Heterocyclic compounds

Abstract

The present invention provides a heterocyclic compound having orexin type 2 receptor agonist activity. The compounds represented by formula (I) are useful as agents for the prevention or treatment of 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 novel 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 syndromes 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] formula

[0045] [ka]

[0046] (Each symbol in the formula is as it appears in the literature.) A compound represented by (Patent Document 17).

[0047] 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]

[0048] [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 [Patent Document 17] WO 2021 / 106975 A1 [Non-Patent Document]

[0049] [Non-Patent Document 1] Cell, Vol.92, 573 - 585, 1998) [Non-Patent Document 2] Cell, Vol.98, 365 - 376, 1999) [Non-Patent Document 3] Proc. Natl. Acad. Sci. USA, Vol.101, 4649 - 4654, 2004) [Non-Patent Document 4] Cell,, Vol.98, 437 - 451, 1999) [[ID=,65]][Non-Patent Document 5] Neuron, Vol.38, 715 - 730, 2003) [Non-Patent Document 6] CNS Drugs, Vol.27, 83-90, 2013) [Non-Patent Document 7] Cell Metabolism, Vol.9, 64-76, 2009) [Non-Patent Document 8] Neuroscience, Vol.121, 855-863, 2003) [Non-Patent Document 9] Respiration, Vol.71, 575-579, 2004) [Non-Patent Document 10] Peptides, Vol.23, 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, 2007, Pages 1586-1595) [Overview of the project] [Problems that the invention aims to solve]

[0050] The present invention aims to provide heterocyclic compounds having orexin type 2 receptor agonist activity. [Means for solving the problem]

[0051] 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.

[0052] In other words, the present invention relates to the following: [1] Formula:

[0053] [ka]

[0054] [wherein, ring W represents a ring which may be further substituted; ring X represents a 5- or 6-membered aromatic ring which may be further substituted; ring Y represents a cyclopropane ring which may be further substituted; ring Z represents a nitrogen-containing heterocyclic ring which may be further substituted; L represents a bond or a methylene which may be substituted; and R represents a C 1-6 alkyl group, a C 3-10 cycloalkyl group which may be substituted, or NR a R b ; where R a represents a C 1-6 alkyl group which may be substituted, or a C 3-10 cycloalkyl group which may be substituted; R b represents a hydrogen atom, a C 1-6 alkyl group which may be substituted, or a C 3-10 cycloalkyl group which may be substituted; or R a and R b together with the adjacent nitrogen atom form a nitrogen-containing heterocyclic ring which may be further substituted.] a compound represented by the formula, or a salt thereof.

[0055] [2] Ring W is a ring which may be further substituted; ring X is a 5- or 6-membered aromatic ring which may be further substituted; ring Y is a cyclopropane ring which may be further substituted; ring Z is a nitrogen-containing heterocyclic ring which may be further substituted; L is a bond or a methylene which may be substituted; and R is a C 1-6 alkyl, a C 3-10A cycloalkyl, or optionally substituted di-C 1-6 alkylamine, The compound or salt according to [1] above.

[0056] [3] Ring W is (1) A 3- to 8-membered monocyclic non-aromatic heterocyclic ring, (2) A 5- to 6-membered monocyclic aromatic heterocyclic ring optionally further substituted with 1 to 3 halogen atoms, (3)(i) A halogen atom, (ii) A C 1-6 alkyl group optionally substituted with 1 to 3 C 1-6 alkoxy groups, and (iii) A C 1-6 alkoxy group and is optionally further substituted with 1 to 3 substituents selected from 6-14 an aromatic hydrocarbon ring, or (4) A C 3-10 cycloalkane; Ring X is (1)(i) A halogen atom, (ii) A C 1-6 alkyl group optionally halogenated, and (iii) A C 1-6 alkoxy group and is optionally further substituted with 1 to 3 substituents selected from (2)(i) A halogen atom, and (ii) A C 1-6 alkyl group and is optionally further substituted with a 5- or 6-membered monocyclic aromatic heterocyclic ring with 1 to 3 substituents selected from Ring Y is (1) A halogen atom, (2) A cyano group, and (3) A C 1-6 alkyl group optionally substituted with 1 to 3 substituents selected from alkoxy, cyano, and hydroxy, 1-6 and A cyclopropane ring which may be further substituted with one to three substituents selected from; Ring Z is (1) Halogen atom, (2) Hydroxyl group, (3) C 1-6 One to three selected from alkoxy groups, halogen atoms, and hydroxyls It may be substituted with a substituent, C 1-6 alkyl group, (4) C 1-6 Alkoxy group, (5) -C(O)-C 1-6 Alkyl, and (6) C 1-6 A 5-membered monocyclic aromatic heterocycle which may be substituted with alkyl groups. A 3- to 14-membered nitrogen-containing heterocycle which may be further substituted with one to three substituents selected from; L, joins, or (1) C 1-6 C may be further substituted with one to three substituents selected from alkoxy groups and hydroxyls. 1-6 alkyl groups, and (2) C which may be further substituted with a hydroxyl group 3-6 Cycloalkyl groups A methylene group which may be substituted with one substituent selected from; R (1)(i) Halogen atom, (ii) C 1-6 Alkoxy, and (iii) Cyclopropyl group C may be substituted with one to three substituents selected from the following. 1-6 alkyl group, (2) C 1-6 C may be further substituted with alkyl groups. 3-10 Cycloalkyl groups, or (3) NR a R b and; Here, R a However, C1-6 Alkyl alkyl group, or C 3-10 It is a cycloalkyl group; R b However, hydrogen atoms, or C 1-6 It is an alkyl group; or R a and R b Together, they form a nitrogen-containing heterocycle with adjacent nitrogen atoms. The compound or salt described in [1] above.

[0057] [4] Ring W may be further substituted with one to three halogen atoms C 6-14 It is an aromatic hydrocarbon ring; Ring X contains a halogen atom and C 1-6 A benzene ring which may be further substituted with one to three substituents selected from alkyl groups; Ring Y is a cyclopropane ring which may be further substituted with one to three halogen atoms; Ring Z contains a halogen atom, a hydroxyl group, and C 1-6 A 3- to 14-membered nitrogen-containing heterocycle which may be further substituted with one to three substituents selected from alkyl groups; L is a bond, or C 1-6 A methylene group which may be substituted with an alkyl group; R (1) C 1-6 Alkyl alkyl group, or (2) NR a R b and; Here, R a However, C 1-6 It is an alkyl group; and R b However, hydrogen atoms, or C 1-6 It is an alkyl group. The compound or salt described in [1] above.

[0058] [5] Ring W is a benzene ring which may be substituted with one to three halogen atoms; ring X is a halogen atom and C 1-6A benzene ring which may be further substituted with one to three substituents selected from alkyl groups; Ring Y is a cyclopropane ring which may be further substituted with one to three halogen atoms; Ring Z contains halogen atoms and C 1-6 An azetidine ring which may be further substituted with one to three substituents selected from alkyl groups; L, C 1-6 A methylene group which may be substituted with an alkyl group; and R, C 1-6 Alkyl or NR a R b and; Here, R a However, C 1-6 It is an alkyl group; and R b However, it is a hydrogen atom. The compound or salt described in [1] above.

[0059] [6] Ring W is a benzene ring which may be substituted with one to three halogen atoms; Ring X is a benzene ring which may be further substituted with one to three halogen atoms; Ring Y is a cyclopropane ring which may be further substituted with one to three halogen atoms; Ring Z is an azetidine ring which may be further substituted with one to three halogen atoms; L is a methylene group; R, C 1-6 Alkyl alkyl group, or NR a R b and; Here, R a However, C 1-6 It is an alkyl group; and R b However, it is a hydrogen atom. The compound or salt described in [1] above.

[0060] [7]N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)ethanesulfonamide: a compound or a salt thereof. [8]N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)-N'-methyl sulfate diamide: a compound or a salt thereof. [9]N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide: a compound or a salt thereof.

[0061]

[10] Formula (II)

[0062] [ka]

[0063] [In formula: Ring W is selected from benzene, a 5- or 6-membered heteroaryl, a 3- to 8-membered cycloalkyl, and a 3- to 8-membered heterocyclyl, where each ring may be substituted with 1, 2, 3, or 4 groups independently selected from halogens, (C1-C6)alkyls, and (C1-C6)alkoxys, where the (C1-C6)alkyl or (C1-C6)alkoxy may be substituted with 1, 2, 3, or 4 halogen atoms; Ring X represents benzene or a 5- or 6-membered heteroaryl group, where each ring may be substituted with 1, 2, or 3 groups independently selected from halogens, (C1-C6)alkyl groups, and (C1-C6)alkoxy groups, where the (C1-C6)alkyl group may be substituted with 1, 2, 3, or 4 halogen atoms; Ring Y is substituted with one, two, or three groups independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-OH, (C1-C6)alkyl-O-(C1-C6)alkyl, (C1-C6)alkyl-CN, and -CN. It may show a cyclopropane ring; Ring Z represents a 3-9 member nitrogen-containing monocyclic ring or a 6-8 member nitrogen-containing bicyclic ring, where each ring may contain one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; where the 3-9 member nitrogen-containing monocyclic ring is composed of one, two, three, or four groups independently selected from halogens, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-OH, (C1-C6)alkyl-O-(C1-C6)alkyl, -OH, and -C(O)-(C1-C6)alkyl The 6-8 member bicyclic ring may be substituted with, and also substituted with, one, two, or three (C1-C6)alkyl groups, and thereafter substituted with one, two, three, or four groups independently selected from halogens, (C1-C6)alkyl groups, halo(C1-C6)alkyl groups, (C1-C6)alkoxy groups, (C1-C6)alkyl-OH groups, (C1-C6)alkyl-O-(C1-C6)alkyl groups, -OH groups, and -C(O)-(C1-C6)alkyl groups; L represents a bond or -CH2-, where the -CH2- may be substituted with one or two groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and 3-6 membered cycloalkyl rings, where the (C1-C6)alkyl and 3-6 membered cycloalkyl rings may be substituted with one, two, or three groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and -OH; or where the -CH2- is substituted with two groups, where the two groups, together with the carbon atoms to which they are bonded, form a 3-6 membered cycloalkyl or a 3-6 membered heterocyclyl ring containing one or two oxygen atoms; and R represents (C1-C6)alkyl, -(C1-C6)alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkyl-O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)2, -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl), and 3-7 membered heterocyclyl, where the (C1-C6)alkyl, -(C1- C6)alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkyl-O-(C1-C6)alkyl, -NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)2, -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl, and 3-7 membered heterocyclyl may be substituted with one, two, or three groups independently selected from halogens and (C1-C6)alkyl; Compounds thereof, or pharmaceutically acceptable salts thereof.

[0064]

[11] Formula (II')

[0065] [ka]

[0066] [In formula: Ring W is selected from benzene, a 5 or 6-membered heteroaryl, a 3-8 membered cycloalkyl, and a 3-8 membered heterocyclyl, where each ring is a halogen, (C1-C6) alkyl The alkyl and (C1-C6)alkoxy groups may be substituted with 1, 2, 3, or 4 groups independently selected from each other, where the (C1-C6)alkyl or (C1-C6)alkoxy groups may be substituted with 1, 2, 3, or 4 halogen atoms; Ring X represents benzene or a 5- or 6-membered heteroaryl group, where each ring may be substituted with 1, 2, or 3 groups independently selected from halogens, (C1-C6)alkyl groups, and (C1-C6)alkoxy groups, where the (C1-C6)alkyl group may be substituted with 1, 2, 3, or 4 halogen atoms; Ring Y represents a cyclopropane ring which may be substituted with one, two, or three groups independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-OH, (C1-C6)alkyl-O-(C1-C6)alkyl, (C1-C6)alkyl-CN, and -CN; Ring Z represents a 3-9 member nitrogen-containing monocyclic ring or a 6-8 member nitrogen-containing bicyclic ring, where each ring may contain one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; where the 3-9 member nitrogen-containing monocyclic ring is composed of one, two, three, or four groups independently selected from halogens, (C1-C6)alkyl, halo(C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6)alkyl-OH, (C1-C6)alkyl-O-(C1-C6)alkyl, -OH, and -C(O)-(C1-C6)alkyl The 6-8 member bicyclic ring may be substituted with, and also substituted with, one, two, or three (C1-C6)alkyl groups, and thereafter substituted with one, two, three, or four groups independently selected from halogens, (C1-C6)alkyl groups, halo(C1-C6)alkyl groups, (C1-C6)alkoxy groups, (C1-C6)alkyl-OH groups, (C1-C6)alkyl-O-(C1-C6)alkyl groups, -OH groups, and -C(O)-(C1-C6)alkyl groups; L represents a bond or -CH2-, where the -CH2- may be substituted with one or two groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and 3-6 membered cycloalkyl rings, where the (C1-C6)alkyl and 3-6 membered cycloalkyl rings may be substituted with one, two, or three groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and -OH; or where the -CH2- is substituted with two groups, where the two groups, together with the carbon atoms to which they are bonded, form a 3-6 membered cycloalkyl or a 3-6 membered heterocyclyl ring containing one or two oxygen atoms; and R represents (C1-C6)alkyl, -(C1-C6)alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkyl-O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)2, -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl), and 3-7 membered heterocyclyl, where the (C1-C6)alkyl, -(C1 -C6)alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkyl-O-(C1-C6)alkyl, -NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)2, -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl, and 3-7 membered heterocyclyl may be substituted with one, two, or three groups independently selected from halogens and (C1-C6)alkyl. Compounds thereof, or pharmaceutically acceptable salts thereof.

[0067]

[12] Ring W is benzene, a 5 or 6-membered heteroaryl, a 3-8-membered cycloalkyl, and a 6-membered heterocyclyl, where each ring may be substituted with 1, 2, 3, or 4 groups independently selected from halogens, (C1-C6)alkyls, and (C1-C6)alkoxys, where the (C1-C6)alkyl or (C1-C6)alkoxy Coxy may be substituted with 1, 2, 3, or 4 halogen atoms; Ring X is benzene or a 5- or 6-membered heteroaryl, where each ring may be substituted with 1, 2, or 3 groups independently selected from halogens, (C1-C6)alkyls, and (C1-C6)alkoxys, where the (C1-C6)alkyl group may be substituted with 1, 2, 3, or 4 halogen atoms; Ring Y is a cyclopropane ring which may be substituted with one, two, or three groups independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-O-(C1-C6)alkyl, (C1-C6)alkyl-CN, and -CN; Ring Z is a 3-9 member nitrogen-containing monocyclic ring or a 6-8 member nitrogen-containing bicyclic ring, where each ring may contain one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; where the 3-9 member nitrogen-containing monocyclic ring is one, two, three, or four groups independently selected from halogens, (C1-C6)alkyl, halo(C1-C6)alkyl, ((C1-C6)alkyl)-OH, (C1-C6)alkoxy, (C1-C6)alkyl-O-(C1-C6)alkyl, -OH, and -C(O)-(C1-C6)alkyl The 6-8 member bicyclic ring may be substituted with, and also substituted with, one, two, or three (C1-C6)alkyl groups, and thereafter substituted with one, two, three, or four groups independently selected from halogens, (C1-C6)alkyl groups, halo(C1-C6)alkyl groups, ((C1-C6)alkyl)-OH groups, (C1-C6)alkoxy groups, (C1-C6)alkyl-O-(C1-C6)alkyl groups, -OH groups, and -C(O)-(C1-C6)alkyl groups; L is a bond or -CH2-, where the -CH2- may be substituted with one or two groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and 3-6 membered cycloalkyl rings, where the (C1-C6)alkyl and 3-6 membered cycloalkyl rings may be substituted with one, two, or three groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and -OH; and R is (C1-C6)alkyl, -(C1-C6)alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C1-C6)alkyl-O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)2, -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl), and 3-7 membered heterocyclyl, where the (C1-C6)alkyl, -(C1-C6)alkyl The 3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkyl-O-(C1-C6)alkyl, -NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)2, -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl, and 3-7 membered heterocyclyl may be substituted with one, two, or three groups independently selected from halogens and (C1-C6)alkyl. The compounds described in

[10] or

[11] above, or their pharmaceutically acceptable salts.

[0068]

[13] Ring W is benzene, a 5 or 6-membered heteroaryl, a 4-6-membered cycloalkyl, and a 6-membered heterocyclyl, where each ring may be substituted with 1, 2, 3, or 4 groups independently selected from halogens, (C1-C6)alkyls, and (C1-C6)alkoxys, where the (C1-C6)alkyl or (C1-C6)alkoxy may be substituted with 1, 2, 3, or 4 halogen atoms; Ring X is benzene or a 5- or 6-membered heteroaryl, where each ring may be substituted with 1, 2, or 3 groups independently selected from halogens, (C1-C6)alkyls, and (C1-C6)alkoxys, where the (C1-C6)alkyl group may be substituted with 1, 2, 3, or 4 halogen atoms; Ring Y is a cyclopropane ring which may be substituted with one, two, or three groups independently selected from halogen, (C1-C6)alkyl, (C1-C6)alkyl-OH, (C1-C6)alkyl-O-(C1-C6)alkyl, (C1-C6)alkyl-CN, and -CN; Ring Z is a 3-9 member nitrogen-containing monocyclic ring or a 6-8 member nitrogen-containing bicyclic ring, where each ring may contain one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; where the 3-9 member nitrogen-containing monocyclic ring contains one, two, or three groups independently selected from halogens, (C1-C6)alkyl, halo(C1-C6)alkyl, ((C1-C6)alkyl)-OH, (C1-C6)alkoxy, (C1-C6)alkyl-O-(C1-C6)alkyl, -OH, and -C(O)-(C1-C6)alkyl The 6-8 member bicyclic ring may be substituted with one, two, three, or more (C1-C6)alkyl groups, and may also be substituted with one, two, three, or more (C1-C6)alkyl groups; where the 6-8 member bicyclic ring may be substituted with one, two, three, or four groups independently selected from halogens, (C1-C6)alkyl groups, halo(C1-C6)alkyl groups, ((C1-C6)alkyl)-OH groups, (C1-C6)alkoxy groups, (C1-C6)alkyl-O-(C1-C6)alkyl groups, -OH groups, and -C(O)-(C1-C6)alkyl groups; L is a bond or -CH2-, where the -CH2- may be substituted with one or two groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and 3-6 membered cycloalkyl rings, where the (C1-C6)alkyl and 3-6 membered cycloalkyl rings may be substituted with one, two, or three groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and -OH; and R is (C1-C6)alkyl, -(C1-C6)alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C1-C6)alkyl-O-(C1-C6)alkyl, -NH2, -NH((C1-C6)alkyl), -N((C1-C6)alkyl)2, -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)2, -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl), and 3-7 membered heterocyclyl, where the (C1-C6)alkyl, -(C1-C6)alkyl The 3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C1-C6)alkoxy, (C1-C6)alkyl-O-(C1-C6)alkyl, -NH((C1-C6)alkyl), N((C1-C6)alkyl)2, -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)2, -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl, and 3-7 membered heterocyclyl may be substituted with one, two, or three groups independently selected from halogens and (C1-C6)alkyl. The compounds described in

[10] or

[11] above, or their pharmaceutically acceptable salts.

[0069]

[14] A compound according to any one of

[10] to

[13] above or a pharmaceutically acceptable salt thereof, wherein the ring W is a benzene which may be further substituted with one, two, or three halogen atoms.

[15] Any one of the compounds

[10] to

[14] above or a pharmaceutically acceptable salt thereof, wherein ring W is a benzene which may be substituted with one, two or three halogen atoms independently selected from chloro and fluoro.

[0070]

[16] Ring X is a halogen atom, and C 1-6 A compound according to any one of the above

[10] to

[15] or a pharmaceutically acceptable salt thereof, which is a benzene that may be substituted with one, two, or three groups independently selected from the alkyl group.

[17] A compound according to any one of

[10] to

[16] above or a pharmaceutically acceptable salt thereof, wherein ring Y is a cyclopropane ring which may be substituted with one, two, or three halogen atoms.

[0071]

[18] Ring Z contains halogen atoms and C 1-6 A compound according to any one of

[10] to

[17] above, or a pharmaceutically acceptable salt thereof, which is a 4- to 8-membered nitrogen-containing monocyclic ring that may be substituted with one, two, or three groups independently selected from the alkyl group.

[19] Any one of the compounds

[10] to

[18] above or a pharmaceutically acceptable salt thereof, wherein ring Z is an azetidine which may be substituted with one, two or three groups independently selected from halogen atoms and (C1-C6) alkyl groups.

[20] Any one of the compounds

[10] to

[19] above or a pharmaceutically acceptable salt thereof, wherein ring Z is an azetidine which may be substituted with one fluoro or methyl group.

[0072]

[21] L is bonded, or C 1-6 A compound or a pharmaceutically acceptable salt thereof described in any one of the above

[10] to

[20] , which is a -CH2-linker that may be substituted with an alkyl group.

[22] A compound or pharmaceutically acceptable salt thereof described in any one of

[10] to

[21] above, wherein R is (C1-C6)alkyl, -NH((C1-C6)alkyl), or N((C1-C6)alkyl)2.

[0073]

[23] Compounds listed in Tables 1-1 to 1-80, or pharmaceutically acceptable salts thereof.

[0074]

[24] Ring W is a benzene which may be substituted with one, two, or three halogen atoms; Ring X contains halogen atoms and C 1-6 A benzene which may be substituted with one, two, or three groups independently selected from the alkyl group; Ring Y is a cyclopropane ring which may be substituted with 1, 2, or 3 halogen atoms; Ring Z is a 4- to 8-membered nitrogen-containing monocyclic ring which may be substituted with 1, 2, or 3 groups independently selected from halogen atoms and (C1-C6) alkyl groups; L is a bonded or possibly substituted (C1-C6) alkyl group -CH2- group; and R is a (C1-C6)alkyl group, -NH((C1-C6)alkyl), or -N((C1-C6)alkyl)2. The compounds or pharmaceutically acceptable salts described in

[10] or

[11] above.

[0075]

[25] Ring W is a benzene which may be substituted with 1, 2, or 3 halogen atoms; Ring X is a benzene ring which may be further substituted with one, two, or three groups independently selected from halogen atoms and (C1-C6) alkyl groups; Ring Y is a cyclopropane ring which may be substituted with 1, 2, or 3 halogen atoms; Ring Z is an azetidine ring which may be further substituted with one, two, or three groups independently selected from halogen atoms and (C1-C6) alkyl groups; L is a -CH2- which may be substituted with a (C1-C6) alkyl group; and R is (C1-C6)alkyl or -NH((C1-C6)alkyl). The compounds or pharmaceutically acceptable salts described in

[10] or

[11] above.

[0076]

[26] Ring W is a benzene which may be substituted with one, two, or three halogen atoms; Ring X is a benzene ring which may be substituted with one, two, or three halogen atoms; Ring Y is a cyclopropane ring which may be substituted with 1, 2, or 3 halogen atoms; Ring Z is an azetidine which may be substituted with 1, 2, or 3 halogen atoms; L is -CH2- and R, C 1-6Alkyl group, or -NH((C1-C6)alkyl), The compounds or pharmaceutically acceptable salts described in

[10] or

[11] above.

[0077]

[27] N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide, N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)ethanesulfonamide, N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)-N'-methylsulfate Diamide, N-[(1S)-1-{(2S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]azetidine-2-yl}ethyl]methanesulfonamide, N-({(2S,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-methylazetidine-2-yl}methyl)methanesulfonamide, N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2- Fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)methanesulfonamide, N-({(2R,3R)-1-[(1R,2R)-2-(5-chloro-2',6'-difluoro[1,1'-biphenyl]-2-yl)-2- Fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide, and N-({(2R,3R)-1-[(1S,2S)-2-(5-chloro-2',6'-difluoro[1,1'-biphenyl]-2-yl)-2- Fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide, A compound selected from, or a pharmaceutically acceptable salt thereof.

[0078]

[28] A pharmaceutical product comprising any one of the compounds or salts described in [1] to

[27] above.

[29] The pharmaceutical product described in

[28] above, which is an orexin type 2 receptor agonist.

[30] The medicine described in

[28] above, which is a preventive or therapeutic agent for narcolepsy.

[31] A compound or salt of any one of the above [1] to

[27] for use in the prevention or treatment of narcolepsy.

[0079]

[32] A method for activating the orexin type 2 receptor in a mammal, comprising administering an effective amount of any one of the compounds or salts described in [1] to

[27] above to the mammal.

[33] A method for preventing or treating narcolepsy in a mammal, comprising administering an effective amount of the compound or salt described in any one of [1] to

[24] above to the mammal.

[34] A method for treating an orexin-mediated disease or disorder in a mammal, comprising administering a therapeutically effective amount of the compound or pharmaceutically acceptable salt described in any one of [1] to

[27] above to a mammal in need thereof.

[35] The method according to

[34] above, wherein the orexin-mediated disorder or disorder is narcolepsy.

[0080]

[36] Use of any one of the compounds or salts described in [1] to

[27] above for the manufacture of an agent for the prevention or treatment of narcolepsy.

[37] Use of any one of the compounds or salts described in [1] to

[24] above for the manufacture of a pharmaceutical product in the treatment of an orexin-mediated disease or disorder.

[38] A compound described in any one of the above [1] to

[27] or a pharmaceutically acceptable compound thereof A pharmaceutical composition containing a salt. [Effects of the Invention]

[0081] The compound of the present invention has orexin type 2 receptor agonist activity and is useful as a preventive or therapeutic agent for narcolepsy.

[0082] (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.

[0083] In this specification, the term "alkyl" refers to a saturated, linear or branched hydrocarbon moiety having a specific number of carbon atoms. The term "(C1-C6)alkyl" refers to an alkyl moiety containing one to six carbon atoms. In this specification, "C 1-6 Examples of alkyl groups 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.

[0084] "Alkoxy" refers to a group containing the alkyl radical as defined above, which is bonded via an oxygen-bonding atom. The term "(C1-C6) alkoxy" refers to a linear or branched hydrocarbon radical having at least one to four carbon atoms bonded via an oxygen-bonding atom. Representative "(C1-C4) alkoxy" groups useful in the present invention include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, s-butoxy, isobutoxy, t-butoxy, n-pentyloxy, and n-hexyloxy.

[0085] In this specification, "C which may be halogenated" 1-6 The alkyl group may, for example, have 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Alkyl groups are examples. 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.

[0086] In this specification, the term "halo(C1-C6)alkyl" means a (C1-C6) alkyl group substituted with 1, 2, 3, 4, 5, 6, or 7 halogen atoms. In this specification, the term "((C1-C6)alkyl)-OH," means a (C1-C6)alkyl group substituted with a hydroxyl group.

[0087] In this specification, "C 2-6Examples of alkenyl groups include 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 Examples of "alkynyl groups" include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2- Examples include pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl.

[0088] In this specification, “5- or 6-membered heteroaryl” refers to a group or part comprising an aromatic monovalent monocyclic radical containing 5 or 6 ring atoms, each containing at least one carbon atom and 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. A selected 5-membered heteroaryl group contains one nitrogen, oxygen, or sulfur ring heteroatom and may contain 1, 2, or 3 additional nitrogen ring atoms. A selected 6-membered heteroaryl group contains 1, 2, or 3 nitrogen ring heteroatoms. Specific examples of 5- or 6-membered heteroaryl groups useful in the present invention include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyridinyl, pyrimidinyl, and triazinyl.

[0089] In this specification, the term "cycloalkyl" means a non-aromatic, saturated cyclic hydrocarbon ring containing a specific number of carbon atoms. 3-10Examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cycloctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl. In this specification, "optionally halogenated C" 3-10 Examples of the "cycloalkyl group" include C cycloalkyl groups which may have 1 to 7, preferably 1 to 5 halogen atoms. 3-10 Specific examples include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cycloctyl. In this specification, "C" 3-10 Examples of the "cycloalkenyl group" include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl.

[0090] In this specification, "C" 6-14 Examples of the "aryl group" include phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl. In this specification, "C" 7-16 Examples of the "aralkyl group" include benzyl, phenethyl, naphthylmethyl, and phenylpropyl.

[0091] In this specification, "C" 1-6 Examples of the "alkoxy group" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, and hexyloxy. In this specification, "optionally halogenated C" 1-6 Examples of the "alkoxy group" include C alkoxy groups which may have 1 to 7, preferably 1 to 5 halogen atoms. 1-6Examples of the alkoxy group 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, the "C 3-10 cycloalkyloxy group" includes, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0092] In this specification, the "C 1-6 alkylthio group" includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, tert-but ylthio, pentylthio, and hexylthio. In this specification, the "optionally halogenated C 1-6 alkylthio group" includes, for example, a C 1-6 alkylthio group that may have 1 to 7, preferably 1 to 5 halogen atoms. Specific examples include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

[0093] In this specification, the "C 1-6 alkyl-carbonyl group" includes, for example, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl. In this specification, the "optionally halogenated C 1-6 alkyl-carbonyl group" includes, for example, a C 1-6Alkyl-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.

[0094] 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" includes, 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.

[0095] 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.

[0096] In this specification, "C 1-6Examples 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.

[0097] In this specification, "substituent" refers to, for example, a halogen atom, a cyano group, a nitro group, or a substitution. Examples include 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.

[0098] 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 halogenated 1-6 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 6-14Aryl-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 1-6Alkyl-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 1-6 Alkylsulfonylamino 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 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.

[0099] 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.

[0100] In this specification, unless otherwise specified, "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.

[0101] 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.

[0102] 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 azilidinyl, oxyranil, thyranil, azetidinil, oxetanil, thietanil, tetrahydrothienyl, tetrahydrofuranil, pyrrolinil, pyrrolidinyl, imidazolinil, imidazolidinyl, oxazolinil, oxazolidinyl, pyrazolinil, pyrazolidinyl, thiazolinil, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydro Three to eight-membered monocyclic non-aromatic heterocyclic groups such as diisoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranil, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranil, tetrahydropyranil, tetrahydrothiopyranil, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; 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.

[0103] 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, “3-8 membered heterocyclyl” refers to a group or part containing a saturated or partially unsaturated, non-aromatic monovalent monocyclic radical containing 3, 4, 5, 6, 7, or 8 ring atoms, each containing one or two heteroatoms independently selected from oxygen, sulfur, and nitrogen.

[0104] In this specification, "a heterocyclic group which may be substituted" refers, for example, to a heterocyclic group which may have substituents selected from the substituent group A described above. The number of substituents in the "optionally substituted heterocyclic group" is, for example, one to three. If there are two or more substituents, each substituent may be the same or different.

[0105] In this specification, "acyl group" means, for example, "halogen atom, optionally halogenated C 1-6 C may have one to three substituents selected from an alkoxy group, a hydroxyl group, a nitro group, a cyano group, an amino group, and a carbamoyl group. 1-6 Alkyl alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 3-10 Cycloalkenyl group, C 6-14 Aryl group, C 7-16 Examples include formyl group, carboxyl group, carbamoyl group, thiocarbamoyl group, sulfino group, sulfo group, sulfamoyl group, and phosphono group, each having one or two substituents selected from an aralkyl group, a 5- to 14-membered aromatic heterocyclic group, and a 3- to 14-membered non-aromatic heterocyclic group. Other examples of "acyl groups" include hydrocarbon-sulfonyl groups, heterocyclic-sulfonyl groups, hydrocarbon-sulfinyl groups, and heterocyclic-sulfinyl groups. Here, a hydrocarbon-sulfonyl group refers to a sulfonyl group to which a hydrocarbon group is attached, a heterocyclic-sulfonyl group refers to a sulfonyl group to which a heterocyclic group is attached, a hydrocarbon-sulfinyl group refers to a sulfinyl group to which a hydrocarbon group is attached, and a heterocyclic-sulfinyl group refers to a sulfinyl group to which a heterocyclic group is attached. Preferred examples of "acyl groups" include formyl groups, carboxyl groups, and 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), C 3-10 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 Aryloxycarbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7-16 Aralkyloxycarbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl groups, mono- or di-C 1-6 a Lukyl-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 groups (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 groups (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 groups (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14Aryl-thiocarbamoyl groups (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl groups (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (e.g., pyridylthiocarbamoyl), sulfino groups, C 1-6 Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C 1-6 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).

[0106] 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 1-6Alkyl)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 7-16 Aralkylamino 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 Aalkyl-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 di-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 6-14Examples include aryl-carbonyl)amino groups (e.g., N-benzoyl-N-methylamino).

[0107] 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, 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 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).

[0108] 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, 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 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 6-14Examples include aryl-carbonyl-thiocarbamoyl groups (e.g., benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (e.g., pyridylthiocarbamoyl).

[0109] In this specification, "a sulfamoyl 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-Carboni 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., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C1-6 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).

[0110] 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 1-6Alkyl-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 1-6 Alkoxy-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).

[0111] 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 2-6Alkenylthio 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 6-14 Examples 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).

[0112] 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).

[0113] 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.

[0114] 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, phlopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyridine, imidazopyrimidine, thienopyrimidine, phlopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxatiin, indole, isoindole, 1H-indazo Examples include 8 to 14-membered condensed polycyclic (preferably 2 or 3-cyclic) aromatic heterocycles such as phosphate, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carbolin, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0115] 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, "four- to six-membered heterocyclic group" refers to aromatic or non-aromatic four- to six-membered heterocyclic groups, specifically including oxetanyl, furyl, pyrazolyl, pyridyl, and pyrimidinyl. In this specification, "ring" refers to "hydrocarbon ring" and "heterocycle ring".

[0116] The definitions of each symbol in equation (I) are described in detail below.

[0117] Ring W represents a ring that may be further substituted. Examples of substituents on the "ring that may be further substituted" mentioned above include substituents selected from substituent group A. The number of substituents is preferably 1 to 3. If there are two or more substituents, each substituent may be the same or different.

[0118] Ring W is preferably, (1) Monocyclic non-aromatic heterocycles with 3 to 8 members (e.g., piperidine), (2) A 5- to 6-membered monocyclic aromatic heterocycle (e.g., furan, pyridine) which may be further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), (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 carbonization Hydrogen rings (e.g., benzene), or (4) C 3-10 These are cycloalkanes (e.g., cyclobutane, cyclopentane, cyclohexane).

[0119] Ring W may more preferably be further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms) C 6-14 It is an aromatic hydrocarbon ring (e.g., benzene). Ring W is particularly preferably further substituted with C by 1 to 3 halogen atoms (e.g., fluorine atoms). 6-14 It is an aromatic hydrocarbon ring (e.g., benzene). In one embodiment, the ring W is a benzene ring which may be further substituted with two fluorine atoms.

[0120] Ring X represents a 5- or 6-membered aromatic ring, which may be further substituted. Examples of substituents on the "five or six-membered aromatic ring that may be further substituted" include substituents selected from substituent group A. The number of substituents is preferably one to three. If there are two or more substituents, each substituent may be the same or different.

[0121] Ring X is preferably, (1)(i) Halogen atoms (e.g., fluorine atom, chlorine atom), (ii) C which may be halogenated1-6 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)(i) Halogen atoms (e.g., fluorine atoms), and (ii) C 1-6 Alkyl group (e.g., methyl) A 5- or 6-membered monocyclic aromatic heterocycle (e.g., thiophene, thiazole, pyridine) which may be further substituted with one to three substituents selected from the above.

[0122] Ring X is more preferably, (i) Halogen atoms (e.g., fluorine atoms, chlorine atoms), and (ii) C 1-6 Alkyl group (e.g., methyl) A benzene ring which may be further substituted with one to three substituents selected from the following.

[0123] In one embodiment, ring X may be further substituted with one or two substituents independently selected from halogens (e.g., fluorine atoms, chlorine atoms) and methyl atoms:

[0124] [ka]

[0125] ; and here,

[0126] [ka]

[0127] is a bonding point to ring W, and

[0128] [ka]

[0129] This is a bonding point to ring Y.

[0130] Ring Y represents a cyclopropane ring that may be further substituted. Examples of substituents on the "cyclopropane ring which may be further substituted" include substituents selected from substituent group A. The number of substituents is preferably 1 to 3. If there are two or more substituents, each substituent may be the same or different.

[0131] Ring Y is preferably, (i) Halogen atoms (e.g., fluorine atoms), (ii) cyano group, and (iii) C 1-6 C may be substituted with one to three substituents selected from alkoxy groups (e.g., methoxy), cyano, and hydroxyl groups. 1-6 Alkyl group (e.g., methyl) A cyclopropane ring which may be further substituted with one to three substituents selected from the above. Ring Y is more preferably a cyclopropane ring that may be further substituted with one to three halogen atoms (e.g., fluorine atoms).

[0132] In one embodiment, ring Y may be further substituted with one fluorine atom:

[0133] [ka]

[0134] ; and here,

[0135] [ka]

[0136] is a bonding point to ring X, and

[0137] [ka]

[0138] This is a bonding point to ring Z.

[0139] Ring Z represents a nitrogen-containing heterocycle that may be further substituted. Examples of substituents on the above-mentioned "nitrogen-containing heterocycle that may be further substituted" include substituents selected from substituent group A. The number of substituents is preferably 1 to 3. If there are two or more substituents, each substituent may be the same or different.

[0140] Ring Z is preferably, (i) Halogen atoms (e.g., fluorine atoms), (ii) Hydroxyl group, (iii) C 1-6 C may be substituted with one to three substituents selected from alkoxy groups (e.g., methoxy), halogen atoms (e.g., fluorine atoms), and hydroxyl groups. 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), (iv) C 1-6 Alkoxy groups (e.g., methoxy), (v) -C(O)-C 1-6 Alkyl, and (vi) C 1-6 Five-membered monocyclic aromatic heterogeneous molecules which may be substituted with alkyl (e.g., methyl) Rings (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl) A 3- to 14-membered nitrogen-containing heterocycle (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).

[0141] Ring Z more preferably comprises a halogen atom (e.g., a fluorine atom), a hydroxyl group, and C1-6 These are 3- to 14-membered nitrogen-containing heterocycles (e.g., azetidine, pyrrolidine, piperidine, azepane, oxazepane, octahydrocyclopenta[c]pyrrole) which may be further substituted with one to three substituents selected from alkyl groups (e.g., methyl).

[0142] In the embodiment, ring Z is a halogen atom (e.g., a fluorine atom), a hydroxyl group, and C 1-6 It may be further substituted with one to three substituents independently selected from alkyl groups (e.g., methyl):

[0143] [ka]

[0144] Selected from the group consisting of,

[0145] [ka]

[0146] is a bond point to the ring Y-(C=O), and

[0147] [ka]

[0148] This is the connection point to L.

[0149] In one embodiment, ring Z is composed of a halogen atom (e.g., a fluorine atom) and C 1-6 It may be further substituted with one to three substituents independently selected from alkyl groups (e.g., methyl):

[0150] [ka]

[0151] ; and here,

[0152] [ka]

[0153] is a bond point to the ring Y-(C=O), and

[0154] [ka]

[0155] This is the connection point to L.

[0156] L represents a methylene group that may be bonded or substituted. Examples of substituents on the "methylene group that may be substituted" include substituents selected from substituent group A. The number of substituents is preferably 1 to 3. If there are two or more substituents, each substituent may be the same or different.

[0157] L is a combination, or (1) C 1-6 C may be further substituted with one to three substituents selected from alkoxy groups (e.g., methoxy) and hydroxyls. 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), and (2) C which may be further substituted with a hydroxyl group 3-6 Cycloalkyl groups (e.g., cyclopropyl) It is a methylene group which may be substituted with one substituent selected from the following.

[0158] L is preferably bonded, or C 1-6 This is a methylene group that may be substituted with an alkyl group (e.g., methyl). L is preferably C 1-6 This is a methylene group that may be substituted with an alkyl group (e.g., methyl). L is preferably a methylene group.

[0159] R may be substituted with C 1-6 Alkyl alkyl groups, or substituted C 3-10 Cycloalkyl groups, or NR a R b This indicates. Here, R a C may be substituted 1-6 Alkyl alkyl groups, or optionally substituted C 3-10 It shows a cycloalkyl group; R b C is a hydrogen atom, which may be substituted. 1-6 Alkyl alkyl groups, or optionally substituted C 3-10 It indicates a cycloalkyl group; or R a and R b These atoms combine with adjacent nitrogen atoms to form a nitrogen-containing heterocycle, which may be further substituted. Examples of "nitrogen-containing heterocycles" include monocyclic non-aromatic heterocycles with 3 to 8 members (preferably 4 members) that contain at least one nitrogen atom as a ring constituent atom other than carbon atoms. A preferred example of a "nitrogen-containing heterocycle" is azetidine. The above "C may be replaced" 1-6 "Alkyl alkyl group", "C which may be substituted" 3-10 Examples of substituents on "cycloalkyl groups" and "nitrogen-containing heterocycles that may be further substituted" include substituents selected from substituent group A. The number of substituents is preferably 1 to 3. If there are two or more substituents, each substituent may be the same or different.

[0160] In one embodiment, R is a C which may be substituted. 1-6 Alkyl, possibly substituted C 3-10 Cycloalkyl or optionally substituted di-C 1-6 It is an alkylamine. The above "C may be replaced" 1-6 "Alkyl alkyl group", "C which may be substituted" 3-10 "Cycloalkyl group" and "Optionally substituted di-C 1-6Examples of substituents on the alkylamine group include substituents selected from substituent group A. The number of substituents is preferably 1 to 3. If there are two or more substituents, each substituent may be the same or different.

[0161] R is preferably, (1)(i) Halogen atoms (e.g., fluorine atoms, bromine atoms), (ii) C 1-6 Alkoxy (e.g., methoxy), and (iii) Cyclopropyl group (e.g., cyclopropyl) C may be substituted with one to three substituents selected from the following. 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), (2) C 1-6 C may be further substituted with an alkyl group (e.g., methyl). 3-10 Cycloalkyl groups (e.g., cyclopropyl), or (3) NR a R b And here, R a C 1-6 Alkyl group (e.g., methyl, ethyl, or isopropyl), or C 3-10 It is a cycloalkyl group (e.g., cyclopropyl); R b is a hydrogen atom, or C 1-6 It is an alkyl group (e.g., methyl); or R a and R b These atoms combine with adjacent nitrogen atoms to form nitrogen-containing heterocycles (e.g., azetidinyl).

[0162] R is more preferably, (1) C 1-6 Alkyl groups (e.g., methyl, ethyl), or (2) NR a R b and; Here, R a C 1-6 It is an alkyl group (e.g., methyl); and R bis a hydrogen atom, or C 1-6 It is an alkyl group (e.g., methyl).

[0163] R is more preferably, (1) C 1-6 Alkyl groups (e.g., methyl, ethyl), or (2) NR a R b and; Here, R a C 1-6 It is an alkyl group (e.g., methyl); and R b This is a hydrogen atom.

[0164] R is more preferably, (1) C 1-6 Alkyl groups (e.g., methyl, ethyl), or (2) Mono-C 1-6 It is an alkylamino group (e.g., methylamino).

[0165] Compound (I) is preferably optically active and more preferably a compound represented by the following formula (I') having stereoisomerism in the ring Y portion.

[0166] [ka]

[0167] Preferred examples of compound (I) include the following compounds. These compounds are preferably represented by the above formula (I').

[0168] [Compound A] Compound (I) is preferably, Ring W is (1) Monocyclic non-aromatic heterocycles with 3 to 8 members (e.g., piperidine), (2) A 5- to 6-membered monocyclic aromatic heterocycle (e.g., furan, pyridine) which may be further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), (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 These are cycloalkanes (e.g., cyclobutane, cyclopentane, cyclohexane); 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); 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 molecule which may be further substituted with 1 to 3 substituents selected from These are elementary heterocycles (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); 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) G-C 1-6 It is an alkylamino group (e.g., dimethylamino), It is compound (I).

[0169] [Compound B] Compound (I) is more preferably, 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 group (e.g., methyl) A benzene ring which may be further substituted with one to three substituents selected from; The ring Y is a cyclopropane which may be further substituted with one to three halogen atoms (e.g., fluorine atoms); Ring Z contains a halogen atom (e.g., a fluorine atom), a hydroxyl group, and C 1-6A 3- to 14-membered nitrogen-containing heterocycle (e.g., azetidine, pyrrolidine, piperidine, azepane, oxazepane, octahydrocyclopenta[c]pyrrole) which may be further substituted with one to three substituents selected from alkyl groups (e.g., methyl); L is a bond or a methylene group; and R (1) C 1-6 Alkyl groups (e.g., methyl, ethyl), or (2) G-C 1-6 It is an alkylamino group (e.g., dimethylamino), It is compound (I).

[0170] [Compound C] Compound (I) is preferably, Ring W is (1) Monocyclic non-aromatic heterocycles with 3 to 8 members (e.g., piperidine), (2) A 5- to 6-membered monocyclic aromatic heterocycle (e.g., furan, pyridine) which may be further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms), (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 These are cycloalkanes (e.g., cyclobutane, cyclopentane, cyclohexane); 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 1-6Alkoxy groups (e.g., methoxy) A benzene ring which may be further substituted with one to three substituents selected from, or (2)(i) Halogen atoms (e.g., fluorine atoms), and (ii) C 1-6 Alkyl group (e.g., methyl) A 5 or 6-membered monocyclic aromatic heterocycle (e.g., thiophene, thiazole, pyridine) which may be further substituted with one to three substituents selected from: Ring Y is (i) Halogen atoms (e.g., fluorine atoms), (ii) cyano group, and (iii) C 1-6 C may be substituted with one to three substituents selected from alkoxy groups (e.g., methoxy), cyano, and hydroxyl groups. 1-6 Alkyl group (e.g., methyl) A cyclopropane ring 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 C may be substituted with one to three substituents selected from alkoxy groups (e.g., methoxy), halogen atoms (e.g., fluorine atoms), and hydroxyl groups. 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), (iv) C 1-6 Alkoxy groups (e.g., methoxy), (v) -C(O)-C 1-6 Alkyl, and (vi) C 1-6 Five-membered monocyclic aromatic heterogeneous molecules which may be substituted with alkyl (e.g., methyl) Rings (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl) A 3- to 14-membered nitrogen-containing heterocycle (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). L, joins, or (1) C 1-6 C may be further substituted with one to three substituents selected from alkoxy groups (e.g., methoxy) and hydroxyls. 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), and (2) C which may be further substituted with a hydroxyl group 3-6 Cycloalkyl groups (e.g., cyclopropyl) A methylene group which may be substituted with one substituent selected from; and R (1)(i) Halogen atoms (e.g., fluorine atoms, bromine atoms), (ii) C 1-6 Alkoxy (e.g., methoxy), and (iii) Cyclopropyl group (e.g., cyclopropyl) C may be substituted with one to three substituents selected from the following. 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl). (2) C 1-6 C may be further substituted with an alkyl group (e.g., methyl). 3-10 Cycloalkyl groups (e.g., cyclopropyl), or (3) NR a R b and; Here, R a However, C 1-6 Alkyl group (e.g., methyl, ethyl, or isopropyl), or C 3-10 It is a cycloalkyl group (e.g., cyclopropyl); R b However, hydrogen atoms, or C 1-6 It is an alkyl group (e.g., methyl); or R a and R b Together with adjacent nitrogen atoms, they form a nitrogen-containing heterocycle (e.g., azetidinyl). ) form, It is compound (I).

[0171] [Compound D] Compound (I) is more preferably, 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, chlorine atoms), and (ii) C 1-6 Alkyl group (e.g., methyl) A benzene ring which may be further substituted with one to three substituents selected from; Ring Y is a cyclopropane ring which may be further substituted with one to three halogen atoms (e.g., fluorine atoms); Ring Z contains a halogen atom (e.g., a fluorine atom), a hydroxyl group, and C 1-6 A 3- to 14-membered (more preferably 4- to 8-membered) nitrogen-containing heterocycle (e.g., azetidine, pyrrolidine, piperidine, azepane, oxazepane, octahydrocyclopenta[c]pyrrole) which may be further substituted with one to three substituents selected from alkyl groups (e.g., methyl); L is a bond, or C 1-6 A methylene group which may be substituted with an alkyl group (e.g., methyl); R (1) C 1-6 Alkyl groups (e.g., methyl, ethyl), or (2) NR a R b and; Here, R a However, C 1-6 It is an alkyl group (e.g., methyl); and R b However, hydrogen atoms, or C 1-6 It is an alkyl group (e.g., methyl), It is compound (I).

[0172] [Compound E] In other embodiments, compound (I) is The ring W is a benzene ring which may be further substituted with two fluorine atoms. Ring X may be further substituted with one or two substituents independently selected from halogens (e.g., fluorine atoms, chlorine atoms) and methyl groups.

[0173] [ka]

[0174] ; and here,

[0175] [ka]

[0176] is a bonding point to ring W, and

[0177] [ka]

[0178] This is a bonding point to ring Y. Ring Y may be further substituted with one fluorine atom.

[0179] [ka]

[0180] ; and here,

[0181] [ka]

[0182] is a bonding point to ring X, and

[0183] [ka]

[0184] is a bonding point to ring Z; Ring Z contains a halogen atom (e.g., a fluorine atom), a hydroxyl group, and C 1-6 It may be further substituted with one to three substituents independently selected from alkyl groups (e.g., methyl):

[0185] [ka]

[0186] Selected from the group consisting of,

[0187] [ka]

[0188] is a bonding point to ring Y, and

[0189] [ka]

[0190] This is the connection point to L. L, C 1-6 A methylene group which may be substituted with an alkyl group (e.g., methyl); and R (1) C 1-6 Alkyl groups (e.g., methyl, ethyl), or (2) NR a R b and; Here, R a However, C 1-6 It is an alkyl group (e.g., methyl); and R b However, hydrogen atoms, or C 1-6 It is an alkyl group (e.g., methyl), It is compound (I).

[0191] [Compound F] Compound (I) is more preferably, Ring W is a benzene ring which may be further substituted with one to three halogen atoms (e.g., fluorine atoms); Ring X is (i) Halogen atoms (e.g., fluorine atoms, chlorine atoms), and (ii) C 1-6 Alkyl group (e.g., methyl) A benzene ring which may be further substituted with one to three substituents selected from; Ring Y is a cyclopropane ring which may be further substituted with one to three halogen atoms (e.g., fluorine atoms); Ring Z contains halogen atoms (e.g., fluorine atoms) and C 1-6 An azetidine ring which may be further substituted with one to three substituents selected from alkyl groups (e.g., methyl); L, C 1-6 A methylene group which may be substituted with an alkyl group (e.g., methyl); R (1) C 1-6 Alkyl groups (e.g., methyl, ethyl), or (2) NR a R b and; Here, R a However, C 1-6 It is an alkyl group (e.g., methyl); and R b However, it is a hydrogen atom. It is compound (I).

[0192] [Compound G] Compound (I) is more preferably, Ring W is a benzene ring which may be further substituted with one to three halogen atoms (e.g., fluorine atoms); Ring X is a benzene ring which may be further substituted with one to three halogen atoms (e.g., fluorine atoms); Ring Y is a cyclopropane ring which may be further substituted with one to three halogen atoms (e.g., fluorine atoms); Ring Z is an azetidine ring which may be further substituted with one to three halogen atoms (e.g., fluorine atoms); L is a methylene group; R, C 1-6 Alkyl alkyl groups (e.g., ethyl), or NR a R b and; Here, R a However, C 1-6 It is an alkyl group (e.g., methyl); and R b However, it is a hydrogen atom. It is compound (I).

[0193] Specific examples of compound (I) include the compounds listed in Examples 1-12, 14-132, 134-138, 140-230, 232-353, 355-368, and 370-450 below.

[0194] Specifically, compound (I) is preferably, N-[(1S)-1-{(2S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]azetidine-2-yl}ethyl]methanesulfonamide, (Example 353) N-({(2S,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-methylazetidine-2-yl}methyl)methanesulfonamide, or a salt thereof (Example 358); N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide, or a salt thereof (Example 393); N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2- Fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)methanesulfonamide, or a salt thereof (Example 411); N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)ethanesulfonamide, or a salt thereof (Example 412); N-({(2R,3R)-1-[(1R,2R)-2-(5-chloro-2',6'-difluoro[1,1'-biphenyl]-2-yl)-2- Fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide, or N-({(2R,3R)-1-[(1S,2S)-2-(5-chloro-2',6'-difluoro[1,1'- Biphenyl]-2-yl)2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide, or a salt thereof (Example 420); or N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)-N'-methylsulfate Diamide, or a salt thereof (Example 423) That is the case.

[0195] Compound (I) is particularly preferably, N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide, or a salt thereof (Example 393); N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)ethanesulfonamide, or a salt thereof (Example 412); or N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)-N'-methylsulfate Diamide, or a salt thereof (Example 423) That is the case.

[0196] The term "therapeutic dose" means an amount that, compared to a corresponding subject who has not received such an amount, improves the treatment, cure, or alleviation of a disease, disorder, or side effect, or reduces the rate of progression of the disease or disorder. This term also includes, within its range, amounts effective in enhancing normal physiological function. For therapeutic use, a therapeutic dose of the compound of formula (I) and its salts may be administered as the active pharmaceutical ingredient. Furthermore, the active ingredient may be provided as a pharmaceutical composition.

[0197] 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, and ornithine. Suitable examples of salts with acidic amino acids include salts with aspartic acid and glutamic acid.

[0198] Due to their potential pharmaceutical applications, salts of the compounds of formulas (II) and (II') are understood to be ideally pharmaceutically acceptable. Medicinally acceptable salts include, in particular, those listed in Berge, J. Pharm. Sci., 66, 1-19, (1977), or those listed in P.H. Stahl and C.G. Wermuth, eds., Handbook of Pharmaceutical Salts; Properties, Selection and Use, Second Edition Stahl / Wermuth: Wiley-VCH / VHCA, (2011) (see http: / / www.wiley.com / WileyCDA / WileyTitle / productCd-3906390519.html). Optionally, an acid or base can be added to the compound of formula (I) in a suitable solvent such as an organic solvent to obtain a salt that can be isolated by various methods, including crystallization and filtration.

[0199] Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidebenzoate, acetate, adipine, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, tartrate, butyrate, calcium edetate, camphorate, camphor sulfonate (cansylate), caprylate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, and citrate. cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecyl sulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucinate), gentisinate (2,5-dihydroxybenzoate), glucoheptoneate (gluceptate), gluconate, g Lucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydravamin (N,N'-di(dehydroabiethyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate) Methyl sulfate, mucinate, naphthalene-1,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicylate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbitalate, phosphate, polygalacturonate, propionate, p-toluenesulfonate ( This includes silates, pyroglutamates, pyruvates, salicylates, sebacinates, stearates, subacetates, succinates, sulfamines, sulfates, tannates, tartrates, theoclates (8-chlorotheophylline), thiocyans, triethiozides, undecanoates, undecylenates, and valersates.

[0200] Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS), arginine, benetamine (N-benzylphenethylamine), benzathine (N,N'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, cremisole (1-p-chlorobenzyl-2-pyrrolildine-1'-ylmethylbenzimidazole), and cyanoacrylate. It contains chlorhexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (N-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t-butylamine, tromethamine (tris(hydroxymethyl)aminomethane), and zinc.

[0201] Salts can be prepared in situ during the final isolation and purification of the compounds of formulas (II) and (II'). If the basic compounds of formulas (II) and (II') are isolated as salts, the corresponding free base form of the compound can be prepared by any suitable method known in the art (including treatment of the salt with an inorganic or organic base). Similarly, if the compounds of formulas (II) and (II') containing a carboxylic acid or other acidic functional group are isolated as salts, the corresponding free acid form of the compound can be prepared by any suitable method known in the art, including treatment of the salt with an inorganic or organic acid.

[0202] If the compounds of formulas (II) and (II') contain two or more basic moieties, it is understood that the stoichiometry of salt formation may include one, two, or more equivalents of acid. Such salts, such as dihydrochloride salts, contain one, two, or more acid counterions.

[0203] The stoichiometric and non-stoichiometric forms of pharmaceutically acceptable salts of the compounds of formulas (II) and (II') are included within the scope of the present invention, including, for example, substoichiometric salts containing more than one counterion of an acidic proton.

[0204] In one embodiment, the present disclosure provides a pharmaceutically acceptable salt of any of the embodiments [1]-

[34] described above.

[0205] The method for producing the compound of the present invention is described below.

[0206] 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.

[0207] 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.

[0208] The compounds obtained in each step can be used as reaction solutions or obtained as crude products before proceeding to the next reaction. 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.

[0209] If the raw materials and reagent compounds for each step are commercially available, the commercially available products can be used as is.

[0210] In each step of the reaction, 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 10 minutes to 8 hours.

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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.

[0216] When a base is used in the reaction of each step, for example, the bases shown below, or in the examples. The listed bases will 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.

[0217] 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.

[0218] 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.

[0219] 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. Protecting groups include cyclic ketal protecting groups such as 1,3-dioxane; oxime protecting groups such as O-methyloxime; and hydrazone 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.

[0220] 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.

[0221] 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).

[0222] 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.

[0223] 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.

[0224] When performing the Horner-Emmons reaction in each step, the reagents used include methyl dimethylphosphonoacetate, ethyl diethylphosphonoacetate, and other phosphonoacetate compounds. Telles; examples include bases such as alkali metal hydrides and organolithium compounds.

[0225] 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.

[0226] 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.).

[0227] 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.

[0228] 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.

[0229] 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).

[0230] In each step of the Vilsmeier-Haack reaction, phosphoryl chloride and amide derivatives (e.g., N,N-dimethylformamide) are used as reagents.

[0231] 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.

[0232] 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.

[0233] 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.

[0234] 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 benzotriazole-1-yloxy-trisdimethylaminophosphonium 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.

[0235] 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.

[0236] 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.

[0237] 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.

[0238] 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.

[0239] When performing the Arbuzov reaction in each step, the reagent used is bromovinegar. Examples include alkyl halides such as ethyl acids; and phosphites such as triethyl phosphite and tri(isopropyl) phosphite.

[0240] 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.

[0241] 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.

[0242] 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.

[0243] 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.

[0244] [ka]

[0245] 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.

[0246] 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.

[0247] 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.

[0248] Compound (6) can be produced by a condensation reaction between compound (1) and hydrazine hydrate.

[0249] 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.

[0250] 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.

[0251] 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.

[0252] [ka]

[0253] 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).

[0254] LG 2Examples of "leaving groups" shown include dihydroxyboryl (e.g., dihydroxyboryl, pinacolateboryl), which may be substituted.

[0255] 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.

[0256] Compounds (8) and (9) can be used as commercially available products or produced by methods known to the public or similar methods.

[0257] Compound (3)-3 can be produced by the cyclopropanation reaction of compound (10) and compound (5) in the presence of a metal catalyst. The metal catalyst used is rhodium acetate. II) Examples include rhodium compounds such as dimers, and ruthenium compounds such as dichloro(p-cymene)ruthenium(II) dimers.

[0258] 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.

[0259] [ka]

[0260] 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.

[0261] [ka]

[0262] 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).

[0263] 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."

[0264] 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.

[0265] 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.

[0266] 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.

[0267] [ka]

[0268] 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.

[0269] 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.

[0270] 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.

[0271] 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.

[0272] 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., compound (I) is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert -Butylated compounds); 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); Examples of compounds in which the carboxyl group of compound (I) is esterified or amidized (e.g., compounds in which the carboxyl group of compound (I) is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, or methyl amidized). These compounds can be produced from compound (I) by methods known in themselves.

[0273] 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) contains isotopes (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.

[0274] 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.

[0275] 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.

[0276] 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).

[0277] 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.

[0278] 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 coating bases. 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.

[0279] 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.

[0280] 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, acute disseminated encephalomyelitis, Guillain-Barré syndrome, Rasmussen's encephalitis, Wernicke's 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 disorder, circadian rhythm-related disorders, fibromyalgia, conditions resulting from poor sleep quality, overeating, obsessive-compulsive eating disorder, obesity-related disorders, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeats. Arrhythmias, 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, children with acute lymphoblastic leukemia, syndrome X, reproductive hormone abnormalities, decreased fertility, infertility, sexual and reproductive dysfunction such as male hypogonadism and female hirsutism, fetal defects associated with maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwick syndrome), respiratory diseases such as dyspnea, and systemic inflammation of the vascular system. The risk of secondary consequences of obesity, such as inflammation, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, left ventricular hypertrophy, 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 disorder Acute neurological and psychiatric disorders such as cerebral malformations after cardiac bypass surgery and transplantation, 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, muscle spasms and related disorders, delirium, amnesia, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug addiction, movement disorders, chronic fatigue syndrome, fatigue, medication-induced Parkinsonian syndrome, Gilles de la Tourette syndrome, chorea, myoclonus, tics,It is useful as a preventative and therapeutic agent for various conditions such as restless limb 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.

[0281] 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 (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, sepsis, impaired consciousness such as coma, side effects and complications of anesthesia, and as an anesthetic antagonist.

[0282] 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.

[0283] 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. It can be configured. (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.

[0284] 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 combination drug or its pharmaceutical composition may be administered to the target patient simultaneously or with a time difference. The dosage of the combination 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.

[0285] 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, 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)methoxytetraline, 6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetraline, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methylbiphenyl-4-yl)methoxytetraline, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetraline, 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, optically active derivatives thereof, salts thereof and hydrates thereof, OM99-2 (International Publication 01 / 00663)), γ-secretase inhibitor, β-amyloid protein aggregation inhibitor (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (Japanese Patent Publication No. Hei 11-514333), PPI-558 (Japanese Patent 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, nicergoline), Parkinson's disease treatments [(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)], amyotrophic lateral sclerosis treatments (e.g., riluzole, neurotrophic factors), treatments for abnormal behavior and wandering associated with the progression of dementia (e.g., sedatives, anxiolytics), apoptosis inhibitors (e.g., CPI-1189, IDN-6556, CE P-1347), neuronal differentiation and regeneration promoters (e.g., leteprinium, 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]isoindorine, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindorine, 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 compounds, salts, and hydrates), nonsteroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroids (dexamethasone, hexestrol, cortisone acetate, etc.), disease-modifying antirheumatic drugs (DMARDs), anti-cytokine drugs (e.g., TNF inhibitors, MAP kinase inhibitors), urinary incontinence and frequent urination treatments (e.g., flavoxate hydrochloride, oxybutynin hydrochloride, propiverine hydrochloride), phosphodiesterase inhibitors (e.g., sildenaf citrate) Phyll, 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 Chlorazepam-based drugs (chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, chlorazepam) L-type calcium channel inhibitors (e.g., lonazepam, alprazolam), L-type calcium channel inhibitors (e.g., pregabalin), tricyclic or tetracyclic antidepressants (e.g., imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride), selective serotonin reuptake inhibitors (e.g., fluvoxamine maleate, floxetine hydrochloride, citalopram bromide, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride), norepinephrine reuptake inhibitors (e.g., leboxetine mesylate), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT 1A Agonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT 2A Antagonist, 5-HT 2AInverse 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, NM DA 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, riluzole, phenelzine (e.g., rubamate), cannabinoid CB1 antagonists (e.g., rimonabant), FAAH inhibitors, sodium channel inhibitors, anti-ADHD drugs (e.g., methylphenidate hydrochloride, 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 limb rest Drugs for treating impotence syndromes, substance addiction, 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 to treat diabetic complications, hypertension drugs, hypotension drugs, diuretics, chemotherapy drugs, immunotherapy drugs, antithrombotic drugs, anticancer drugs, etc.

[0286] The above-mentioned concomitant drugs may be used in combination of two or more 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. Gene therapy methods include, for example, using genes related to cytokines, renin-angiotensin system enzymes and their products, G proteins, G protein-coupled receptors and their phosphorylation enzymes. Examples of therapies include: treatments using DNA decoys such as NFκB decoys; treatments using antisense; treatments 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); treatments using genes related to enzymes and proteins involved in angiogenesis therapy for peripheral vascular occlusion (e.g., growth factors such as HGF and VEGF); treatments 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]

[0287] 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.

[0288] 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 following conditions were used: mobile phase: 0.05% aqueous ammonia / MeCN. When C18 is written, it refers to octa Decyl-bonded silica gel was used. Unless otherwise specified, the ratios shown for the elution solvent are volume ratios.

[0289] 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.

[0290] 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 Na2SO4: Anhydrous sodium sulfate NaBH4: Sodium borohydride LiBH4: Lithium borohydride PPh3: Triphenylphosphine DIAD: Diisopropyl azodicarboxylate rt: room temperature alkyl: ethyl acetate Tf2O: Trifluoromethanesulfonic anhydride TBAF: Tetrabutylammonium fluoride SPhos: 2-Dicyclohexylphosphino-2',6'-Dimethoxybiphenyl DBU: 1,8-Diazabicyclo[5.4.0]undeca-7-en (S,S)-pybox(iPr): (S,S)-2,6-bis(4-isopropyl-2-oxazolin-2-yl)pyridine Pd(OH)2: Palladium(II) hydroxide Lindler catalyst: Palladium-calcium carbonate NaHCO3: Sodium bicarbonate Boc2O: Di-tert-butyl dicarbonate Cs2CO3: Cesium Carbonate CuCl: Copper(I) chloride Pd(OAc)2: Palladium(II) acetate MeMgBr: Methylmagnesium bromide MsCl: Methanesulfonyl chloride TsOH: p-toluenesulfonic acid HCl: Hydrogen chloride BuLi: Butyllithium

[0291] Example 23 N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidine-3-yl}methanesulfonamide

[0292] 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 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).

[0293] B) (S)-N-(pyrrolidine-3-yl)methanesulfonamide hydrochloride tert-butyl (S)-3-(methylsulfonamide)pyrrolidine-1-carboxylate (6.39 g) The mixture of the solution 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).

[0294] 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 saline solution, 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). 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).

[0295] D) rac-ethyl (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate A mixture of 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). To the mixture, Xphos Pd G3 (1.57 g) and tripotassium phosphate (11.8 g) were added 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 then removed with saline solution. After washing, 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.

[0296] 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, diluted with water, the pH was adjusted to 4 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 (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)

[0297] 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 A mixture of 2.00 g of bonic acid, 1.46 g of (S)-N-(pyrrolidine-3-yl)methanesulfonamide hydrochloride, 2.91 g of HATU, and 15 mL of DMF was mixed with 3.77 g of DIPEA and stirred at room temperature for 12 hours. 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.

[0298] 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).

[0299] Example 24 N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]piperidine-3-yl}methanesulfonamide

[0300] 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 saline solution, 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).

[0301] B) (S)-N-(piperidine-3-yl)methanesulfonamide hydrochloride tert-butyl (S)-3-(methylsulfonamide)piperidine-1-carboxylate (14.9 g) The mixture of the CPME solution and 4 M hydrogen chloride 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).

[0302] 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 A mixture of 3.00 g of benzoic acid, 2.35 g of (S)-N-(piperidine-3-yl)methanesulfonamide hydrochloride, 4.37 g of HATU, and 30 mL of DMF was mixed with 5.65 g of DIPEA 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 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.

[0303] 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).

[0304] Example 25 N-{(4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azepan-4-yl}methanesulfonamide

[0305] 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 washed with saline solution. After purification, the solution 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).

[0306] B) N-(azepan-4-yl)methanesulfonamide hydrochloride A mixture of tert-butyl 4-(methylsulfonamide)azepane-1-carboxylate (28.5 g) and 4 M hydrogen chloride dioxane solution (100 mL) was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure. 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).

[0307] 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 Add HATU (312 mg) at 0°C to a mixture of bonic acid (150 mg), N-(azepan-4-yl)methanesulfonamide hydrochloride (150 mg), DIPEA (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 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 (105 mg) was obtained. MS: [M+H] + 449.3.

[0308] 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).

[0309] 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

[0310] A) Ethyl (2E)-3-(2-bromo-6-fluorophenyl)propa-2-enoate A mixture of ethyl 2-diethoxyphosphoryl acetate (64.6 g) and THF (450 mL) contains 60% NaH (10.6 g) was added at 0°C. After stirring at room temperature for 15 minutes, 2-bromo-6-fluorobenz Aldehyde (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).

[0311] 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 saline solution, 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).

[0312] 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 Rad (15.0 g), 2,6-difluorophenylboronic acid (33.0 g), and DME (100 mL) To the mixture, an aqueous solution of tripotassium phosphate (33.3 g / 100 mL) and Xphos Pd G3 (4.42 g) were added and the mixture was stirred at 100 °C for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was then fermented. After washing with brine, the sample was dried over sodium sulfate and concentrated under reduced pressure. The residue was separated by preparative HPLC (C18, 0.05%). The compound was purified with aqueous ammonia (MeCN), freeze-dried, and the title compound (2.00 g) was obtained. MS: [M+H] + 321.0.

[0313] 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)cyclopropane-1-carboxylate (1.00 g) was processed in SFC (column: DAIEL CHIRALCEL OD-H, 250 mm x 30) The compounds were separated using a mobile phase of CO2 / 0.1% aqueous ammonia solution (IPA = 90 / 10 v / v) at a density of mm and 5 μm, and the compound with the longer retention time was obtained as the title compound (320 mg). MS: [M+H] + 321.0.

[0314] E) rel-(1R,2R)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylic acid A mixture of rel-ethyl (1R,2R)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate (320 mg) synthesized in step D), aqueous sodium hydroxide solution (400 mg / 1.5 mL), and EtOH (4.5 mL) was stirred at room temperature for 16 hours. The mixture was adjusted to pH 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).

[0315] 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), synthesized in step E) 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 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. . 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).

[0316] 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

[0317] A) Ethyl (2E)-3-(2-bromo-4-fluorophenyl)propa-2-enoate A mixture of ethyl 2-diethoxyphosphoryl acetate (35.9 g) and THF (250 mL) contains 60% NaH (5.91 g) was added at 0°C. After stirring at room temperature for 15 minutes, 2-bromo-4-fluorobenz Aldehyde (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).

[0318] 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).

[0319] 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) [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloro 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 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).

[0320] 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 [Phenyl-2-yl]cyclopropane-1-carboxylate (3.96 g) and 1,3-difluoro-2 - To a mixture of iodobenzene (2.84 g) and DME (35 mL), Xphos Pd G3 (1.00 g) and tripotassium phosphate (7.55 g) were added and stirred at 100 °C under a nitrogen atmosphere 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).

[0321] 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), ethyl ethyl (20 mL), and water (5 mL) is mixed with rac-ethyl (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).

[0322] 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).

[0323] 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 A mixture of hydrochloride (20.6 mg) and DMF (1 mL) is mixed with HATU (39.0 mg) and DIPEA (66.3 mg). The mixture was added at °C and stirred at room temperature for 16 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 separated by preparative HPLC (C18, 0.05% ammonia). The compound was purified with near-water / MeCN and freeze-dried to obtain the title compound (18.0 mg). 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).

[0324] 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

[0325] A) 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 A mixture of {(3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidine-3-yl}carbamates 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 saline solution, 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 got it. MS, found: 437.1.

[0326] 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 a mixture of DCM (5 mL) were 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 saline solution, 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 (38.9 mg) was obtained. MS: [M+H] + 471.2.

[0327] 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).

[0328] 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

[0329] 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 benzoic acid (100 mg), tert-butyl N-(3R,4S)-4-fluoro-3-piperidyl]carbamate (96 mg), and DMF (3 mL) was mixed with HOBt (49 mg), EDCI (105 mg), and TEA (148 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 saline solution, 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 got it. MS, found: 375.1.

[0330] 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}carbamate (215 mg), trifluoroacetic acid (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'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate and [(3R,4S)-3-amino-4-fluoropiperidine-1-yl][(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl] A mixture of phenyl-2-yl cyclopropyl methanone trifluoroacetate (250 mg) I got 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 saline solution, 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 (47.2 mg) was obtained. MS: [M+H] + 453.2.

[0331] 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 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 A mixture of 44 mg of 4-4-fluoropiperidine-3-ylmethanesulfonamide 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).

[0332] 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

[0333] 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 saline solution, then dried with sodium sulfate. The mixture was then 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), 2.90-3.01 (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).

[0334] 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 then removed with saline solution. After washing, 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). 1 H 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).

[0335] 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. The mixture was stirred. The mixture was diluted with water and extracted with DCM. The organic layer was washed with saline solution and then sodium sulfate was used. The mixture was dried with thorium 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).

[0336] 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 EtOH = 85 / 15 v / v), and the fraction with the longest retention time was extracted. The solution 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.

[0337] 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 saline solution, 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).

[0338] 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

[0339] 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 (18.6 g) 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 50 mL of 10% aqueous acetic acid solution. The organic layer was washed with water and 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 mixture (18.6 g). . MS: [M+H] + 268.9.

[0340] 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.

[0341] 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.

[0342] 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 compound was concentrated under reduced pressure to obtain the title compound (5.90 g). MS: [MH] - 272.9.

[0343] 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 To a mixture of acid (40 mg), tert-butyl N-[(3S,5R)-5-fluoro-3-piperidyl]carbamate (35 mg), and DMF (2 mL), add EDCI (42 mg), HOBt (20 mg), and TEA (59 mg). 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 saline solution, 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.

[0344] 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 A mixture of tert-butyl {(3S,5R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-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 saline solution, 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 (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).

[0345] Example 238 N-2-[(2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]octahydrocyclopenta[c]pyrrole-4-yl}methanesulfonamide optical isomer

[0346] A) rac-tert-butyl(3aR,4S,6aS)-4-[(methanesulfonyl)amino]hexahydrocyclopeptide Nta[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 saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) and named. A combined solution (664 mg) was obtained. MS, found: 249.0.

[0347] B) rac-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrole-4-yl]methanesulfonamide trifluoroacetate A mixture of rac-tert-butyl(3aR,4S,6aS)-4-[(methanesulfonyl)amino]hexahydrocyclopenta[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).

[0348] 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 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 was collected. (4.3 mg) was obtained. MS: [M+H] + 461.2.

[0349] 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).

[0350] 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

[0351] 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 saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was analyzed by silica gel column chromatography (ethyl acetate / hexyl acetate). The compound was purified using a sterilizer (San) 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).

[0352] 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 A mixture of ruboxylate (104 mg) and trifluoroacetic acid (0.500 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and azeotropically analyzed with toluene. The resulting residue (67.6 mg) was (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carb Prepare a mixture of nic acid (106 mg), HATU (160 mg), TEA (0.146 mL), and DMF (2 mL) at room temperature. The mixture was stirred overnight. The reaction was stopped by adding water and extracted with ethyl acetate. The organic layer was washed with water and saline solution, 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 (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).

[0353] 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

[0354] 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) is mixed with methanesulfonyl chloride (43 mg) at 0°C. The mixture was added 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 saline solution, dried over sodium sulfate, concentrated under reduced pressure, and tert-butyl(2S,4S)-4-[(methanesulfate). Rufonyl)amino]-2-methylpyrrolidine-1-carboxylate (83 mg) was obtained. 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.

[0355] 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 saline solution, 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. I obtained it. 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).

[0356] 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

[0357] 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 saline solution, dry with sodium sulfate, concentrate under reduced pressure, and tert-butyl(3S,4R)-3-[(Me Tansulfonyl)amino]-4-methylpyrrolidine-1-carboxylate (67 mg) was obtained. 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.

[0358] 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-category 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 saline solution, 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. I obtained it. 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).

[0359] 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

[0360] 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 saline solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The compound was prepared, and the title compound (501 mg) was obtained. 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).

[0361] 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).

[0362] 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 saline solution, 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).

[0363] 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

[0364] 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 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).

[0365] B) rac-ethyl (1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluoromethyl 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).

[0366] 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-fluoromethyl Lopropane-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). The above rel-ethyl(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluor A mixture of rocyclopropane-1-carboxylate (370 mg), MeOH (2 mL), THF (2 mL), and water (2 mL) was mixed with sodium hydroxide (462 mg) and 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).

[0367] 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 saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to preparative HPLC (C18, 0.05%). The compound was purified with aqueous ammonia (MeCN) and freeze-dried to obtain the title compound (36 mg). 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).

[0368] 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 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 subjected to preparative HPLC (C). The compound was purified with 18.05% 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).

[0369] 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

[0370] 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) was mixed with 60% NaH (1.21 g) at 0 °C. After stirring at room temperature for 30 minutes, 2-bromo-4-methylbenzaldehyde (5.00 g) was added at room temperature and stirred at the same temperature for 2 hours. Mix acetate (7.32 g) and THF (50 mL) with 60% NaH (400 mg) and the mixture The reaction mixture was added to the material. After stirring for 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 saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ethanol). The compound was purified using a ionizer 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).

[0371] 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 washed with 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 (2.14 g). Ta. 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).

[0372] 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. Add 1M tripotassium phosphate aqueous solution (5.30 mL) and Xphos Pd G3 (150 mg), and stir under a nitrogen atmosphere at 100 °C for 14 hours. Dilute the mixture with water and extract with ethyl acetate. The organic layer was then prepared. After washing with 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 (461 mg). . MS: [M+H] + 317.0.

[0373] 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).

[0374] 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.

[0375] 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-yl]methanesulfonamide (16 mg) was subjected to SFC (column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / 0.1% ammonia water-containing MeOH = 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).

[0376] 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

[0377] 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 saline solution, 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).

[0378] 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 Add trifluoroacetic acid (2 mL) to a mixture of tert-butyl (3S,5S)-3-hydroxy-5-[(methanesulfonyl)amino]piperidine-1-carboxylate (47 mg) and DCM (6 mL), and then in a chamber The mixture was stirred at warm 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 saline solution, 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).

[0379] Example 353 N-[(1S)-1-{(2S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]azetidine-2-yl}ethyl]methanesulfonamide

[0380] A) tert-butyl (S)-2-acetylazetidine-1-carboxylate To a stirred solution of (2S)-1-tert-butoxycarbonylazetidine-2-carboxylic acid (4.50 g) and N,O-dimethylhydroxylamine (2.29 g, HCl salt) in DMF (40 mL), HATU (8.50 g) and then DIPEA (10.6 g) were added at 0°C. The reaction mixture was stirred at 20°C for 16 hours under an N2 atmosphere. The mixture was mixed. The reaction mixture was diluted with water and extracted with pharmaceutically acceptable ammonium compounds. The combined organic layer was washed with saline solution. The mixture was dried with Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography (siRNA) to obtain tert-butyl (S)-2-(methoxy(methyl)carbamoyl)azetidine-1-carbohydrate. Luboxilate (5.46 g) was obtained. To a stirred solution of tert-butyl (S)-2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate (5.45 g) in THF (70 mL), add MeMgBr (22.3 mL 3 M in THF) at -78°C. The reaction mixture was stirred at 20°C for 3 hours under an N2 atmosphere. The reaction mixture was diluted with water and toluene was added. Extraction was performed using [method]. The combined organic layers were washed with saline solution, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (siRNA / petroleum ether) to obtain the title compound. A substance (4.40 g) was obtained. 1 H NMR (400 MHz, CDCl3) δ 1.45 (9H, s), 2.08-2.18 (1H, m), 2.27 (3H, s), 2.41-2.52 (1H, m), 3.84-4.00 (2H, m), 4.55-4.67 (1H, m).

[0381] B) tert-butyl(S)-2-((R*)-1-((methylsulfonyl)oxy)ethyl)azetidine-1-carboxylate NaBH4 (380 mg) was added at 0°C to a mixture of tert-butyl (S)-2-acetylazetidine-1-carboxylate (1.00 g) and MeOH (10 mL). The mixture was stirred at 0°C for 1 hour. The mixture was diluted with water and extracted with SiO2. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. Crude product was obtained. The crude product was purified by silica gel column chromatography (SiO / petroleum ether) to obtain tert-butyl (S)-2-((R*)-1-hydroxyethyl)azetidine-1-carboxy We obtained RATH (430 mg, higher polarity on the column). A mixture of tert-butyl(S)-2-((R*)-1-hydroxyethyl)azetidine-1-carboxylate (430 mg) and TEA (432 mg) in DCM (5 mL) was dissolved with MsCl (367 mg) at 0°C. The liquid was stirred at 25°C for 2 hours under an N2 atmosphere. Water was added to this mixture and extracted with DCM. The combined organic layers were washed with saline solution, dried over Na2SO4, and concentrated under reduced pressure. Purification by silica gel column chromatography (siRNA / petroleum ether) yielded the title compound (591 mg). 1 H NMR (400 MHz, CDCl3) δ 1.34 (3H, d, J = 6.8 Hz), 1.43 (9H, s), 2.14-2.33 (2H, m), 3.00 (3H, s), 3.71-3.89 (2H, m), 4.16-4.24 (1H, m), 5.00-5.09 (1H, m).

[0382] C) tert-butyl (S)-2-((S)-1-azidoethyl)azetidine-1-carboxylate The tert-butyl (S)-2-((R*)-1-((methylsulfonyl)oxy)ethyl)azetidine-1-carboxylate (5.66 g) synthesized in step B) and tetrabutylammonium azide (19.0 g) were dissolved in MeCN (150 mL) and stirred at 80°C for 6 hours. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (SiO2 / hexane) to obtain the title compound (4.03 g). 1 H NMR (400 MHz, CDCl3) δ 1.34 (3H, d, J = 6.7 Hz), 1.45 (9H, s), 2.00-2.14 (1H, m), 2.19-2.34 (1H, m), 3.61-3.73 (1H, m), 3.74-3.90 (2H, m), 4.22-4.33 (1H, m).

[0383] D) tert-butyl (S)-2-((S)-1-(methylsulfonamide)ethyl)azetidine-1-carboxylate tert-butyl (S)-2-((S)-1-azidoethyl)azetidine-1-carboxylate (4.03 g) A mixture of 20% Pd(OH)2-carbon (2.50 g) and MeOH (100 mL) was stirred at room temperature under an H2 atmosphere (using a balloon) for 18 hours. The mixture was filtered through a Celite pad, and the solvent was removed under vacuum to obtain tert-butyl (S)-2-((S)-1-aminoethyl)azetidine-1-carboxylate (4.03 g). This was used in the next process without further purification. tert-butyl (S)-2-((S)-1-aminoethyl)azetidine-1-carboxylate (3.57 g) To a solution of TEA (9.94 mL), methanesulfonic anhydride (4.66 g) was added at 0°C, and the resulting solution was stirred at room temperature for 1 hour. The solvent was removed under vacuum, and the residue was subjected to silica gel column chromatography. The title compound (4.16 g) was obtained by purification using Graph (HCl / hexane) and silica gel column chromatography (NH, HCl / hexane). 1 H NMR (400 MHz, CDCl3) δ 1.20 (3H, d, J = 6.2 Hz), 1.46 (9H, s), 1.93-2.02 (1H, m), 2.30-2.41 (1H, m), 2.94 (3H, s), 3.48-3.58 (1H, m), 3.76-3.90 (2H, m), 4.05-4.15 (1H, m), 6.18-6.75 (1H, m).

[0384] E) N-[(1S)-1-{(2S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-f Luorocyclopropane-1-carbonyl]azetidine-2-yl]ethyl]methanesulfonamide tert-butyl (S)-2-((S)-1-(methylsulfonamide)ethyl)azetidine-1-carboxy To 120 mL of SiO2 containing 3.27 g of rad, 2.68 g of TsOH·H2O was added at room temperature, the mixture was stirred at 65°C for 16 hours, and then the solvent was removed under vacuum to obtain crude N-((S)-1-((S)-azetidine-2-yl)ethyl)methanesulfonamide 4-methylbenzenesulfonate. Crude N-((S)-1-((S)-azetidine-2-yl)ethyl)methanesulfonamide 4-methylbenz Add 120 mL of DMF to the sulfonate at 0°C, and rel-(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbone synthesized in step C) of Example 304. Acid (3.78 g), TEA (6.55 mL), and HATU (6.70 g) were added, and the resulting solution was stirred at that temperature for 1 hour. The mixture was quenched with sat. NH4Cl aq. at 0°C and extracted with SiO2. Organic The layers were separated, washed with saline solution, dried with MgSO4, and concentrated under vacuum. The residue was then collected in silica gel. The title compound (2.31 g) was purified by lamb chromatography (HCl / hexane) and silica gel column chromatography (NH, HCl / hexane) as a white amorphous solid. I got it. Amorphous solid N-[(1S)-1-{(2S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]azetidine-2-yl}ethyl]meth Dissolve 2.30 g of sulfonamide in 6.00 mL of butyl, and stir the solution at room temperature. After 5 minutes... A white precipitate formed. Small amounts of seed crystal and heptane (1.00 mL) were added sequentially. The mixture was stirred overnight at room temperature. The resulting precipitate was collected and dried under vacuum at 50°C to obtain the title compound (1.85 g) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 1.18-1.32 (4H, m), 1.87-1.99 (1H, m), 2.01-2.18 (2H, m), 2.39-2.52 (1H, m), 2.90 (3H, s), 3.58-3.69 (1H, m), 4.18-4.36 (3H, m), 6.82 (1H, br s), 6.94-7.02 (2H, m), 7.31-7.55 (5H, m).

[0385] Example 358 N-({(2S,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-methylazetidine-2-yl}methyl)methanesulfonamide

[0386] A) A mixture of [(2R,3R)-1-benzyl-3-methylazetidine-2-yl]methanol and [(2S,3R)-1-benzyl-3-methylazetidine-2-yl]methanol A mixture of tert-butyl (2R,3R)-1-benzyl-3-methylazetidine-2-carboxylate and tert-butyl (2S,3R)-1-benzyl-3-methylazetidine-2-carboxylate (10.0 g) and THF (300 mL) was mixed with LiBH4 (3.33 g) and EtOH (8.81 g) at 20°C, and the reaction mixture was stirred at 60°C for 60 hours. The reaction mixture was diluted with sat. NH4Cl aq. (100 mL) and extracted with ELISA (50 mL x 2). The aqueous phase was concentrated under vacuum, and then DCM (50 mL x 10) was added. The mixture was then filtered, and the combined organic solution was concentrated under reduced pressure to obtain the title compound (4.80 g). 1 H NMR (400 MHz, CD3OD) δ 1.22-1.29 (3H, m), 2.81-3.14 (1H, m), 3.54-3.89 (3H, m), 4.13-4.57 (4H, m), 7.39-7.58 (5H, m).

[0387] B) tert-butyl(2S,3R)-2-{[(tert-butoxycarbonyl)(methanesulfonyl)amino]methyl}-3-methylazetidine-1-carboxylate [(2R,3R)-1-benzyl-3-methylazetidine-2-yl]methanol and [(2S. A mixture of zyl-3-methylazetidine-2-yl]methanol (12.0 g) and MeOH (100 mL) was mixed with 20% Pd(OH)2-carbon (7.00 g) under an N2 atmosphere. The suspension was degassed under vacuum and purged three times with H2. The mixture was stirred at 15°C for 16 hours under an H2 (15 psi) atmosphere. The mixture was filtered to obtain a filtrate, which was concentrated under reduced pressure to obtain a mixture of [(2R,3R)-3-methylazetidine-2-yl]methanol and [(2S,3R)-3-methylazetidine-2-yl]methanol (6.30 g). A mixture of [(2R,3R)-3-methylazetidine-2-yl]methanol and [(2S,3R)-3-methylazetidine-2-yl]methanol (6.30 g), dioxane (30 mL), and water (40 mL). NaOH (6.23 g) and Boc2O (20.4 g) were added to the mixture. The mixture was stirred at 15°C for 16 hours. The mixture was quenched with water (100 mL) and extracted with SiO2 (100 mL x 3). The combined organic layers were then extracted. The solution is concentrated under reduced pressure to obtain tert-butyl (2R,3R)-2-(hydroxymethyl)-3-methylazetidine-1-carboxylate and tert-butyl (2S,3R)-2-(hydroxymethyl)-3-methylazetidine A mixture of din-1-carboxylate (17.5 g) was obtained. A mixture of tert-butyl (2R,3R)-2-(hydroxymethyl)-3-methylazetidine-1-carboxylate and tert-butyl (2S,3R)-2-(hydroxymethyl)-3-methylazetidine-1-carboxylate (17.5 g), tert-butyl N-methylsulfonylcarbamate (20.4 g), PPh3 (34.2 g), and THF (150 mL) was mixed with DIAD (26.4 g, 95% purity) at 0°C under an N2 atmosphere. The mixture was stirred at 15°C for 16 hours. The mixture was quenched with water and extracted with phenylethylamine. The combined organic layer was concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (phenylethylamine / petroleum ether) to obtain the title compound (5.10 g). 1 H NMR (400 MHz, CDCl3) δ 1.15 (3H, d, J = 7.2 Hz), 1.40 (9H, s), 1.53 (9H, s), 2.74-2.84 (1H, m), 3.30-3.57 (4H, m), 3.69-3.79 (1H, m), 3.98 (1H, t, J = 8.8 Hz), 4.23-4.35 (1H, m), 4.40-4.50 (1H, m).

[0388] C) N-({(2S,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluor Rocyclopropane-1-carbonyl]-3-methylazetidine-2-yl}methyl)methanesulfonamide A mixture of tert-butyl (2S,3R)-2-{[(tert-butoxycarbonyl)(methanesulfonyl)amino]methyl}-3-methylazetidine-1-carboxylate (5.00 g) and phenylalanine (100 mL). TsOH·H2O (3.30 g) was added at room temperature. The mixture was stirred at 70°C for 5 hours under an N2 atmosphere. The mixture was concentrated under vacuum to obtain crude N-(((2S,3R)-3-methylazetidine-2-yl)methyl)methanesulfonamide 4-methylbenzenesulfonate. rel-(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylic acid (3.87 g), EDCI (2.57 g), HOBt (1.84 g) synthesized in step C) of Example 304. g) and DMF (80 mL) were mixed, to which TEA (5.6 mL) was added at 0°C. Stirred at 0°C for 5 minutes. Afterward, crude N-(((2S,3R)-3-methylazetidine-2-yl)methyl)methanes are added to the mixture at 0°C. A mixture of sulfonamide 4-methylbenzenesulfonate and DMF (20 mL) was added. The mixture was stirred overnight at 0°C to room temperature under an N2 atmosphere. 100 mL of toluene and 200 mL of water were sequentially added to the mixture at 0°C, and the mixture was extracted with toluene. The organic layer was separated and sat. NaHCO3 aq. The mixture was washed with water and saline solution, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (siRNA / hexane) to obtain the title compound (3.84 g) as a white amorphous solid. Amorphous solid N-({(2S,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-methylazetidine-2-yl}methyl)methanesulfonamide (4.64 g) was dissolved in 10 mL of butyl. The stirred solution was then heated at room temperature. Xan (3 mL) and a seed crystal of the compound were added. After 30 minutes, hexane (3 mL) was added. 30 minutes Next, hexane (6 mL) was added. After 1 hour, the resulting solid was collected and hydrated in hexane with 30% AcOEt. The compound was washed to obtain the title compound (4.09 g) as a colorless crystal. 1 H NMR (400 MHz, CDCl3) δ 1.18-1.36 (4H, m), 1.85-1.98 (1H, m), 1.98-2.06 (1H, m), 2.84-2.97 (4H, m), 3.31-3.49 (2H, m), 3.74-3.87 (1H, m), 4.42-4.59 (2H, m), 6.75-6.85 (1H, m), 6.94-7.03 (2H, m), 7.32-7.40 (2H, m), 7.45-7.58 (3H, m).

[0389] Example 393 N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide

[0390] A) ((2R,3S)-1-benzyl-3-(benzyloxy)azetidine-2-yl)methanol (2R,3S)-1-benzyl-3-(benzyloxy)-2-(((tert-butyldiphenylsilyl)oxy)methyl)azetidine (30.9 g) and THF (50 mL) were mixed, and 1 M TBAF in THF (89 mL) was added at 0°C. The mixture was stirred at 60°C for 30 minutes. The reaction mixture was concentrated under vacuum. The residue was sieved. The crude title compound was obtained by purification using ricagel column chromatography (¼ / hexane). This substance is dissolved in ammonium, eluted with ammonium through an NH silica gel pad, filtered, and true The compound was concentrated under open air to obtain the title compound (15.2 g). 1H NMR (400 MHz, CDCl3) δ 2.56 (1H, br s), 2.83-2.90 (1H, m), 3.22-3.38 (3H, m), 3.54-3.60 (1H, m), 3.61-3.74 (2H, m), 4.11-4.21 (1H, m), 4.45 (2H, s), 7.22-7.40 (10H, m).

[0391] B) tert-butyl(2R,3S)-3-hydroxy-2-(hydroxymethyl)azetidine-1-carboxylate A mixture of ((2R,3S)-1-benzyl-3-(benzyloxy)azetidine-2-yl)methanol (15.2 g), 20% Pd(OH)2-carbon (3.05 g), Boc2O (13.7 mL), and MeOH (130 mL) was hydrogenated at room temperature under balloon pressure for 4.5 hours. The balloon was then replaced with a new one, and the mixture was hydrogenated under balloon pressure. Below, it was hydrogenated overnight at room temperature. Then, 20% Pd(OH)2-carbon (3.05 g) and MeOH (70 mL) were added. In addition, the balloon was replaced with a new one, and the mixture was hydrogenated for a further 24 hours at room temperature under balloon pressure. The catalyst was eluted and filtered off with siRNA through a silica gel / NH₃ silica gel / Celite pad, and the filtrate was concentrated under vacuum. The residue was purified by silica gel column chromatography (siRNA / hexane; MeOH / siRNA) to obtain the title compound (9.53 g). 1 H NMR (400 MHz, CDCl3) δ 1.45 (9H, s), 2.87 (1H, br d, J = 5.7 Hz), 3.69-3.90 (3H, m), 3.99-4.06 (1H, m), 4.16-4.36 (2H, m).

[0392] C) tert-butyl(2R,3S)-2-(azidomethyl)-3-(((trifluoromethyl)sulfonyl)oxy)azetidine-1-carboxylate To a chilled (0°C) mixture of tert-butyl (2R,3S)-3-hydroxy-2-(hydroxymethyl)azetidine-1-carboxylate (3.83 g), 2,6-lutidine (26.3 mL), and MeCN (64 mL), Tf2O (9.27 mL) was added dropwise by syringe, and the mixture was stirred at the same temperature for 1 hour. Then, tetra-n-butylammonium azide (5.90 g) was added all at once, and the mixture was gradually heated to room temperature overnight. The mixture was diluted at 0°C with SiO2 (100 mL) and water (100 mL). The mixture was uncooked, stirred at the same temperature for 5 minutes, and then extracted with ethyl acetate. The organic layer was washed with water and saline solution, dried over Na2SO4, eluted with ethyl acetate through a silica gel / NH3 silica gel pad, and filtered. The mixture was concentrated under vacuum. This crude substance was purified by silica gel column chromatography (¼ / hexane) to obtain the title compound (5.19 g). 1 H NMR (400 MHz, CDCl3) δ 1.47 (9H, s), 3.45-3.51 (1H, m), 3.86-3.97 (1H, m), 4.03-4.09 (1H, m), 4.20-4.27 (1H, m), 4.48-4.54 (1H, m), 5.23-5.31 (1H, m).

[0393] D) tert-butyl (2R,3R)-2-(azidomethyl)-3-fluoroazetidine-1-carboxylate To a chilled (0°C) mixture of tert-butyl (2R,3S)-2-(azidomethyl)-3-(((trifluoromethyl)sulfonyl)oxy)azetidine-1-carboxylate (10.6 g) and THF (58.6 mL), 1 M TBAF in THF (58.6 mL) was added dropwise using a syringe, and the mixture was stirred at the same temperature for 0.5 hours. The mixture was then stirred at room temperature for 2 hours. The mixture was diluted with ELISA (200 mL) and incubated at 0°C until aq. NH4Cl (100 mL) was added dropwise, and the mixture was stirred at the same temperature for 5 minutes. The organic layer was separated and the brine was removed. Washed with [method]. The combined aqueous layer was extracted with pharmaceutically acceptable [method]. The combined organic layer was concentrated under vacuum, and the residue was [details omitted]. The result was purified by silica gel column chromatography (siRNA / hexane) to obtain the title compound (6.16 g) was obtained. 1 H NMR (300 MHz, CDCl3) δ 1.45 (9H, s), 3.54-3.65 (1H, m), 3.71-3.81 (1H, m), 3.92-4.07 (1H, m), 4.18 (1H, ddd, J = 19.7, 10.7, 6.3 Hz), 4.36-4.49 (1H, m), 5.18-5.45 (1H, m).

[0394] E) tert-butyl(2R,3R)-2-(ethylsulfonamidemethyl)-3-fluoroazetidine-1-carboxylate A mixture of tert-butyl (2R,3R)-2-(azidomethyl)-3-fluoroazetidine-1-carboxylate (5.27 g) and Lindler catalyst (2.64 g) in SiO (80 mL) was subjected to balloon pressure in a chamber. Hydrogenation was carried out overnight at a warm temperature. The catalyst was eluted with siRNA through a Celite pad and filtered off, and the filtrate was... The solution was concentrated under vacuum. The residue was dissolved in THF (80 mL), TEA (4.79 mL) was added, and ethanesulfonyl chloride (2.39 mL) was added dropwise to it over 2 minutes at 0°C using a syringe. The mixture was then cooled to the same temperature. The mixture was stirred at 0°C for 3.5 hours. The mixture was diluted with toluene and water at 0°C, and the mixture was stirred at the same temperature for 5 minutes. The organic layer was separated, washed with brine, dried over Na2SO4, filtered through a silica gel / NH3 silica gel pad, and concentrated under vacuum. The residue was purified by silica gel column chromatography (toluene / hexane) to obtain the title compound (6.17 g). 1H NMR (400 MHz, CDCl3) δ 1.37 (3H, t, J = 7.4 Hz), 1.46 (9H, s), 3.06 (2H, q, J = 7.3 Hz), 3.44-3.58 (2H, m), 3.91-4.05 (1H, m), 4.13-4.28 (1H, m), 4.45-4.57 (1H, m), 5.17-5.42 (1H, m), 5.85 (1H, br s).

[0395] F) N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluor Rocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide A mixture of tert-butyl (2R,3R)-2-(ethylsulfonamidemethyl)-3-fluoroazetidine-1-carboxylate (1.39 g), p-toluenesulfonic acid monohydrate (1.78 g), and phenylethylamine (20 mL) was heated at 80°C for 16 hours. The mixture was concentrated under vacuum to obtain N-(((2R,3R)-3-fluoroazetidine-1-carboxylate. Luoroazetidine-2-yl)methyl)ethanesulfonamide 4-methylbenzenesulfonate (1.73 g) was obtained as the crude material. This was used in the next step. In the cooled (0°C) mixture of N-(((2R,3R)-3-fluoroazetidine-2-yl)methyl)ethanesulfonamide 4-methylbenzenesulfonate (1.73 g) and DMF (30 mL), Example 304 In step C), rel-(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylic acid (1.37 g), EDCI (1.08 g), HOBt (0.760 g), and DIPEA (3.28 mL) was added sequentially, and the mixture was gradually heated to room temperature overnight. The mixture was diluted with Depositphotos and aq. NaHCO30°C, and the mixture was stirred at the same temperature for 5 minutes. The organic layer was separated. The residue was washed with saline solution, dried with Na2SO4, filtered through silica gel / NH3 silica gel pads, and concentrated under vacuum. The residue was then analyzed by silica gel column chromatography (Â1 / hexane). The compound was purified to obtain the title compound (1.57 g). 1 H NMR (400 MHz, CDCl3) δ 1.29-1.40 (4H, m), 1.89-2.04 (2H, m), 2.97-3.07 (2H, m), 3.44-3.53 (1H, m), 3.55-3.64 (1H, m), 4.29-4.42 (1H, m), 4.52-4.73 (2H, m), 5.26-5.48 (1H, m), 6.09 (1H, br d, J = 8.1 Hz), 6.92-7.03 (2H, m), 7.31-7.55 (5H, m).

[0396] Example 411 N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2- Fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)methanesulfonamide

[0397] A) 2-Bromo-1-ethenyl-4-methylbenzene A solution of methyltriphenylphosphonium iodide (36.5 g) in THF (360 mL) is prepared by adding N2 Under controlled conditions, n-butyllithium (33.2 mL, 2.5 M in hexane) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour, and then a solution of 2-bromo-4-methylbenzaldehyde (15.0 g) in THF (100 mL) was slowly added at -78°C. The mixture was then allowed to stand and raised to 25°C. The mixture was stirred for 16 hours. The mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was then fermented in saline solution. The mixture was washed, dried over Na2SO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to obtain the title compound (12.0 g). 1 H NMR (400 MHz, CDCl3) δ 2.32 (3H, s), 5.30 (1H, d, J = 12.0 Hz), 5.62 (1H, d, J = 18.4 Hz), 6.98-7.11 (2H, m), 7.36-7.46 (2H, m).

[0398] B) 2-Bromo-1-(2-Bromo-1-fluoroethyl)-4-methylbenzene To a mixture of 2-bromo-1-ethenyl-4-methylbenzene (12.0 g) in DCM (150 mL), triethylamine hydrofluoric acid (19.6 g) and N-bromosuccinimide (13.0 g) were added at 0°C, and the mixture was then stirred at 25°C for 16 hours. The mixture was concentrated under reduced pressure. The residue was then collected. The title compound (14.5 g) was purified by silica gel column chromatography (petroleum ether). I obtained it. 1 H NMR (400 MHz, CDCl3) δ 2.34 (3H, s), 3.51-3.83 (2H, m), 5.80-6.02 (1H, m), 7.17-7.22 (1H, m), 7.37-7.43 (2H, m).

[0399] C) 2-Bromo-1-(1-fluoroethenyl)-4-methylbenzene A mixture of 2-bromo-1-(2-bromo-1-fluoroethyl)-4-methylbenzene (34.0 g) and DCM (150 mL) was mixed with DBU (21.0 g), and the mixture was then stirred at 50°C for 16 hours. The solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether). Thus, the title compound (22.0 g) was obtained. 1 H NMR (400 MHz, CDCl3) δ 2.35 (3H, s), 4.87-5.09 (2H, m), 7.10-7.15 (1H, m), 7.34-7.38 (1H, m), 7.46 (1H, s).

[0400] D) 2',6'-difluoro-2-(1-fluoroethenyl)-5-methyl-1,1'-biphenyl 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (24.6 g), 2-bromo-1-(1-fluoroethenyl)-4-methylbenzene (11.0 g), cesium carbonate (66.7 g) A mixture of copper(I) chloride (5.06 g), SPhos (4.20 g), and palladium(II) acetate (459 mg) in DMF (150 mL) was stirred at 100°C for 20 minutes under an N2 atmosphere. The mixture was filtered and phosphate was removed. The layers were washed with water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether) to obtain the title compound (20.0 g). I obtained it. 1 H NMR (400 MHz, CDCl3) δ 2.41 (3H, s), 4.20-4.83 (2H, m), 6.90-7.00 (2H, m), 7.13 (1H, s), 7.26-7.35 (2H, m), 7.49-7.58 (1H, m).

[0401] E) Ethyl(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2-fluor Rocyclopropane-1-carboxylate Dichloro(p-cymene)ruthenium(II) (949 mg) and (S,S)-pybox(iPr) (934 mg) in THF To a 50 mL mixture, a solution of 2',6'-difluoro-2-(1-fluoroethenyl)-5-methyl-1,1'-biphenyl (14.8 g) in THF (150 mL) was added dropwise at 20°C under an N2 atmosphere. After heating the mixture to 55°C, a solution of ethyl 2-diazoacetate (17.0 g) in toluene (150 mL) was added dropwise over 3 hours under an N2 atmosphere. The mixture was then stirred at 55°C for 14 hours under an N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (SiO2 / petroleum ether) and reversed-phase column chromatography (C18, MeOH / water), and the crude solution was extracted. 16.0 g of 2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylate was obtained. Crude ethyl 2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2-fluoromethyl Lopropane-1-carboxylate (9.00 g) was purified by SFC (column: DAICEL chiral PAK IC, 250 mm x 50 mm, 10 μm, mobile phase: CO2 / 0.1% aqueous ammonia EtOH = 80 / 20 v / v). The fraction of the third peak with the longest retention time was concentrated under reduced pressure and freeze-dried to produce the title. A compound (6.00 g) was obtained. 1 H NMR (400 MHz, CDCl3) δ 1.17-1.24 (3H, m), 1.32-1.44 (1H, m), 1.84-1.96 (1H, m), 2.01-2.09 (1H, m), 2.41 (3H, s), 3.93-4.15 (2H, m), 6.90-7.03 (2H, m), 7.13 (1H, s), 7.27-7.37 (2H, m), 7.45-7.52 (1H, m).

[0402] F) (1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2-fluoromethyl Lopropane-1-carboxylic acid Ethyl (1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2-fluor Rocyclopropane-1-carboxylate (6.00 g) in MeOH (20 mL), THF (20 mL), and water. (20 mL) of the mixture was mixed with NaOH (7.18 g) and then stirred at 60°C for 16 hours. The mixture was acidified to pH = 3 with 1 M HCl aq., and then extracted with siRNA. The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to obtain the title compound (5.60 g). I obtained it. 1 H NMR (400 MHz, DMSO-d6) δ 1.41-1.51 (1H, m), 1.55-1.66 (1H, m), 1.96-2.06 (1H, m), 2.37 (3H, s), 7.11-7.20 (3H, m), 7.32-7.38 (1H, m), 7.43-7.54 (2H, m), 12.25 (1H, br s).

[0403] G) tert-butyl(2R,3R)-3-fluoro-2-(methylsulfonamidemethyl)azetidine-1-carboxylate tert-butyl (2R,3R)-2-(azidomethyl)-3-fluoroazetidine-1-carboxylate ( A mixture of 0.701 g of phosphate (10 mL) and Lindler catalyst (0.701 g) was subjected to balloon pressure. Hydrogenation was carried out overnight at room temperature. The catalyst was eluted with siRNA through a Celite pad and filtered out, and the filtrate was obtained. The solution was concentrated under vacuum. The residue was dissolved in THF (10 mL), and then TEA (1.27 mL) and metabolites. Anhydrous sulfonic acid (0.796 g) was added sequentially at 0°C. The mixture was stirred at the same temperature for 5 minutes. The mixture was then stirred at room temperature for 4 hours. The mixture was then heated with ¼ and aq. NaHCO3 at 0°C. The mixture was diluted and stirred at the same temperature for 5 minutes. The organic layer was separated, washed with saline solution, and treated with Na2SO4. The mixture was dried, filtered through a silica gel / NH3 silica gel pad, and concentrated under vacuum. The residue was purified by silica gel column chromatography (siRNA / hexane) to obtain the title compound (0.789 g). I obtained it. 1 H NMR (400 MHz, CDCl3) δ 1.46 (9H, s), 2.97 (3H, s), 3.47-3.61 (2H, m), 3.92-4.05 (1H, m), 4.15-4.27 (1H, m), 4.44-4.58 (1H, m), 5.18-5.42 (1H, m), 5.88 (1H, br s).

[0404] H) N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)methanesulfonamide A mixture of tert-butyl (2R,3R)-3-fluoro-2-(methylsulfonamidemethyl)azetidine-1-carboxylate (0.327 g), p-toluenesulfonic acid monohydrate (0.441 g), and phenylethylamine (5 mL) was refluxed for 3.5 hours. The mixture was concentrated under vacuum to obtain N-(((2R,3R)-3-fluoro Azetidine-2-yl)methyl)methanesulfonamide 4-methylbenzenesulfonate was obtained as the crude substance. This was used in the next step. To a chilled (0°C) mixture of crude N-(((2R,3R)-3-fluoroazetidine-2-yl)methyl)methanesulfonamide 4-methylbenzenesulfonate (0.410 g) and DMF (5 mL), (1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylic acid (0.354 g), EDCI (0.288 g), HOBt (0.203 g), and DIPEA (0.808 mL) were sequentially added, and the mixture was gradually heated to room temperature overnight. The mixture was diluted with SiO and aq. NaHCO3 at 0°C, and the mixture was stirred at the same temperature for 5 minutes. The organic layer was separated and washed with brine. The mixture was dried with Na2SO4, filtered through a silica gel / NH3 silica gel pad, and concentrated under vacuum. The residue was purified by silica gel column chromatography (siRNA / hexane) to obtain the title compound. The substance was obtained as a white solid. This substance (0.333 g) was dissolved in SiO2 (5 mL) with stirring at 80°C, and heptane (4 mL) was added dropwise. The resulting suspension was cooled to room temperature and stirred overnight. The title compound (0.305 g) was then obtained as a white solid. 1 H NMR (400 MHz, CDCl3) δ 1.26-1.37 (1H, m), 1.84-2.03 (2H, m), 2.41 (3H, s), 2.93 (3H, s), 3.45-3.56 (1H, m), 3.56-3.67 (1H, m), 4.27-4.42 (1H, m), 4.51-4.73 (2H, m), 5.24-5.49 (1H, m), 6.17 (1H, br d, J = 8.2 Hz), 6.91-7.04 (2H, m), 7.12-7.18 (1H, m), 7.27-7.42 (3H, m).

[0405] Example 412 N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)ethanesulfonamide

[0406] A) 2-Bromo-1-ethenyl-4-fluorobenzene To a solution of methyltriphenylphosphonium iodide (120 g) in THF (800 mL), n-butyllithium (108 mL, 2.5 M in hexane) was added dropwise at 0°C under an N2 atmosphere. The reaction mixture was then prepared. Stir the mixture at 0°C for 1 hour, then add 2-bromo-4-fluorobenzaldehyde (50.0 g) to THF (300 mL). The solution was slowly added at -78°C. Then, it was allowed to stand to 25°C, followed by heating at 25°C for 16 hours. The mixture was diluted with water and extracted with toluene. The organic layer was concentrated under reduced pressure to extract the residue. The residue was purified by silica gel column chromatography (petroleum ether) to obtain the title compound (33.6 g). 1 H NMR (400 MHz, CDCl3) δ 5.34 (1H, d, J = 11.2 Hz), 5.63 (1H, d, J = 17.2 Hz), 6.90-7.05 (2H, m), 7.27-7.32 (1H, m), 7.49-7.56 (1H, m).

[0407] B) 2-Bromo-1-(2-Bromo-1-fluoroethyl)-4-fluorobenzene A mixture of 2-bromo-1-ethenyl-4-fluorobenzene (33.6 g) and DCM (400 mL) is heated at 0°C, and triethylamine hydrofluoric acid (80.8 g) and N-bromosuccinimide (59.5 g) are added. g) was added, and the mixture was stirred at 20°C for 16 hours. The mixture was concentrated under reduced pressure. Residue The compound was purified by silica gel column chromatography (petroleum ether) to obtain the title compound (40.2 g). 1 H NMR (400 MHz, CDCl3) δ 3.56-3.65 (1H, m), 3.71-3.87 (1H, m), 5.83-6.05 (1H, m), 7.11-7.20 (1H, m), 7.31-7.40 (1H, m), 7.50-7.58 (1H, m).

[0408] C) 2-Bromo-4-fluoro-1-(1-fluoroethenyl)benzene To a mixture of 2-bromo-1-(2-bromo-1-fluoroethyl)-4-fluorobenzene (30.3 g) and DCM (300 mL), DBU (23.1 g) was added, and the mixture was then stirred at 50°C for 16 hours. The substance was concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography (petroleum ether) to obtain the title compound (18.5 g). 1 H NMR (400 MHz, CDCl3) δ 4.86-5.01 (1H, m), 5.05-5.13 (1H, m), 7.00-7.10 (1H, m), 7.35-7.41 (1H, m), 7.43-7.52 (1H, m).

[0409] D) 2',5,6'-trifluoro-2-(1-fluoroethenyl)-1,1'-biphenyl This reaction was carried out in three batches. 2-bromo-4-fluoro-1-(1-fluoroethenyl)benzene (13.8 g × 3), 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxabond A mixture of lorane (30.3 g × 3), cesium carbonate (82.1 g × 3), copper(I) chloride (6.24 g × 3), palladium(II) acetate (566 mg × 3), and SPhos (5.17 g × 3) in DMF (200 mL × 3) was stirred at 100°C for 20 minutes under an N2 atmosphere. The three reaction mixtures were combined and filtered. The filtrate was then prepared. The mixture was diluted with water and then extracted with siRNA. The combined organic layers were concentrated under reduced pressure to obtain the crude product. The crude product was obtained. The crude product was purified by silica gel column chromatography (petroleum ether) to obtain the title compound (22.9 g). 1 H NMR (400 MHz, CDCl3) δ 4.24-4.49 (1H, m), 4.71-4.81 (1H, m), 6.94-7.07 (3H, m), 7.11-7.20 (1H, m), 7.29-7.41 (1H, m), 7.58-7.65 (1H, m).

[0410] E) Ethyl (1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate This reaction was carried out in 4 batches. Dichloro(p-cymene)ruthenium(II) (1.10 g x 4) A mixture of (S,S)-pybox(iPr) (1.09 g x 4) and THF (20 mL x 4) was heated under an N2 atmosphere for 20 minutes. At °C, 2',5,6'-trifluoro-2-(1-fluoroethenyl)-1,1'-biphenyl (17.5 g x 4) A solution of THF (120 mL x 4) was added. After heating the mixture to 60°C, a solution of ethyl 2-diazoacetate (19.8 g x 4) in toluene (130 mL x 4) was added to the mixture under an N2 atmosphere for 5 hours. The mixture was added dropwise over time. The mixture was then stirred at 60°C for 12 hours. The four reaction mixtures were combined and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether, then RINKAN / petroleum ether) and reversed-phase column chromatography (C18, MeOH / water) to obtain crude ethyl 2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate (35.3 g). Crude ethyl 2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate (750 mg) was processed using SFC (column: DAICEL chiral PAK IC, 250 mm x 30). Purified using a mobile phase of CO2 / 0.1% aqueous ammonia IPA (75 / 25 v / v) at a density of 10 μm. The fraction of the third peak, which had the longest duration, was concentrated under reduced pressure to obtain the title compound (660 mg). 1 H NMR (400 MHz, CDCl3) δ 1.17-1.23 (3H, m), 1.33-1.43 (1H, m), 1.87-1.98 (1H, 7.56-7.64 (1H, m).

[0411] F) (1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylic acid To a mixture of ethyl (1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate (3.30 g) with THF (15 mL), MeOH (15 mL), and water (15 mL), NaOH (3.90 g) was added, and the mixture was then stirred at 20°C for 16 hours. The mixture was acidified to pH 6-7 with 4M HCl aq. The mixture was extracted with toluene. The organic layer was concentrated under reduced pressure to obtain the title compound (3.30 g). 1 H NMR (400 MHz, DMSO-d6) δ 1.40-1.50 (1H, m), 1.56-1.63 (1H, m), 2.04-2.11 (1H, m), 7.15-7.22 (2H, m), 7.32-7.43 (2H, m), 7.48-7.58 (1H, m), 7.68-7.74 (1H, m).

[0412] G) N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-bi Phenyl-2-yl cyclopropane-1-carbonyl azetidine-2-yl methyl ethanesulfonamide To a chilled (0°C) mixture of tert-butyl (2R,3R)-2-(ethylsulfonamidemethyl)-3-fluoroazetidine-1-carboxylate (5.87 g), toluene (30 mL), and water (1.5 mL), TFA (15 mL) was added, and the mixture was stirred at room temperature for 2.5 hours. The mixture was concentrated under vacuum. Next, azeotrope was performed with toluene (20 mL x 2) to obtain N-(((2R,3R)-3-fluoroazetidine-2-yl)methyl)ethanesulfonamide 2,2,2-trifluoroacetate (6.15 g) as the crude substance. Obtained. This was used in the next step. A cooled (0°C) mixture of (1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylic acid (6.15 g) and DMF (20 mL) is mixed with EDCI (3.99 Add (g), HOBt (2.81 g), and DIPEA (13.9 mL) in sequence, and stir the mixture at room temperature for 1 hour. To the mixture, add 20 mL of DMF containing 6.15 g of N-(((2R,3R)-3-fluoroazetidine-2-yl)methyl)ethanesulfonamide 2,2,2-trifluoroacetate, and then mix the mixture in a chamber. The mixture was stirred overnight at warm temperature. The mixture was diluted with ¼ and aq. NaHCO3 at 0°C, and the mixture was heated at the same temperature for 5 minutes. The mixture was stirred for 1 minute. The organic layer was separated, washed with brine, dried over Na2SO4, filtered through a silica gel / NH3 silica gel pad, and concentrated under vacuum. The residue was purified by silica gel column chromatography (ÃO / hexane) to obtain the title compound (8.81 g) as a white amorphous solid. Amorphous solid N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl} Methyl)ethanesulfonamide (1.25 g) was suspended in sorb / hexane, and a seed crystal was added to the mixture. After crystallization, the mixture was concentrated under vacuum. The remaining solid (1.25 g) was dissolved in sorb, Hexane was added dropwise at 50°C to prepare a saturated solution. Seed crystals were then added, and the mixture was stirred at the same temperature for 30 minutes to form a precipitate. The mixture was then cooled to room temperature and stirred overnight. The resulting precipitate was filtered to obtain the title compound (1.13 g) as a white solid. 1H NMR (400 MHz, CDCl3) δ 1.25-1.38 (4H, m), 1.86-2.01 (2H, m), 3.01 (2H, q, J = 7.4 Hz), 3.42-3.68 (2H, m), 4.27-4.42 (1H, m), 4.47-4.72 (2H, m), 5.25-5.48 (1H, m), 6.06 (1H, br d, J = 8.9 Hz), 6.95-7.03 (2H, m), 7.05-7.09 (1H, m), 7.12-7.21 (1H, m), 7.33-7.46 (2H, m).

[0413] Example 420 N-({(2R,3R)-1-[(1R,2R)-2-(5-chloro-2',6'-difluoro[1,1'-biphenyl]-2-yl)-2- Fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide, or N-({(2R,3R)-1-[(1S,2S)-2-(5-chloro-2',6'-difluoro[1,1'-bi Phenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2- Il(methyl)ethanesulfonamide

[0414] A) 2-Bromo-4-chloro-1-ethenylbenzene A solution of methyltriphenylphosphonium iodide (55.3 g) in THF (300 mL) is prepared by adding N2 Under atmospheric conditions, n-BuLi (50.1 mL, 2.5 M in hexane) was added dropwise at 0°C. The resulting orange reaction mixture was stirred at 0°C for 1 hour, and 2-bromo-4-chlorobenzaldehyde (25.0 g) in THF (150 mL) was slowly added at -78°C. The mixture was then allowed to stand to 25°C and then heated for 16 hours at 25°C. The mixture was stirred. The reaction mixture was diluted with water and extracted with pharmaceutically acceptable phosphate. The combined organic layer was washed with saline solution. The solution was purified, dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether) to obtain the title compound (15.9 g). 1 H NMR (400 MHz, CDCl3) δ 5.38 (1H, d, J = 11.2 Hz), 5.69 (1H, d, J = 17.2 Hz), 6.94-7.04 (1H, m), 7.24-7.29 (1H, m), 7.45-7.50 (1H, d, J = 8.4 Hz), 7.55-7.58 (1H, m)

[0415] B) 2-Bromo-4-chloro-1-(1-fluoroethenyl)benzene To a mixture of 2-bromo-1-ethenyl-4-chlorobenzene (15.9 g) and DCM (150 mL), add triethylamine hydrofluoric acid (23.6 g) and NBS (15.6 g) at 0°C, then mix The mixture was stirred at 20°C for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to obtain crude 2-bromo-1-(2-bromo-1-fluoroethyl)-4-chlorobenzene (14.4 g). Crude 2-bromo-1-(2-bromo-1-fluoroethyl)-4-chlorobenzene (14.4 g) DCM (150 To the mixture (mL), 8.31 g of DBU was added, and the mixture was then stirred at 50°C for 12 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to obtain the title compound (9.60 g). 1 H NMR (400 MHz, CDCl3) δ 4.78-5.32 (2H, m), 7.26-7.36 (1H, m), 7.38-7.47 (1H, m), 7.56-7.67 (1H, m).

[0416] C) 5-Chloro-2',6'-difluoro-2-(1-fluoroethenyl)-1,1'-biphenyl A mixture of 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.4 g), 2-bromo-4-chloro-1-(1-fluoroethenyl)benzene (9.00 g), Cs2CO3 (49.8 g), CuCl (3.78 g), Pd(OAc)2 (343 mg), and SPhos (3.14 g) in DMF (100 mL) is heated in N2 The mixture was stirred at 100°C for 20 minutes under controlled conditions. The mixture was diluted with toluene and then filtered. The solution was washed with water, dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether) to obtain the title compound (4.40 g). 1 H NMR (400 MHz, CDCl3) δ 4.46 (1H, dd, J = 48.8, 3.6 Hz), 4.80 (1H, dd, J = 17.6, 3.6 Hz), 6.94-7.01 (2H, m), 7.32-7.45 (3H, m), 7.53-7.59 (1H, m).

[0417] D) Ethyl(1R*,2R*)-2-(5-chloro-2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-flu Orocyclopropane-1-carboxylate To a mixture of dichloro(p-cymene)ruthenium(II) (261 mg) and (S,S)-pybox (257 mg) in THF (20 mL), a solution of 5-chloro-2',6'-difluoro-2-(1-fluoroethenyl)-1,1'-biphenyl (4.40 g) in THF (50 mL) was added dropwise at 20°C under an N2 atmosphere, and the mixture was then added at 55°C. Heat the mixture and add ethyl 2-diazoacetate (4.67 g) to toluene (50°C) under an N2 atmosphere. The solution (mL) was added dropwise over 3 hours. The mixture was stirred under an N2 atmosphere at 55°C for 14 hours. Concentrated under vacuum. Shrinkage occurred. The residue was analyzed by silica gel column chromatography (.'' / petroleum ether) and reversed phase chromatography. Purified by column chromatography (C18, MeOH / water), crude ethyl 2-(5-chloro-2',6'- Difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylate (2.00 g) was obtained. Crude ethyl 2-(5-chloro-2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocycline Lopropane-1-carboxylate (2.00 g) was processed using SFC (column: DAICEL chiral PAK IC, 250 m). Purified using a 50 mm x 10 μm mobile phase (CO2 / 0.1% aqueous ammonia solution containing EtOH = 85 / 15 v / v). The fraction of the third peak with the longest retention time was concentrated under reduced pressure and freeze-dried. The title compound (1.10 g) was obtained. 1 H NMR (400 MHz, CDCl3) δ 1.20 (3H, t, J = 6.8 Hz), 1.34-1.44 (1H, m), 1.85-2.10 (2H, m), 3.90-4.15 (2H, m), 6.90-7.05 (2H, m), 7.30-7.60 (4H, m).

[0418] E) (1R*,2R*)-2-(5-chloro-2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorosil Clopropane-1-carboxylic acid MeOH (3 mL), THF of ethyl (1R*,2R*)-2-(5-chloro-2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylate (1.10 g) synthesized in step D). To a mixture of (3 mL) and water (3 mL), NaOH (1.24 g) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was acidified to pH = 3 with 1 M HCl aq. The mixture was extracted with SiO2. The combined organic layers were washed with saline solution, dried over Na2SO4, and then concentrated under reduced pressure to obtain the title compound (978 mg). 1 H NMR (400 MHz, CDCl3) δ 1.41-1.52 (1H, m), 1.87-2.11 (2H, m), 6.91-7.03 (2H, m), 7.29-7.40 (2H, m), 7.43-7.57 (2H, m).

[0419] F) N-({(2R,3R)-1-[(1R,2R)-2-(5-chloro-2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl) ethanesulfonamide, or N-({(2R,3R)-1-[(1S,2S)-2-(5-chloro-2',6'-difluoro[1,1'- Biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide To a solution of tert-butyl (2R,3R)-2-(ethylsulfonamidemethyl)-3-fluoroazetidine-1-carboxylate (422 mg) in toluene (12 mL), add TFA (4 mL) at room temperature to obtain... The mixture was stirred for 1 hour. The solvent was removed under vacuum, and the crude N-(((2R,3R)-3-fluoroaze Thidin-2-yl)methyl)ethanesulfonamide 2,2,2-trifluoroacetate (442 mg) was obtained. This was used without further purification. (1R*,2R*)-2-(5-chloro-2',6'-difluoro[1,1'-biphenyl]-2-i) synthesized in step E) (L)-2-fluorocyclopropane-1-carboxylic acid (558 mg), Crude N-(((2R,3R)-3-fluoroazetidine-2-yl)methyl)ethanesulfonamide 2,2,2-trifluoroacetate (442 mg) To a solution of TEA (0.993 mL) in DMF (10 mL), HATU (1.09 g) was added at room temperature, and the resulting solution was stirred for 1 hour. The mixture was quenched with sat. NH4Cl aq. at room temperature and extracted with toluene. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated under vacuum. The residue was silicified. The title compound (656 mg) was obtained by purification using toluene / hexane chromatography. 1 H NMR (400 MHz, CDCl3) δ 1.29-1.40 (4H, m), 1.88-2.02 (2H, m), 2.95-3.08 (2H, m), 3.44-3.64 (2H, m), 4.26-4.41 (1H, m), 4.49-4.73 (2H, m), 5.27-5.47(1H, m), 6. 00-6.09 (1H, m), 6.92-7.05 (2H, m), 7.31-7.48 (4H, m).

[0420] Example 423 N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)-N'-methylsulfate Diamide

[0421] A) tert-butyl(2R,3R)-3-fluoro-2-(((N-methylsulfamoyl)amino)methyl)aze Thidine-1-carboxylate A mixture of tert-butyl (2R,3R)-2-(azidomethyl)-3-fluoroazetidine-1-carboxylate (2.50 g) and 20% Pd(OH)2-carbon (0.723 g) in butyl phosphate (35 mL) was subjected to balloon pressure. Hydrogenation was performed at room temperature for 4.5 hours. The catalyst was eluted and filtered off with siRNA through a Celite pad, and the filtrate was concentrated under vacuum. The residue was dissolved in THF (30 mL), and then TEA (4.54 mL), DMAP (0 Add 0.133 g) and methylsulfamoyl chloride (1.09 mL) to THF (5 mL) at 0°C. Next, it was added. The mixture was stirred overnight at room temperature. The mixture was diluted with toluene and aq. NaHCO3 at 0°C and stirred at the same temperature for 5 minutes. The organic layer was separated, washed with brine, and treated with Na2SO4. The mixture was dried, filtered through a silica gel / NH3 silica gel pad, and concentrated under vacuum. The residue was purified by silica gel column chromatography (siRNA / hexane) to obtain the title compound (2.11 g). 1 H NMR (400 MHz, CDCl3) δ 1.46 (9H, s), 2.68-2.78 (3H, m), 3.35-3.54 (2H, m), 3.90-4.05 (1H, m), 4.10-4.29 (2H, m), 4.48-4.63 (1H, m), 5.15-5.44 (1H, m), 5.81 (1H, br s).

[0422] B) N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-bi Phenyl-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)-N'-methylsulfate diamide tert-butyl (2R,3R)-3-fluoro-2-(((N-methylsulfamoyl)amino)methyl)aze A mixture of thidine-1-carboxylate (2.08 g), p-toluenesulfonic acid monohydrate (2.66 g), and SiO2 (20 mL) was refluxed for 1 hour. The mixture was concentrated under vacuum to obtain N-{[(2R,3R)-3-fluoroazetidine-2-yl]methyl}-N'-methylsulfate diamide 4-methylbenzenesulfate Honart (2.58 g) was obtained as the crude material. This was used in the next step. Crude N-{[(2R,3R)-3-fluoroazetidine-2-yl]methyl}-N'-methylsulfate diamide 4-methyl To a cooled (0°C) mixture of ethylbenzenesulfonate (2.58 g) and DMF (20 mL), (1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylic acid (2.17 g), EDCI (1.61 g), HOBt (1.13 g), and DIPEA (4.88 mL) were sequentially added, and the mixture was stirred overnight at room temperature. The mixture was diluted with SiO2 and aq. NaHCO3 at 0°C, and the mixture was stirred at the same temperature for 5 minutes. The organic layer was separated, washed with brine, dried over Na2SO4, and the sieve was removed. The mixture was filtered through a Ricagel / NH silica gel pad and concentrated under vacuum. A portion of the residue was purified by silica gel column chromatography (siRNA / hexane) to obtain the title compound as white amorph. It was obtained as a solid. This substance was treated with sonication in acetone (10 mL) / heptane (20 mL). The mixture was suspended in (mL), the seed crystal was added, and the suspension was further sonicated for 15 minutes until a solid was formed. The mixture was concentrated under vacuum, and the remaining solid (1.75 g) was dissolved in toluene (16 mL) with stirring at 80°C, and heptane (8 mL) was added dropwise to form a suspension. After adding the seed crystal, the resulting suspension was stirred at 80°C for 5 minutes, cooled to room temperature, and stirred overnight. Thanh (4 mL) was added, and the mixture was stirred at room temperature for a further 30 minutes. The precipitate was collected and dried under vacuum at 60°C to obtain the title compound (1.66 g) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 1.24-1.37 (1H, m), 1.86-2.05 (2H, m), 2.69 (3H, d, J = 5.5 Hz), 3.40-3.56 (2H, m), 4.11-4.21 (1H, m), 4.29-4.43 (1H, m), 4.50-4.63 (1H, m), 4.66-4.78 (1H, m), 5.25-5.48 (1H, m), 5.95-6.04 (1H, m), 6.95-7.03 (2H, m), 7.04-7.10 (1H, m), 7.12-7.20 (1H, m), 7.34-7.54 (2H, m).

[0423] The example compounds are shown in the table below. MS values ​​in the table represent 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, 320-352, 355-357, 359-368, 370-392, 394-410, 413-419, 421, 422 and 424-450 in the table below were prepared according to the methods shown in the above examples or methods similar thereto.

[0424] [Table 1-1]

[0425] [Table 1-2]

[0426] [Table 1-3]

[0427] Table 1-4

[0428] Table 1-5

[0429] Table 1-6

[0430] Table 1-7

[0431] Table 1-8

[0432] Table 1-9

[0433] Table 1-10

[0434] Table 1-11

[0435] Table 1-12

[0436] Table 1-13

[0437] Table 1-14

[0438] Table 1-15

[0439] Table 1-16

[0440] Table 1-17

[0441] Table 1-18

[0442] Table 1-19

[0443] Table 1-20

[0444] Table 1-21

[0445] Table 1-22

[0446] Table 1-23

[0447] Table 1-24

[0448] Table 1-25

[0449] Table 1-26

[0450] Table 1-27

[0451] Table 1-28

[0452] Table 1-29

[0453] Table 1-30

[0454] Table 1-31

[0455] Table 1-32

[0456] Table 1-33

[0457] Table 1-34

[0458] Table 1-35

[0459] Table 1-36

[0460] Table 1-37

[0461] Table 1-38

[0462] Table 1-39

[0463] Table 1-40

[0464] Table 1-41

[0465] Table 1-42

[0466] Table 1-43

[0467] Table 1-44 Table 1-45

[0468] Table 1-46

[0469] Table 1-47

[0470] Table 1-48

[0471] Table 1-49

[0472] Table 1-50

[0473] Table 1-51

[0474] Table 1-52

[0475] Table 1-53

[0476] Table 1-54

[0477] Table 1-55

[0478] Table 1-56

[0479] Table 1-57

[0480] Table 1-58

[0481] Table 1-59

[0482] Table 1-60

[0483] Table 1-61

[0484] Table 1-62

[0485] Table 1-63

[0486] Table 1-64

[0487] Table 1-65

[0488] Table 1-66

[0489]

Table 1-67

[0490] Table 1-68

[0491]

Table 1-69

[0492] Table 1-70

[0493] Table 1-71

[0494] Table 1-72

[0495] Table 1-73

[0496] [Table 1-74]

[0497] [Table 1-75]

[0498] [Table 1-76]

[0499] [Table 1-77]

[0500] [Table 1-78]

[0501] [Table 1-79]

[0502] [Table 1-80]

[0503] 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.

[0504] Test Example 2: Measurement of Orexin 2 Receptor Agonist Activity Human OX2 receptor forced expression in each well of a 384-well black transparent bottom plate (BD Falcon). CHO cells were seeded at a density of 10,000 cells / well and cultured for 1 day in a 37°C, 5% CO2 incubator. After removing the culture medium from the cell plate, assay buffer A containing calcium indicators (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 (ibid.)) was used. 30 μL / well of 1.25 mM probenecid (Dōjin Chemical Co., Ltd.) was added. The plate was left to stand in a 37 °C, 5 % CO2 incubator for 30 minutes, and then left to stand at room temperature for another 30 minutes. The test compound, diluted in buffer B (HBSS, 20 mM HEPES, 0.1% BSA), was added to 10 μL / well, and the fluorescence value was measured using FDSSμCELL (Hamamatsu Photonics) at 1-second intervals for 1 minute, and then at 2-second intervals for 1 minute and 40 seconds. Measurements were taken. The change in fluorescence value when DMSO was added instead of the test compound was set to 0%, and the change in fluorescence value when orexin A (human) (Peptide Institute) at a final concentration of 10 nM was set to 100%. The activity (%) of the test compound was calculated. Table 2 shows the activity of each compound at a 3 μM concentration. As is clear from these results, the compound of the present invention has been shown to have human orexin type 2 receptor agonist activity.

[0505] [Table 2-1]

[0506] Table 2-2

[0507] Table 2-3

[0508] Table 2-4

[0509] Table 2-5

[0510] Table 2-6-1

[0511] Table 2-6-2

[0512] Table 2-6-3

[0513] Table 2-6-4

[0514] Test Example 3: X-ray crystal structure analysis The absolute stereochemistry of the compounds in Examples 358, 411, 412, and 423 was determined by X-ray crystallography. All measurements were performed using a Rigaku XtaLAB P200 diffractometer with multilayer mirror monochromatic Cu-Kα radiation. The structures were determined by a direct method using SHELXT-2018 / 2. The analysis was performed, and refinement was carried out using the F2 complete matrix least squares method with SHELXL-2018 / 3. The non-H atoms were refined using anisotropic displacement parameters.

[0515] Regarding Example 358 The structure was determined to be N-({(2S,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-methylazetidine-2-yl}methyl)methanesulfonamide. (Confidence factors R1 = 0.0267, wR2 = 0.0732, Flack variable χ = 0.005(4))

[0516] Regarding Example 411 The structure is N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2 It was determined to be -yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)methanesulfonamide. (Confidence factors R1 = 0.0702, wR2 = 0.1823, Flack variable χ = 0.056(14))

[0517] Regarding Example 412 The structure was determined to be N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)ethanesulfonamide. (Confidence factors R1 = 0.0210, wR2 = 0.0541, Flack variable χ = 0.000(4))

[0518] Regarding Example 423 The structure was determined to be N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)-N'-methyl sulfate diamide. (Confidence factors R1 = 0.0247, wR2 = 0.0642, Flack variable χ = 0.000(8))

[0519] Test Example 4: Evaluation of the wakefulness-promoting effect in cynomolgus monkeys The awakening-promoting effect was evaluated by measuring electroencephalography (EEG) and electromyography (EMG) in cynomolgus monkeys. Under isoflurane anesthesia (0.5-5%, Pfizer Japan Inc., Tokyo, Japan), male cynomolgus monkeys (2-3 years old, Hamri Corporation, Ibaraki, Japan) were surgically implanted with a wireless telemetry transmitter (L03-F3, Data Science International, MN, USA). The EEG electrode was screwed into the vertex of the skull. The EMG electrode was implanted in the neck muscle. Postoperatively, each monkey was administered penicillin (100,000 units / head, im, Meiji Seika Pharma Co., Ltd., Tokyo, Japan), buprenorphine (0.02 mg / kg, im, Otsuka Pharmaceutical Co., Ltd., Tokyo, Japan), and prednisolone (1 mg / kg, sc, Kyoritsu Pharmaceutical Co., Ltd., Tokyo, Japan) daily for one week. After a recovery period of at least one month in their home cages, the monkeys were acclimatized to a recording chamber in a shielded room. EEG and EMG signals were recorded using a telemetry system (Ponemah software, Data Science International, MN, USA), and the signals were analyzed using SleepSign software (Kissei Comtec Co., Ltd., Nagano, Japan). After confirming prolonged dark-period sleep in the laboratory, the wakefulness-promoting effect of the compounds was investigated using animals. The test compounds (10 mg / kg) suspended in a 0.5% methylcellulose aqueous solution, or a vehicle (i.e., a 0.5% methylcellulose aqueous solution), were orally administered to monkeys at a volume of 5 mL / kg body weight at Zeitgeber time 12 (ZT12) using a pre-post design (n=2). EEG and EMG were recorded for 4 hours after compound administration. The wakefulness time (percentage of vehicle treatment) for 4 hours after administration was calculated using SleepSign. The results are shown in Table 3.

[0520] [Table 3]

[0521] As is clear from Table 3, the compounds of the present invention increased wakefulness time in cynomolgus monkeys compared to the vehicle-treated group. This suggests that these compounds may be potential therapeutic agents for narcolepsy.

[0522] 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.

[0523] 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]

[0524] The compound of the present invention has orexin type 2 receptor agonist activity and is usefu...

Claims

1. Formula (II) 【Chemistry 1】 [In the formula: Ring W is selected from benzene, a 5 or 6-membered heteroaryl, a 4-6 membered cycloalkyl, and a 6-membered heterocyclyl, where each ring is a halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) It may be substituted with one, two, three, or four groups independently selected from the alkoxy; Ring X represents benzene or a 5- or 6-membered heteroaryl, where each ring may be substituted with 1, 2 or 3 groups independently selected from halogen, (C １ -C ６ )alkyl, and (C １ -C ６ )alkoxy, where the (C １ -C ６ )alkyl may be substituted with 1, 2, 3 or 4 halogen atoms; Ring Y is halogen, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkyl-OH, (C １ -C ６ ) Alkyl-O-(C １ -C ６ ) alkyl, (C １ -C ６ ) Represents a cyclopropane ring which may be substituted with alkyl-CN and one, two, or three groups independently selected from -CN; Ring Z represents a 4-7 member nitrogen-containing monocyclic ring or a 6-8 member nitrogen-containing bicyclic ring, where each ring may contain one oxygen atom; where the 4-7 member nitrogen-containing monocyclic ring is a halogen, (C １ -C ６ ) alkyl, halo(C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy, (C １ -C ６ ) alkyl-OH, (C １ -C ６ ) Alkyl-O-(C １ -C ６ ) alkyl, -OH, and -C(O)-(C １ -C ６ ) may be substituted with 1, 2, 3 or 4 groups independently selected from alkyl, and also with 1, 2 or 3 (C １ -C ６ ) may be substituted with a five-membered heteroaryl which may be substituted with an alkyl group; and here, the six- to eight-membered bicyclic ring may be substituted with one, two, three or four halogens; L represents a bond, or -CH ２ - indicates, where the -CH ２ - is (C １ -C ６ (C) may be substituted with one or two groups independently selected from alkyl and 3-6 membered cycloalkyl groups, where (C) １ -C ６ ) Alkyl and 3-6 membered cycloalkyl groups are (C １ -C ６ ) may be substituted with one, two, or three groups independently selected from the alkoxy and -OH groups; and R is (C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-3-7 member cycloalkyl, 3-7 member cycloalkyl, (C １ -C ６ ) Alkyl-O-(C １ -C ６ ) alkyl, -NH((C １ -C ６ )alkyl), -N((C １ -C ６ )alkyl) ２ This represents -NH (3-7 membered cycloalkyl), and 3-7 membered heterocycline, where the (C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-3-7 member cycloalkyl, 3-7 member cycloalkyl, (C １ -C ６ ) Alkyl-O-(C １ -C ６ ) Alkyl, -NH((C １ -C ６ )alkyl), -N((C １ -C ６ )alkyl) ２ ,-NH (3-7 membered cycloalkyl), and 3-7 membered heterocyclyl are halogens and (C １ -C ６ ) It may be substituted with one, two, or three groups independently selected from the alkyl group. Compounds thereof, or pharmaceutically acceptable salts thereof.

2. Formula (II') 【Chemistry 2】 [In the formula: Ring W is selected from benzene, a 5 or 6-membered heteroaryl, a 4-6 membered cycloalkyl, and a 6-membered heterocyclyl, where each ring is a halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) It may be substituted with one, two, three, or four groups independently selected from the alkoxy; Ring X represents benzene or a 5- or 6-membered heteroaryl, where each ring is a halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) may be substituted with one, two, or three groups independently selected from the alkoxy, where (C １ -C ６ The alkyl group may be substituted with one, two, three, or four halogen atoms; Ring Y is a cyclopropane ring optionally substituted with one, two or three groups independently selected from halogen, (C １ -C ６ ), alkyl, (C １ -C ６ ), alkyl-OH, (C １ -C ６ ), alkyl-O-(C １ -C ６ ), alkyl, (C １ -C ６ ), alkyl-CN, and -CN; Ring Z represents a 4- to 7-member nitrogen-containing monocyclic ring or a 6- to 8-member nitrogen-containing bicyclic ring, where each ring may contain one oxygen; where the 4- to 7-member nitrogen-containing monocyclic ring is halogen, (C １ -C ６ )alkyl, halo(C １ -C ６ )alkyl, (C １ -C ６ )alkoxy, (C １ -C ６ )alkyl-OH, (C １ -C ６ )alkyl-O-(C １ -C ６ )alkyl, -OH, and -C(O)-(C １ -C ６ )alkyl may be independently selected from 1, 2, 3 or 4 groups and may also be substituted with 1, 2 or 3 (C １ -C ６ )alkyl groups and may also be substituted with a 5-member heteroaryl group; and where the 6- to 8-member bicyclic ring may be substituted with 1, 2, 3 or 4 halogens; L represents a bond, or -CH ２ - indicates, where the -CH ２ - is (C １ -C ６ (C) may be substituted with one or two groups independently selected from alkyl and 3-6 membered cycloalkyl groups, where (C) １ -C ６ ) Alkyl and 3-6 membered cycloalkyl groups are (C １ -C ６ ) may be substituted with one, two, or three groups independently selected from the alkoxy and -OH groups; and R is (C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-3-7 member cycloalkyl, 3-7 member cycloalkyl, (C １ -C ６ ) Alkyl-O-(C １ -C ６ ) Alkyl, -NH((C １ -C ６ )alkyl), -N((C １ -C ６ )alkyl) ２ This represents -NH (3-7 membered cycloalkyl), and 3-7 membered heterocycline, where the (C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-3-7 member cycloalkyl, 3-7 member cycloalkyl, (C １ -C ６ ) Alkyl-O-(C １ -C ６ ) Alkyl, -NH((C １ -C ６ )alkyl), -N((C １ -C ６ )alkyl) ２ ,-NH (3-7 membered cycloalkyl), and 3-7 membered heterocyclyl are halogens and (C １ -C ６ ) It may be substituted with one, two, or three groups independently selected from the alkyl group. Compounds thereof, or pharmaceutically acceptable salts thereof.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein the ring W is a benzene which may be substituted with one, two, or three halogen atoms.

4. The compound or pharmaceutically acceptable salt according to claim 1 or 2, wherein ring W is a benzene which may be substituted with one, two or three halogen atoms independently selected from chloro and fluoro.

5. Ring X contains halogen atoms and (C １ -C ６ The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, which is a benzene that may be further substituted with one, two or three groups independently selected from the alkyl group.

6. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring Y is a cyclopropane ring which may be substituted with one, two, or three halogen atoms.

7. Ring Z contains halogen atoms and (C １ -C ６ The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the compound is a 4- to 7-membered nitrogen-containing monocyclic ring that may be substituted with one, two, or three groups independently selected from the alkyl group.

8. Ring Z contains halogen atoms and (C １ -C ６ The compound or pharmaceutically acceptable salt according to claim 1 or 2, which is an azetidine that may be substituted with one, two, or three groups independently selected from the alkyl group.

9. The compound or pharmaceutically acceptable salt according to claim 1 or 2, wherein ring Z is an azetidine which may be substituted with one fluoro or methyl group.

10. L is a combination, or C １－６ It may be substituted with an alkyl group -CH ２ - The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

11. R is (C １ -C ６ ) Alkyl, -NH((C １ -C ６ )alkyl), or -N((C １ -C ６ )alkyl) ２ The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof.

12. Ring W is a benzene which may be substituted with one, two, or three halogen atoms; Ring X contains halogen atoms and C １－６ A benzene which may be substituted with one, two, or three groups independently selected from the alkyl group; Ring Y is a cyclopropane ring which may be substituted with one, two, or three halogen atoms; Ring Z contains halogen atoms and (C １ -C ６ ) A 4- to 7-membered nitrogen-containing monocyclic ring which may be substituted with one, two, or three groups independently selected from the alkyl group; L is combined, or (C １ -C ６ ) May be substituted with an alkyl group -CH ２ - is a base; and R is (C １ -C ６ ) alkyl group, -NH((C １ -C ６ )alkyl), or -N((C １ -C ６ )alkyl) ２ That is, The compound or pharmaceutically acceptable salt according to claim 1 or 2.

13. Ring W is a benzene which may be substituted with one, two, or three halogen atoms; Ring X contains halogen atoms and (C １ -C ６ ) A benzene which may be further substituted with one, two, or three groups independently selected from the alkyl group; Ring Y is a cyclopropane ring which may be substituted with one, two, or three halogen atoms; Ring Z contains halogen atoms and (C １ -C ６ ) an azetidine ring which may be substituted with one, two, or three groups independently selected from the alkyl group; L is (C １ -C ６ ) May be substituted with an alkyl group -CH ２ - and; and R is (C １ -C ６ ) alkyl or -NH((C １ -C ６ )alkyl) The compound or pharmaceutically acceptable salt according to claim 1 or 2.

14. Ring W is a benzene which may be substituted with one, two, or three halogen atoms; Ring X is a benzene which may be substituted with one, two, or three halogen atoms; Ring Y is a cyclopropane ring which may be substituted with one, two, or three halogen atoms; Ring Z is an azetidine which may be substituted with one, two, or three halogen atoms; L is -CH ２ - and; and R is C １－６ Alkyl alkyl group, or -NH((C １ -C ６ )alkyl) The compound or pharmaceutically acceptable salt according to claim 1 or 2.

15. N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide, N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)ethanesulfonamide, N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)-N'-methyl sulfate diamide, N-[(1S)-1-{(2S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]azetidine-2-yl}ethyl]methanesulfonamide, N-({(2S,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-methylazetidine-2-yl}methyl)methanesulfonamide, N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)methanesulfonamide, N-({(2R,3R)-1-[(1R,2R)-2-(5-chloro-2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide, and N-({(2R,3R)-1-[(1S,2S)-2-(5-chloro-2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide, A compound selected from, or a pharmaceutically acceptable salt thereof.

16. A compound which is N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

17. A compound that is N-({(2R,3R)-3-fluoro-1-[(1S,2S)-2-fluoro-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azetidine-2-yl}methyl)-N'-methylsulfate diamide, or a pharmaceutically acceptable salt thereof.

18. A compound which is N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2-yl}methyl)ethanesulfonamide, or a pharmaceutically acceptable salt thereof.

19. A pharmaceutical product comprising a compound or pharmaceutically acceptable salt according to any one of claims 1, 2, and 15 to 18.

20. The pharmaceutical product according to claim 19, which is an orexin type 2 receptor agonist.

21. The pharmaceutical agent according to claim 19, which is a preventive or therapeutic agent for narcolepsy.

22. The pharmaceutical agent according to claim 19, which is an agent for the prevention or treatment of orexin-mediated diseases or disorders.

23. A pharmaceutical composition comprising a compound according to any one of claims 1, 2, and 15 to 18 or a pharmaceutically acceptable salt thereof.

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