259] B) rac-ethyl (1R,2R)-2-(2-bromo-4-methylphenyl)cyclopropane-1-carboxylate A mixture of 60% NaH (1.06 g) and DMSO (50 mL) contains trimethylsulfoxonium iodide. Add (7.97 g) at 0°C, stir at room temperature for 30 minutes, then add dropwise a mixture of ethyl (2E)-3-(2-bromo-4-methylphenyl)propa-2-enoate (6.50 g) and DMSO (40 mL), and then... The mixture was stirred at warm temperature for 14 hours. Water was added at 0°C to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was then removed. After washing with saturated saline solution, the mixture was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (2.14 g). I obtained it. 1 H NMR (400 MHz, CDCl3) δ 1.27-1.32 (4H, m), 1.59-1.63 (1H, m), 1.68-1.83 (1H, m), 2.29 (3H, s), 2.58-5.73 (1H, m), 4.13-4.27 (2H, m), 6.89 (1H, d, J = 8.0 Hz), 7.02 (1H, d, J = 8.0 Hz), 7.39 (1H, s).

[0260] C) rac-ethyl (1R,2R)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl) ethyl Lopropane-1-carboxylate rac-ethyl (1R,2R)-2-(2-bromo-4-methylphenyl)cyclopropane-1-carboxylate A mixture of 500 mg of iodine (DME) and 15 mL of DME contains 1.39 g of 2,6-difluorophenylboronic acid. Tripotassium phosphate aqueous solution (5.30 mL) and Xphos Pd G3 (150 mg) were added, and the mixture was stirred at 100 °C under a nitrogen atmosphere for 14 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (461 mg). . MS: [M+H] + 317.0.

[0261] D) rac-(1R,2R)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylic acid A mixture of sodium hydroxide (132 mg), ethyl ethanol (4 mL), and water (3 mL) is mixed with rac-ethyl ethanol. (1R,2R)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane-1- A mixture of carboxylate (87 mg) and EtOH (3 mL) was added and stirred at room temperature for 14 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with DCM. The aqueous layer was diluted with 1 M hydrochloric acid to pH 3 ~ The solution was adjusted to 4 and extracted with DCM. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and then the title was obtained. A compound (85 mg) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 1.12-1.19 (1H, m), 1.25-1.33 (1H, m), 1.53-1.60 (1H, m), 1.95-2.04 (1H, m), 2.30 (3H, s), 6.92-7.28 (5H, m), 7.40-7.54 (1H, m), 12.05 (1H, br s).

[0262] E) N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl) cytomethyl [Pyrolorpan-1-carbonyl]pyrroridine-3-yl]methanesulfonamide and N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane-1-carb Mixture of [nyl]pyrrolidine-3-yl]methanesulfonamide rac-(1R,2R)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane To a mixture of n-1-carboxylic acid (28 mg) and DMF (1 mL), (S)-N-(pyrrolidine-3-yl)methanesulfonamide hydrochloride (18 mg), HATU (38 mg), and DIPEA (47 mg) were added and stirred at room temperature for 14 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was extracted with sodium sulfate. The mixture was dried and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN), lyophilized, and the title compound (16 mg) was obtained. MS: [M+H] + 435.2.

[0263] F) N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl) cytomethyl Lopropan-1-carbonyl]pyrroridine-3-yl}methanesulfonamide, or N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropan-1- Carbonyl pyrrolidine-3-yl methanesulfonamide N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide and N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl A mixture of pyrrolidine-3-ylmethanesulfonamide (16 mg) is placed in SFC (column: Phenomenon). nex-Cellulose-2, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / 0.1% MeOH containing aqueous ammonia = The fraction was divided at 60 / 40 v / v and concentrated to obtain the fraction with the shorter retention time. The residue was dissolved in MeCN (3 mL) and water (30 mL) and lyophilized to obtain the title compound (5.2 mg). 1 H NMR (400 MHz, CDCl3) δ 1.26-1.34 (1H, m), 1.39-1.50 (1H, m), 1.63-1.70 (1H, m), 1.76-2.10 (1H, m), 2.13-2.29 (1H, m), 2.29-2.39 (4H, m), 3.00 (3H, s), 3.27-3.81 (4H, m), 3.94-4.12 (1H, m), 4.42 (1H, s), 6.92-7.05 (3H, m), 7.07 (1H, s), 7.18 (1H, d, J = 7.8 Hz), 7.27-7.39 (1H, m).

[0264] Example 319 N-{(3S,5S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-5-hydroxypiperidine-3-yl}methanesulfonamide

[0265] A) tert-butyl (3S,5S)-3-hydroxy-5-[(methanesulfonyl)amino]piperidine-1-ca Luboxylart tert-butyl (3S,5S)-3-amino-5-hydroxypiperidine-1-carboxylate (50 mg) To a mixture of DCM (3 mL), add TEA (35 mg) and methanesulfonyl chloride (32 mg) at 0°C. The mixture was added and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with DCM. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (54 mg). 1 H NMR (400 MHz, CDCl3) δ 1.47 (9H, s), 1.77-2.08 (2H, m), 2.93-3.11 (4H, m), 3.28-3.57 (2H, m), 3.75-3.85 (1H, m), 3.95-4.10 (1H, m), 4.25-4.44 (1H, m).

[0266] B) N-{(3S,5S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopro Pan-1-carbonyl]-5-hydroxypiperidine-3-yl}methanesulfonamide A mixture of tert-butyl (3S,5S)-3-hydroxy-5-[(methanesulfonyl)amino]piperidine-1-carboxylate (47 mg) and DCM (6 mL) was mixed with trifluoroacetic acid (2 mL) and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to obtain N-[(3S,5S)-5-hydroxypiperidine-3-yl]methanesulfonamide trifluoroacetate (75 mg). (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbone A mixture of acid (50 mg), N-[(3S,5S)-5-hydroxypiperidine-3-yl]methanesulfonamide trifluoroacetate (67 mg), and DMF (2 mL) is mixed with HOBt (25 mg), EDCI (52 mg), The mixture was then mixed with TEA (74 mg) and stirred at room temperature for 13 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN), lyophilized, and the title compound (27 mg) was obtained. 1 H NMR (400 MHz, CDCl3) δ 1.20-1.50 (2H, m), 1.79-2.50 (5H, m), 2.75-3.00 (3H, m), 3.33-3.65 (3H, m), 3.67-4.05 (3H, m), 4.58-5.15 (1H, m), 6.91-7.24 (4H, m), 7.26-7.44 (3H, m).

[0267] The example compounds are shown in the table below. The MS values ​​in the table are measured values. Compounds 1-12, 14-22, 26-132, 134-138, 140-194, 196-199, 201-214, 217-225, 227-230, 233-237, 239-258, 260, 261, 263, 265-293, 295-303, 305, 307-317, and 320 in the table below were prepared according to the methods shown in the above examples or methods similar thereto.

[0268] Table 1-1

[0269] Table 1-2

[0270] Table 1-3

[0271] Table 1-4

[0272] Table 1-5

[0273] Table 1-6

[0274] Table 1-7

[0275] Table 1-8

[0276] Table 1-9

[0277] Table 1-10

[0278] Table 1-11

[0279] Table 1-12

[0280] Table 1-13

[0281] Table 1-14

[0282] Table 1-15

[0283] Table 1-16

[0284] Table 1-17

[0285] Table 1-18

[0286] Table 1-19

[0287] Table 1-20

[0288] Table 1-21

[0289] Table 1-22

[0290] Table 1-23

[0291] Table 1-24

[0292] Table 1-25

[0293] Table 1-26

[0294] Table 1-27

[0295] Table 1-28

[0296] Table 1-29

[0297] Table 1-30

[0298] Table 1-31

[0299] Table 1-32

[0300] Table 1-33

[0301] Table 1-34

[0302] Table 1-35

[0303] Table 1-36

[0304] Table 1-37

[0305] Table 1-38

[0306] Table 1-39

[0307] Table 1-40

[0308] Table 1-41

[0309] Table 1-42

[0310] Table 1-43

[0311] Table 1-44

[0312] Table 1-45

[0313] Table 1-46

[0314] Table 1-47

[0315] Table 1-48

[0316] Table 1-49

[0317] Table 1-50

[0318] Table 1-51

[0319] [Table 1-52]

[0320] [Table 1-53]

[0321] [Table 1-54]

[0322] Test Example 1: Acquisition of cells stably expressing human orexin type 2 receptor (hOX2R) To obtain cell clones that stably express the human orexin type 2 receptor, human orexin type 2 receptor cDNA was inserted into a pcDNA3.1(+) plasmid vector (Invitrogen), and a plasmid DNA for human orexin type 2 receptor expression (pcDNA3.1(+) / h OX2R) was cloned. This plasmid DNA was electrolyzed into CHO-K1 cells. Human orexin type 2 receptor-expressing cloned cells were obtained by induction using electroporation and limiting dilution, with G418 drug resistance as a selectable marker.

[0323] Test Example 2: Measurement of Orexin 2 Receptor Agonist Activity Human OX2 receptor-overexpressing CHO cells were seeded at a rate of 10,000 cells / well in 384-well black transparent-bottom plates (BD Falcon) and cultured for 1 day in a 37°C, 5% CO2 incubator. After removing the culture medium from the cell plate, 30 μL / well of assay buffer A containing a calcium indicator (HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Sigma-Aldrich), 2.5 μg / mL Fluo-4 AM (Dojin Chemical), 0.08% Pluronic F127 (Dojin Chemical), 1.25 mM probenecid (Dojin Chemical)) was added. The cells were incubated in a 37 °C, 5% CO2 incubator for 30 minutes, followed by a further 30 minutes at room temperature. Assay buffer B (HBSS, 20 mM) was then added. 10 μL / well of the test compound, diluted with HEPES (0.1% BSA), was added, and the fluorescence value was measured at 1-second intervals for 1 minute, and then at 2-second intervals for 1 minute and 40 seconds using FDSSμCELL (Hamamatsu Photonics). When DMSO is added instead, the change in fluorescence value is 0%, and the final concentration of orexin A (human) is 10 nM. The activity (%) of the test compound was calculated by defining the change in fluorescence when (Peptide Institute) was added as 100%. Table 2 shows the activity of each compound at a 3 μM concentration. As shown, the compound of the present invention has been demonstrated to have orexin type 2 receptor agonist activity.

[0324] [Table 2-1]

[0325] [Table 2-2]

[0326] [Table 2-3]

[0327] [Table 2-4]

[0328] [Table 2-5]

[0329] [Table 2-6]

[0330] Formulation Example 1 (Capsule Manufacturing) 1) Compound from Example 1: 30 mg 2) Finely powdered cellulose 10 mg 3) Lactose 19mg 4) Magnesium stearate 1 mg Total 60mg Mix 1), 2), 3), and 4) and fill into gelatin capsules.

[0331] Formulation Example 2 (Tablet Manufacturing) 1) Compound from Example 1, 30g 2) Lactose 50g 3) Corn starch 15g 4) Carboxymethylcellulose calcium 44g 5) Magnesium stearate 1 g 1000 tablets total 140g 1), 2), and 3) are mixed with water in their entirety, along with 30g of 4), which is then vacuum-dried and granulated. 14 g of 4) and 1 g of 5) are mixed with this whole granule powder and compressed into tablets using a tablet press. In this way, 1000 tablets containing 30 mg of the compound of Example 1 per tablet are obtained. [Industrial applicability]

[0332] The compound of the present invention has orexin type 2 receptor agonist activity and is useful as a preventive or therapeutic agent for narcolepsy.

Claims

1. formula: 【Chemistry 1】 [In the formula, Ring W may further be a ring that is substituted; Ring X may further consist of a 5 or 6-membered aromatic ring; Ring Y may further contain a cyclopropyl group; Ring Z may be a nitrogen-containing heterocycle that is further substituted; L is a bond, or a methylene group which may be substituted; R may be substituted with C 1-6 Alkyl, possibly substituted C 3-10 Cycloalkyl or optionally substituted diC 1-6 [Indicates alkylamine.] A compound represented by or a salt thereof.

2. A pharmaceutical product containing the compound or a salt thereof as described in claim 1.

3. The pharmaceutical product according to claim 2, which is an orexin type 2 receptor agonist.

4. The pharmaceutical agent according to claim 2, which is a preventive or therapeutic agent for narcolepsy.

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