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 a heterocyclic compound, in particular a heterocyclic compound having orexin type 2 receptor agonist activity.

[0002] BACKGROUND OF THEINVENTION Orexin is a neuropeptide that is specifically produced by certain neurons scattered in the lateral hypothalamus and its surrounding areas, and consists of two subtypes, orexin A and orexin B. Both orexin A and orexin B are endogenous ligands of the orexin receptor, a G protein-coupled receptor that exists mainly in the brain, and two subtypes of the orexin receptor, type 1 and type 2, are known (Non-Patent Document 1).

[0003] Orexin-producing neurons (orexin neurons) are localized near the feeding center, and intracerebroventricular administration of orexin peptides increases food intake. Therefore, when orexin was first discovered, it attracted attention as a neuropeptide that regulates feeding. However, it was later reported that canine narcolepsy is caused by genetic mutations in the orexin type 2 receptor (Non-Patent Document 2), and attention has also been focused on the role of orexin in regulating sleep and wakefulness.

[0004] Studies using transgenic mice with degenerated orexin neurons and double transgenic mice, which are a cross between these mice and transgenic mice that overexpress orexin, have revealed that narcolepsy-like symptoms caused by degeneration of orexin neurons disappear when sustained expression of orexin is used. Similarly, when orexin peptides were administered intracerebroventricularly to transgenic mice with degenerated orexin neurons, improvement of narcolepsy-like symptoms was observed (Non-Patent Document 3). Furthermore, studies on orexin type 2 receptor knockout mice have shown that the orexin type 2 receptor maintains wakefulness. It has been suggested that orexin type 2 receptor agonists are important for the treatment of narcolepsy and other sleep disorders that involve hypersomnia (Non-Patent Document 6).

[0005] In addition, it has been suggested that a peptide agonist that selectively acts on the orexin type 2 receptor improves obesity induced by a high-fat diet in mice (Non-Patent Document 7). It has also been suggested that intracerebroventricular administration of orexin peptides shortens the time of general anesthesia in rats (Non-Patent Document 8). It has also been suggested that patients with sleep apnea syndrome have low plasma orexin A concentration levels (Non-Patent Document 9). It has also been suggested that intracerebroventricular administration of orexin peptides improves memory retention in senescence-accelerated mouse model (SAMP8) with cognitive impairment (Non-Patent Document 10). In addition, it has been suggested that orexin type 2 receptor agonists could be used as therapeutic agents for heart failure (Patent Document 1, Non-Patent Document 11). It has also been suggested that daytime sleepiness in Parkinson's disease patients is caused by loss of orexin neurons (Non-Patent Document 12). In addition, orexin controls bone formation and bone loss, and it has been suggested that orexin type 2 receptor agonists could be used as therapeutic agents for diseases associated with bone loss, such as osteoporosis and rheumatoid arthritis (Patent Document 2). Furthermore, since it was found that the mortality rate was significantly improved by simply continuously administering orexin from the peripheral blood in a septic shock model mouse, it has been suggested that orexin receptor agonists are useful for preventing or treating sepsis, severe sepsis, and septic shock (Patent Document 3).

[0006] Therefore, compounds having orexin type 2 receptor agonist activity are expected to be useful as new therapeutic agents for narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, disorders of consciousness such as coma, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by 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 associated with bone loss, sepsis, and the like, as well as anesthetic antagonists and as preventive or therapeutic agents for side effects and complications caused by anesthesia.

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

[0008] [ka]

[0009] (The symbols in the formula are as described in the literature.) A compound represented by the following formula (Patent Document 4) has been reported.

[0010] In addition, the following compounds have been reported as having orexin type 2 receptor agonist activity. formula

[0011] [ka]

[0012] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 5). formula

[0013] [ka]

[0014] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 6). formula

[0015] [ka]

[0016] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 7).

[0017] formula

[0018] [ka]

[0019] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 8).

[0020] formula

[0021] [ka]

[0022] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 9).

[0023] formula

[0024] [ka]

[0025] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 10).

[0026] formula

[0027] [ka]

[0028] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 11).

[0029] formula

[0030] [ka]

[0031] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 12).

[0032] formula

[0033] [ka]

[0034] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 13).

[0035] formula

[0036] [ka]

[0037] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 14).

[0038] formula

[0039] [ka]

[0040] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 15).

[0041] formula

[0042] [ka]

[0043] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 16).

[0044] formula

[0045] [ka]

[0046] (The symbols in the formula are as described in the literature.) A compound represented by the formula (Patent Document 17).

[0047] However, these compounds are considered to be insufficient in terms of activity, pharmacokinetics, or safety, and there is still a need for the development of compounds having orexin type 2 receptor agonist activity. [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 literature]

[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) [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) Summary of the Invention [Problem to be solved by the invention]

[0050] An object of the present invention is to provide a heterocyclic compound having orexin type 2 receptor agonist activity. [Means for solving the problem]

[0051] The present inventors found that a compound represented by the following formula (I) or a salt thereof (sometimes referred to as compound (I) in this specification) has orexin type 2 receptor agonist activity, and as a result of further research, they have completed the present invention.

[0052] That is, the present invention relates to the following. [1] Formula:

[0053] [ka]

[0054] [In the formula, Ring W is an optionally further substituted ring; Ring X represents an optionally further substituted 5- or 6-membered aromatic ring; Ring Y represents an optionally further substituted cyclopropane ring; Ring Z is an optionally further substituted nitrogen-containing heterocycle; L represents a bond or an optionally substituted methylene; and R is an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-10 Cycloalkyl group, or NR a R b where: R a is optionally substituted C 1-6 Alkyl group or optionally substituted C 3-10 represents a cycloalkyl group; R b is a hydrogen atom, optionally substituted C 1-6 Alkyl group or optionally substituted C 3-10 represents a cycloalkyl group; or R a and R b are taken together with the adjacent nitrogen atom to form an optionally further substituted nitrogen-containing heterocycle. A compound represented by the formula:

[0055] [2] Ring W is an optionally further substituted ring; Ring X is an optionally further substituted 5- or 6-membered aromatic ring; Ring Y is an optionally further substituted cyclopropane ring; Ring Z is an optionally further substituted nitrogen-containing heterocycle; L is a bond or optionally substituted methylene; and R is optionally substituted C 1-6 Alkyl, optionally substituted C 3-10Cycloalkyl or optionally substituted di-C 1-6 is an alkylamine, The compound or salt according to the above [1].

[0056] [3] Ring W is (1) 3- to 8-membered monocyclic non-aromatic heterocycles, (2) a 5- or 6-membered monocyclic aromatic heterocycle optionally further substituted by 1 to 3 halogen atoms; (3)(i) a halogen atom, (ii) 1 to 3 C 1-6 C optionally substituted with an alkoxy group 1-6 Alkyl groups, and (iii) C 1-6 Alkoxy group C which may be further substituted with 1 to 3 substituents selected from 6-14 an aromatic hydrocarbon ring, or (4) C 3-10 is a cycloalkane; Ring X is (1)(i) a halogen atom, (ii) Optionally halogenated C 1-6 Alkyl groups, and (iii) C 1-6 Alkoxy group A benzene ring which may be further substituted by 1 to 3 substituents selected from (2)(i) a halogen atom, and (ii) C 1-6 Alkyl group is a 5- or 6-membered monocyclic aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from Ring Y is (1) a halogen atom, (2) a cyano group, and (3) C 1-6 C may be substituted with 1 to 3 substituents selected from an alkoxy group, a cyano group, and a hydroxy group; 1-6 Alkyl group is a cyclopropane ring optionally further substituted by 1 to 3 substituents selected from Ring Z is (1) a halogen atom, (2) a hydroxy group, (3) C 1-6 1 to 3 selected from an alkoxy group, a halogen atom, and a hydroxyl group; C 1-6 Alkyl groups, (4) C 1-6 Alkoxy groups, (5) -C(O)-C 1-6 Alkyl, and (6) C 1-6 5-membered monocyclic aromatic heterocycle optionally substituted with alkyl is a 3- to 14-membered nitrogen-containing heterocycle optionally further substituted by 1 to 3 substituents selected from L is a bond, or (1) C 1-6 C which may be further substituted with 1 to 3 substituents selected from an alkoxy group and a hydroxy group 1-6 Alkyl groups, and (2) C optionally further substituted with a hydroxy group 3-6 Cycloalkyl group is a methylene group optionally substituted with one substituent selected from R, (1)(i) a halogen atom, (ii) C 1-6 Alkoxy, and (iii) Cyclopropyl group C which is optionally substituted by 1 to 3 substituents selected from 1-6 Alkyl groups, (2) C 1-6 C which may be further substituted with an alkyl group 3-10 a cycloalkyl group, or (3) NR a R b and; Where: R a But, C1-6 Alkyl group, or C 3-10 is a cycloalkyl group; R b is a hydrogen atom or C 1-6 is an alkyl group; or R a and R b together with the adjacent nitrogen atom form a nitrogen-containing heterocycle; The compound or salt according to the above [1].

[0057] [4] Ring W is a C group optionally further substituted with 1 to 3 halogen atoms. 6-14 is an aromatic hydrocarbon ring; Ring X is a halogen atom, and C 1-6 a benzene ring optionally further substituted by 1 to 3 substituents selected from an alkyl group; Ring Y is a cyclopropane ring optionally further substituted with 1 to 3 halogen atoms; Ring Z is a halogen atom, a hydroxyl group and C 1-6 a 3- to 14-membered nitrogen-containing heterocycle optionally further substituted by 1 to 3 substituents selected from an alkyl group; L is a bond or C 1-6 a methylene group optionally substituted with an alkyl group; R, (1) C 1-6 an alkyl group, or (2) NR a R b and; Here, R a But, C 1-6 is an alkyl group; and R b is a hydrogen atom or C 1-6 is an alkyl group, The compound or salt according to the above [1].

[0058] [5] Ring W is a benzene ring optionally substituted with 1 to 3 halogen atoms; ring X is a halogen atom, and 1-6a benzene ring optionally further substituted by 1 to 3 substituents selected from an alkyl group; Ring Y is a cyclopropane ring optionally further substituted with 1 to 3 halogen atoms; Ring Z is a halogen atom and C 1-6 an azetidine ring optionally further substituted by 1 to 3 substituents selected from an alkyl group; L is C 1-6 a methylene group optionally substituted with an alkyl group; and R is C 1-6 Alkyl group or NR a R b and; Here, R a But, C 1-6 is an alkyl group; and R b is a hydrogen atom, The compound or salt according to the above [1].

[0059] [6] Ring W is a benzene ring optionally substituted with 1 to 3 halogen atoms; ring X is a benzene ring optionally further substituted with 1 to 3 halogen atoms; ring Y is a cyclopropane ring optionally further substituted with 1 to 3 halogen atoms; Ring Z is an azetidine ring optionally further substituted with 1 to 3 halogen atoms; L is a methylene group; R is C 1-6 Alkyl group, or NR a R b and; Here, R a But, C 1-6 is an alkyl group; and R b is a hydrogen atom, The compound or salt according to the above [1].

[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]azetidin-2-yl}methyl)ethanesulfonamide, 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]azetidin-2-yl}methyl)-N'-methylsulfuric acid diamide, 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-fluoroazetidin-2-yl}methyl)ethanesulfonamide, or a salt thereof.

[0061]

[10] Formula (II)

[0062] [ka]

[0063] [In formula: Ring W is selected from benzene, 5- or 6-membered heteroaryl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl, where each ring is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, (C1-C6)alkyl, and (C1-C6)alkoxy, where the (C1-C6)alkyl or (C1-C6)alkoxy is optionally substituted with 1, 2, 3, or 4 halogen atoms; Ring X represents benzene or 5- or 6-membered heteroaryl, where each ring is optionally substituted with 1, 2, or 3 groups independently selected from halogen, (C1-C6)alkyl, and (C1-C6)alkoxy, where the (C1-C6)alkyl is optionally substituted with 1, 2, 3, or 4 halogen atoms; Ring Y is substituted with 1, 2, or 3 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. represents an optionally substituted cyclopropane ring; Ring Z represents a 3-9 membered nitrogen-containing monocyclic ring or a 6-8 membered nitrogen-containing bicyclic ring, where each ring may contain one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; and where the 3-9 membered nitrogen-containing monocyclic ring may contain one, two, three, or four groups independently selected from halogen, (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. and a 5- or 6-membered heteroaryl ring optionally substituted with 1, 2, or 3 (C1-C6)alkyl groups; and wherein the 6-8 membered bicyclic ring is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, (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; L represents a bond or -CH2-, where the -CH2- is optionally substituted with one or two groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and 3-6 membered cycloalkyl, where the (C1-C6)alkyl and 3-6 membered cycloalkyl rings are optionally substituted with one, two, or three groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and -OH; or where the -CH2- is optionally substituted with two groups which, together with the carbon atom to which they are attached, 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), -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl), and 3-7 membered heterocyclyl, wherein 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 are optionally substituted with 1, 2, or 3 groups independently selected from halogen and (C1-C6)alkyl; or a pharma- ceutically acceptable salt thereof.

[0064]

[11] Formula (II')

[0065] [ka]

[0066] [In formula: Ring W is selected from benzene, 5- or 6-membered heteroaryl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl, wherein each ring is independently selected from halogen, (C1-C6)alkoxy, 1, 2, 3 or 4 groups independently selected from (C1-C6)alkyl and (C1-C6)alkoxy, wherein said (C1-C6)alkyl or (C1-C6)alkoxy are optionally substituted with 1, 2, 3 or 4 halogen atoms; Ring X represents benzene or 5- or 6-membered heteroaryl, where each ring is optionally substituted with 1, 2, or 3 groups independently selected from halogen, (C1-C6)alkyl, and (C1-C6)alkoxy, where the (C1-C6)alkyl is optionally substituted with 1, 2, 3, or 4 halogen atoms; Ring Y represents a cyclopropane ring optionally substituted with 1, 2, or 3 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 membered nitrogen-containing monocyclic ring or a 6-8 membered nitrogen-containing bicyclic ring, where each ring may contain one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; and where the 3-9 membered nitrogen-containing monocyclic ring may contain one, two, three, or four groups independently selected from halogen, (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. and a 5- or 6-membered heteroaryl ring optionally substituted with 1, 2, or 3 (C1-C6)alkyl groups; and wherein the 6-8 membered bicyclic ring is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, (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; L represents a bond or -CH2-, where the -CH2- is optionally substituted with one or two groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and 3-6 membered cycloalkyl, where the (C1-C6)alkyl and 3-6 membered cycloalkyl rings are optionally substituted with one, two, or three groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and -OH; or where the -CH2- is optionally substituted with two groups which, together with the carbon atom to which they are attached, 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), -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl), and 3-7 membered heterocyclyl, wherein 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), -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl, and 3-7 membered heterocyclyl are optionally substituted with 1, 2, or 3 groups independently selected from halogen and (C1-C6)alkyl. or a pharma- ceutically acceptable salt thereof.

[0067]

[12] Ring W is benzene, 5- or 6-membered heteroaryl, 3- to 8-membered cycloalkyl, and 6-membered heterocyclyl, where each ring is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, (C1-C6)alkyl, and (C1-C6)alkoxy, where the (C1-C6)alkyl or (C1-C6)alkoxy is independently selected from the group consisting of benzene, 5- or 6-membered heteroaryl, 3- to 8-membered cycloalkyl, and 6-membered heterocyclyl. koxy is optionally substituted with 1, 2, 3 or 4 halogen atoms; Ring X is benzene or 5- or 6-membered heteroaryl, where each ring is optionally substituted with 1, 2, or 3 groups independently selected from halogen, (C1-C6)alkyl, and (C1-C6)alkoxy, where the (C1-C6)alkyl is optionally substituted with 1, 2, 3, or 4 halogen atoms; Ring Y is a cyclopropane ring optionally substituted with 1, 2, or 3 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 membered nitrogen-containing monocyclic ring or a 6-8 membered nitrogen-containing bicyclic ring, wherein each ring optionally contains 1 or 2 additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; and wherein the 3-9 membered nitrogen-containing monocyclic ring is optionally heteroconverted to 1, 2, 3, or 4 groups independently selected from halogen, (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. and a 5- or 6-membered heteroaryl ring optionally substituted with 1, 2, or 3 (C1-C6)alkyl groups; and wherein the 6-8 membered bicyclic ring is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, (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; L is a bond or -CH2-, where the -CH2- is optionally substituted with 1 or 2 groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and 3-6 membered cycloalkyl, where the (C1-C6)alkyl and 3-6 membered cycloalkyl rings are optionally substituted with 1, 2, or 3 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), -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl), and 3-7 membered heterocyclyl, wherein the (C1-C6)alkyl, -(C1-C6)alkyl, aryl-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), -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl, and 3-7 membered heterocyclyl are optionally substituted by 1, 2, or 3 groups independently selected from halogen and (C1-C6)alkyl; The compound according to the above

[10] or

[11] , or a pharma- ceutically acceptable salt thereof.

[0068]

[13] Ring W is benzene, 5- or 6-membered heteroaryl, 4- to 6-membered cycloalkyl, and 6-membered heterocyclyl, where each ring is optionally substituted with 1, 2, 3, or 4 groups independently selected from halogen, (C1-C6)alkyl, and (C1-C6)alkoxy, where the (C1-C6)alkyl or (C1-C6)alkoxy is optionally substituted with 1, 2, 3, or 4 halogen atoms; Ring X is benzene or 5- or 6-membered heteroaryl, where each ring is optionally substituted with 1, 2, or 3 groups independently selected from halogen, (C1-C6)alkyl, and (C1-C6)alkoxy, where the (C1-C6)alkyl is optionally substituted with 1, 2, 3, or 4 halogen atoms; Ring Y is a cyclopropane ring optionally substituted with 1, 2, or 3 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 membered nitrogen-containing monocyclic ring or a 6-8 membered nitrogen-containing bicyclic ring, wherein each ring may contain one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; and wherein the 3-9 membered nitrogen-containing monocyclic ring is optionally substituted with one, two, or three groups independently selected from halogen, (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. a 5- or 6-membered heteroaryl ring which may be substituted and may also be substituted with 1, 2 or 3 (C1-C6)alkyl groups; and wherein the 6-8 membered bicyclic ring is optionally substituted with 1, 2, 3 or 4 groups independently selected from halogen, (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; L is a bond or -CH2-, where the -CH2- is optionally substituted with 1 or 2 groups independently selected from (C1-C6)alkyl, (C1-C6)alkoxy, and 3-6 membered cycloalkyl, where the (C1-C6)alkyl and 3-6 membered cycloalkyl rings are optionally substituted with 1, 2, or 3 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), -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl), and 3-7 membered heterocyclyl, wherein the (C1-C6)alkyl, -(C1-C6)alkyl, aryl-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), -NH(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring), -N(3-7 membered cycloalkyl ring)(C1-C6)alkyl, and 3-7 membered heterocyclyl are optionally substituted by 1, 2, or 3 groups independently selected from halogen and (C1-C6)alkyl; The compound according to the above

[10] or

[11] , or a pharma- ceutically acceptable salt thereof.

[0069]

[14] The compound according to any one of the above

[10] to

[13] , wherein ring W is benzene optionally further substituted with 1, 2 or 3 halogen atoms, or a pharma- ceutically acceptable salt thereof.

[15] Any one of the compounds according to the above

[10] to

[14] , wherein ring W is benzene optionally substituted with 1, 2 or 3 halogen atoms independently selected from chloro and fluoro, or a pharma- ceutically acceptable salt thereof.

[0070]

[16] Ring X is a halogen atom or C 1-6 The compound according to any one of the above-mentioned

[10] to

[15] , which is benzene optionally substituted with 1, 2 or 3 groups independently selected from alkyl groups, or a pharma- ceutical acceptable salt thereof.

[17] The compound according to any one of the above-mentioned

[10] to

[16] , wherein ring Y is a cyclopropane ring optionally substituted with 1, 2 or 3 halogen atoms, or a pharma- ceutically acceptable salt thereof.

[0071]

[18] Ring Z is a halogen atom or C 1-6 The compound according to any one of the above-mentioned

[10] to

[17] , which is a 4- to 8-membered nitrogen-containing monocyclic ring optionally substituted by 1, 2 or 3 groups independently selected from alkyl groups, or a pharma- ceutical acceptable salt thereof.

[19] Any one of the compounds according to the above

[10] to

[18] , wherein ring Z is azetidine optionally substituted by 1, 2 or 3 groups independently selected from halogen atoms and (C1-C6) alkyl groups, or a pharma- ceutical acceptable salt thereof.

[20] The compound or a pharma- ceutically acceptable salt thereof according to any one of the above

[10] to

[19] , wherein ring Z is azetidine optionally substituted with one fluoro or methyl group.

[0072]

[21] L is a bond or C 1-6 The compound according to any one of the above

[10] to

[20] , wherein the linker is -CH2- which may be substituted with an alkyl group, or a pharma- ceutically acceptable salt thereof.

[22] The compound according to any one of the above

[10] to

[21] , wherein R is (C1-C6) alkyl, -NH((C1-C6) alkyl), or N((C1-C6) alkyl), or a pharma- ceutically acceptable salt thereof.

[0073]

[23] A compound of Tables 1-1 to 1-80, or a pharma- ceutically acceptable salt thereof.

[0074]

[24] Ring W is benzene optionally substituted with 1, 2 or 3 halogen atoms; Ring X is a halogen atom and C 1-6 benzene optionally substituted with 1, 2 or 3 groups independently selected from alkyl; Ring Y is a cyclopropane ring optionally substituted with 1, 2 or 3 halogen atoms; Ring Z is a 4- to 8-membered nitrogen-containing monocyclic ring optionally substituted with 1, 2 or 3 groups independently selected from halogen atoms and (C1-C6)alkyl groups; L is a bond or a -CH2- group optionally substituted with a (C1-C6)alkyl group; and R is a (C1-C6)alkyl group, -NH((C1-C6)alkyl), or -N((C1-C6)alkyl); The compound or a pharma- ceutical acceptable salt thereof according to the above

[10] or

[11] .

[0075]

[25] Ring W is benzene optionally substituted with 1, 2 or 3 halogen atoms; Ring X is benzene optionally further substituted with 1, 2 or 3 groups independently selected from halogen atoms and (C1-C6)alkyl groups; Ring Y is a cyclopropane ring optionally substituted with 1, 2 or 3 halogen atoms; Ring Z is an azetidine ring optionally further substituted with 1, 2 or 3 groups independently selected from halogen atoms and (C1-C6)alkyl groups; L is -CH2- optionally substituted with a (C1-C6)alkyl group; and R is (C1-C6)alkyl or -NH((C1-C6)alkyl); The compound or a pharma- ceutical acceptable salt thereof according to the above

[10] or

[11] .

[0076]

[26] Ring W is benzene optionally substituted with 1, 2 or 3 halogen atoms; Ring X is benzene optionally substituted with 1, 2 or 3 halogen atoms; Ring Y is a cyclopropane ring optionally substituted with 1, 2 or 3 halogen atoms; Ring Z is azetidine optionally substituted with 1, 2 or 3 halogen atoms; L is -CH2-; and R is C 1-6an alkyl group, or -NH((C1-C6)alkyl); The compound or a pharma- ceutical acceptable salt thereof according to the above

[10] or

[11] .

[0077]

[27] N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidin-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]azetidin-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]azetidin-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]azetidin-2-yl}ethyl]methanesulfonamide, N-({(2S,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-methylazetidin-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-fluoroazetidin-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-fluoroazetidin-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-fluoroazetidin-2-yl}methyl)ethanesulfonamide, or a pharma- ceutically acceptable salt thereof.

[0078]

[28] A medicine comprising the compound or salt according to any one of the above [1] to

[27] .

[29] The pharmaceutical agent described in

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

[30] The pharmaceutical agent according to

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

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

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

[0079]

[32] A method for activating orexin type 2 receptor in a mammal, comprising administering to the mammal an effective amount of the compound or salt according to any one of the above [1] to

[27] .

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

[24] .

[34] A method for treating an orexin-mediated disease or disorder in a mammal in need thereof, which comprises administering to the mammal a therapeutically effective amount of the compound or pharma- ceutical acceptable salt described in any one of the above [1] to

[27] .

[35] The method according to

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

[0080]

[36] Use of the compound or salt according to any one of the above [1] to

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

[37] Use of a compound or salt according to any one of the above [1] to

[24] for the manufacture of a medicament for the treatment of an orexin mediated disease or disorder.

[38] The compound according to any one of the above [1] to

[27] or a pharma- ceutical acceptable salt thereof. A pharmaceutical composition comprising a salt thereof. Effect of the Invention

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

[0082] Detailed Description of the Invention The definition of each substituent used in the present specification is described in detail below. Unless otherwise specified, each substituent has the following definition. In the present specification, examples of the "halogen atom" include fluorine, chlorine, bromine and iodine.

[0083] As used herein, the term "alkyl" refers to a saturated, straight or branched chain hydrocarbon moiety having the specified number of carbon atoms. The term "(C1-C6)alkyl" refers to an alkyl moiety containing from 1 to 6 carbon atoms. 1-6 Examples of the "alkyl group" include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl.

[0084] "Alkoxy" refers to a group containing an alkyl radical as defined above attached through an oxygen linking atom. The term "(C1-C6)alkoxy" refers to a straight or branched chain hydrocarbon radical having at least one and up to four carbon atoms attached through an oxygen linking 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 the present specification, "optionally halogenated C 1-6 The alkyl group may, for example, be a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of the alkyl group 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] As used herein, the term "halo(C1-C6)alkyl," refers to a (C1-C6)alkyl group substituted with 1, 2, 3, 4, 5, 6, or 7 halogen atoms. As used herein, the term "((C1-C6)alkyl)-OH," refers to a (C1-C6)alkyl group substituted with a hydroxy group.

[0087] In this specification, "C 2-6Examples of the "alkenyl group" 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 the "alkynyl group" 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] As used herein, "5- or 6-membered heteroaryl" refers to a group or moiety that contains an aromatic monovalent monocyclic radical containing 5 or 6 ring atoms, including at least one carbon atom and from 1 to 4 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom and may contain 1, 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 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, pyrazinyl, pyrimidinyl, and triazinyl.

[0089] As used herein, the term "cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. 3-10Examples of the "cycloalkyl group" include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, and adamantyl. In the present specification, "optionally halogenated C 3-10 The "cycloalkyl group" is, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 3-10 Specific examples of the cycloalkyl group include cyclopropyl, 2,2-difluorocyclopropyl, 2,3-difluorocyclopropyl, cyclobutyl, difluorocyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 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 The "aryl group" includes, for example, phenyl, 1-naphthyl, 2-naphthyl, 1-anthryl, 2-anthryl, and 9-anthryl. In this specification, "C 7-16 The aralkyl group includes, for example, 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 the present specification, "optionally halogenated C 1-6 The "alkoxy group" is, for example, a C alkyl group optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6Specific examples 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, "C 3-10 Examples of the "cycloalkyloxy group" include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

[0092] In this specification, "C 1-6 Examples of the "alkylthio group" include methylthio, ethylthio, propylthio, isopropylthio, butylthio, sec-butylthio, and tert-butylthio. Examples include ruthio, pentylthio, and hexylthio. In the present specification, "optionally halogenated C 1-6 The "alkylthio group" includes, for example, C alkylthio groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples of the alkylthio group include methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, and hexylthio.

[0093] In this specification, "C 1-6 Examples of the "alkyl-carbonyl group" include acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 3-methylbutanoyl, 2-methylbutanoyl, 2,2-dimethylpropanoyl, hexanoyl, and heptanoyl. In the present specification, "optionally halogenated C 1-6 The "alkyl-carbonyl group" includes, for example, C alkyl groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6Examples of the alkyl-carbonyl group include acetyl, chloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, and hexanoyl. In this specification, "C 1-6 Examples of the "alkoxy-carbonyl group" include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, and hexyloxycarbonyl.

[0094] In this specification, "C 6-14 The "aryl-carbonyl group" includes, for example, benzoyl, 1-naphthoyl, and 2-naphthoyl. In this specification, "C 7-16 The "aralkyl-carbonyl group" includes, for example, phenylacetyl and phenylpropionyl.

[0033] In the present specification, examples of the "5- to 14-membered aromatic heterocyclyl carbonyl group" include nicotinoyl, isonicotinoyl, thenoyl and furoyl.

[0043] In the present specification, examples of the "3- to 14-membered non-aromatic heterocyclylcarbonyl group" include morpholinylcarbonyl, piperidinylcarbonyl, and pyrrolidinylcarbonyl.

[0095] As used herein, "mono- or di-C 1-6 The "alkyl-carbamoyl group" includes, for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl, diethylcarbamoyl, and N-ethyl-N-methylcarbamoyl. As used herein, "mono- or di-C 7-16 The "aralkyl-carbamoyl group" includes, for example, benzylcarbamoyl and phenethylcarbamoyl.

[0096] In this specification, "C 1-6Examples of the "alkylsulfonyl group" include methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, sec-butylsulfonyl, and tert-butylsulfonyl. In the present specification, "optionally halogenated C 1-6 The "alkylsulfonyl group" includes, for example, C alkylsulfonyl groups optionally having 1 to 7, preferably 1 to 5, halogen atoms. 1-6 Specific examples include methylsulfonyl, difluoromethylsulfonyl, trifluoromethylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, 4,4,4-trifluorobutylsulfonyl, pentylsulfonyl, and hexylsulfonyl. In this specification, "C 6-14 The "arylsulfonyl group" includes, for example, phenylsulfonyl, 1-naphthylsulfonyl, and 2-naphthylsulfonyl.

[0097] In the present specification, examples of the "substituent" include a halogen atom, a cyano group, a nitro group, a substituted Examples of the alkyl group include an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group, an acyl group, an optionally substituted amino group, an optionally substituted carbamoyl group, an optionally substituted thiocarbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted hydroxy group, an optionally substituted sulfanyl (SH) group, and an optionally substituted silyl group. In the present specification, examples of the "hydrocarbon group" (including the "hydrocarbon group" in the "optionally substituted hydrocarbon group") include, for example, 1-6 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 Examples of such groups include aralkyl groups.

[0098] In the present specification, examples of the "optionally substituted hydrocarbon group" include a hydrocarbon group which may have a substituent selected from the following Substituent Group A. [Substituent group A] (1) a halogen atom, (2) a nitro group, (3) a cyano group, (4) an oxo group, (5) a hydroxy group, (6) Optionally halogenated C 1-6 Alkoxy groups, (7) C 6-14 Aryloxy groups (e.g., phenoxy, naphthoxy), (8) C 7-16 aralkyloxy groups (e.g., benzyloxy), (9) 5- to 14-membered aromatic heterocyclyloxy group (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) a 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), (17) a 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., morpholinylcarbonyloxy, piperidinylcarbonyloxy), (18) Optionally halogenated C 1-6 Alkylsulfonyloxy groups (e.g., methylsulfonyloxy, trifluoromethylsulfonyloxy), (19)C 1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonyloxy groups (e.g., phenylsulfonyloxy, toluenesulfonyloxy), (20) Optionally halogenated C 1-6 Alkylthio groups, (21) a 5- to 14-membered aromatic heterocyclic group, (22) a 3- to 14-membered non-aromatic heterocyclic group, (23) a formyl group, (24) a carboxy group, (25) Optionally halogenated C 1-6 Alkyl-carbonyl groups, (26)C 6-14 Aryl-carbonyl groups, (27) a 5- to 14-membered aromatic heterocyclic carbonyl group, (28) a 3- to 14-membered non-aromatic heterocyclic carbonyl group, (29)C 1-6 Alkoxy-carbonyl groups, (30)C 6-14 Aryloxy-carbonyl groups (e.g., phenyloxycarbonyl, 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl), (31)C 7-16 aralkyloxy-carbonyl groups (e.g., benzyloxycarbonyl, phenethyloxycarbonyl); (32) a carbamoyl group, (33) a thiocarbamoyl group, (34) Mono- or di-C 1-6 Alkyl-carbamoyl groups, (35)C 6-14Aryl-carbamoyl groups (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., morpholinylcarbamoyl, piperidinylcarbamoyl), (38) Optionally halogenated C 1-6 Alkylsulfonyl groups, (39)C 6-14 Arylsulfonyl groups, (40) 5- to 14-membered aromatic heterocyclylsulfonyl groups (e.g., pyridylsulfonyl, thienylsulfonyl), (41) Optionally halogenated C 1-6 Alkylsulfinyl groups, (42)C 6-14 Arylsulfinyl groups (e.g., phenylsulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl), (43) 5- to 14-membered aromatic heterocyclylsulfinyl groups (e.g., pyridylsulfinyl, thienylsulfinyl), (44) an 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 groups (e.g., phenylamino), (47) 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), (48)C 7-16 aralkylamino groups (e.g., benzylamino), (49) a formylamino group, (50)C 1-6 Alkyl-carbonylamino groups (e.g., acetylamino, propanoylamino, butanoylamino), (51)(C 1-6 Alkyl)(C 1-6alkyl-carbonyl)amino groups (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 groups (e.g., methylsulfonylamino, ethylsulfonylamino), (56)C 1-6 C optionally substituted with an alkyl group 6-14 Arylsulfonylamino groups (e.g., phenylsulfonylamino, toluenesulfonylamino), (57) Optionally halogenated C 1-6 Alkyl groups, (58)C 2-6 Alkenyl groups, (59)C 2-6 Alkynyl groups, (60)C 3-10 Cycloalkyl groups, (61)C 3-10 cycloalkenyl groups, and (62)C 6-14 Aryl groups.

[0099] The number of the above-mentioned substituents in the "optionally substituted hydrocarbon group" is, for example, 1 to 5, preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0100] In this specification, unless otherwise specified, examples of the "heterocyclic group" (including the "heterocyclic group" in the "optionally substituted heterocyclic group") include (i) an aromatic heterocyclic group, (ii) a non-aromatic heterocyclic group, and (iii) a 7- to 10-membered bridged heterocyclic group, each of which contains, in addition to carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom, and an oxygen atom as ring-constituting atoms.

[0101] In the present specification, examples of the "aromatic heterocyclic group" (including "5- to 14-membered aromatic heterocyclic group") include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable 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, pyridazinyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, triazolyl, tetrazolyl, and triazinyl; Benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzotriazolyl, imidazopyridinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl, pyrazolopyridinyl, oxazolopyridinyl, thiazolopyridinyl, imidazopyrazinyl, imidazopyrimidinyl, thienopyrimidinyl, furopyrimidinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, oxazolopyrimidinyl, thia and 8- to 14-membered fused polycyclic (preferably bi- or tricyclic) aromatic heterocyclic groups such as pyrimidinyl, pyrazolotriazinyl, naphtho[2,3-b]thienyl, phenoxathiinyl, indolyl, isoindolyl, 1H-indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl.

[0102] In the present specification, examples of the "non-aromatic heterocyclic group" (including "3- to 14-membered non-aromatic heterocyclic group") include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocyclic groups containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocyclic group" include aziridinyl, oxiranyl, thiiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrothienyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, oxazolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrrolinyl, oxazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl, tetrahydrooxazolyl, tetrahydoroyl, tetrahydrofuranyl, pyrrolinyl, pyrrolidinyl, pyrrolinyl, oxazolidinyl, pyrazolinyl, thiazolinyl, thiazolidinyl, tetrahydroisothiazolyl ... 3- to 8-membered monocyclic non-aromatic heterocyclic groups such as isoxazolyl, piperidinyl, piperazinyl, tetrahydropyridinyl, dihydropyridinyl, dihydrothiopyranyl, tetrahydropyrimidinyl, tetrahydropyridazinyl, dihydropyranyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, thiomorpholinyl, azepanyl, diazepanyl, azepinyl, oxepanyl, azocanyl, and diazocanyl; Dihydrobenzofuranyl, dihydrobenzimidazolyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, dihydrobenzisothiazolyl, dihydronaphtho[2,3-b]thienyl, tetrahydroisoquinolyl, tetrahydroquinolyl, 4H-quinolizinyl, indolinyl, isoindolinyl, tetrahydrothieno[2,3-c]pyridinyl, tetrahydrobenzazepinyl, tetrahydroquinoxalinyl, tetrahydrophenanthridinyl, hexyl Examples of such 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocyclic groups include tetrahydrophenothiazinyl, hexahydrophenoxazinyl, tetrahydrophthalazinyl, tetrahydronaphthyridinyl, tetrahydroquinazolinyl, tetrahydrocinnolinyl, tetrahydrocarbazolyl, tetrahydro-β-carbolinyl, tetrahydroacridinyl, tetrahydrophenazinyl, tetrahydrothioxanthenyl, and octahydroisoquinolyl.

[0103] In the present specification, preferable examples of the "7- to 10-membered heterobridged ring group" include quinuclidinyl and 7-azabicyclo[2.2.1]heptanyl. In the present specification, the term "nitrogen-containing heterocyclic group" includes "heterocyclic groups" which contain at least one nitrogen atom as a ring-constituting atom. As used herein, "3-8 membered heterocyclyl" refers to a group or moiety containing a saturated or partially unsaturated, non-aromatic, monovalent monocyclic radical containing 3, 4, 5, 6, 7, or 8 ring atoms including 1 or 2 heteroatoms independently selected from oxygen, sulfur, and nitrogen.

[0104] In the present specification, examples of the "optionally substituted heterocyclic group" include a heterocyclic group which may have a substituent selected from the above-mentioned Substituent group A. The number of substituents in the "optionally substituted heterocyclic group" is, for example, 1 to 3. When the number of substituents is 2 or more, the respective substituents may be the same or different.

[0105] As used herein, the term "acyl group" refers to, for example, a halogen atom, an optionally halogenated C 1-6 C may have 1 to 3 substituents selected from an alkoxy group, a hydroxy group, a nitro group, a cyano group, an amino group and a carbamoyl group; 1-6 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 of the heterocyclic group include a formyl group, a carboxy group, a carbamoyl group, a thiocarbamoyl group, a sulfino group, a sulfo group, a sulfamoyl group, and a phosphono group, each of which optionally has "1 or 2 substituents selected from an aralkyl group, a 5- to 14-membered aromatic heterocyclic group, and a 3- to 14-membered non-aromatic heterocyclic group." Further, the "acyl group" also includes a hydrocarbon-sulfonyl group, a heterocycle-sulfonyl group, a hydrocarbon-sulfinyl group, and a heterocycle-sulfinyl group. Here, the term "hydrocarbon-sulfonyl group" refers to a sulfonyl group having a hydrocarbon group bonded thereto, the term "heterocycle-sulfonyl group" refers to a sulfonyl group having a heterocyclic group bonded thereto, the term "hydrocarbon-sulfinyl group" refers to a sulfinyl group having a hydrocarbon group bonded thereto, and the term "heterocycle-sulfinyl group" refers to a sulfinyl group having a heterocyclic group bonded thereto. Suitable examples of the "acyl group" include a formyl group, a carboxy group, 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 Aryloxy-carbonyl group (e.g., phenyloxycarbonyl, naphthyloxycarbonyl), C 7-16 Aralkyloxy-carbonyl group (e.g., benzyloxycarbonyl, phenethyloxycarbonyl), carbamoyl group, mono- or di-C 1-6 a alkyl-carbamoyl group, mono- or di-C 2-6 Alkenyl-carbamoyl group (e.g., diallylcarbamoyl), mono- or di-C 3-10 Cycloalkyl-carbamoyl group (e.g., cyclopropylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, 5- to 14-membered aromatic heterocyclic carbamoyl group (e.g., pyridylcarbamoyl), thiocarbamoyl group, mono- or di-C 1-6 Alkyl-thiocarbamoyl group (e.g., methylthiocarbamoyl, N-ethyl-N-methylthiocarbamoyl), mono- or di-C 2-6 Alkenyl-thiocarbamoyl group (e.g., diallylthiocarbamoyl), mono- or di-C 3-10 Cycloalkyl-thiocarbamoyl group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), 5- to 14-membered aromatic heterocyclic thiocarbamoyl group (e.g., pyridylthiocarbamoyl), sulfino group, C 1-6 Alkyl sulfinyl group (e.g., methyl sulfinyl, ethyl sulfinyl), sulfo group, C 1-6 Alkylsulfonyl group, C 6-14 Arylsulfonyl group, phosphono group, mono- or di-C 1-6 Examples of the alkylphosphono group include dimethylphosphono, diethylphosphono, diisopropylphosphono, and dibutylphosphono groups.

[0106] As used herein, the term "optionally substituted amino group" refers to, for example, "amino group optionally having 1 to 3 substituents selected from substituent group A, 1-6 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 group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and an arylsulfonyl group, optionally having 1 or 2 substituents selected from the group consisting of arylsulfonyl groups. Preferable examples of the optionally substituted amino group include an amino group, a mono- or di-(optionally halogenated C 1-6alkyl)amino group (e.g., methylamino, trifluoromethylamino, dimethylamino, ethylamino, diethylamino, propylamino, dibutylamino), mono- or di-C 2-6 Alkenylamino groups (e.g., diallylamino), mono- or di-C 3-10 Cycloalkylamino groups (e.g., cyclopropylamino, cyclohexylamino), mono- or di-C 6-14 Arylamino groups (e.g., phenylamino), mono- or di-C 7-16 Aralkylamino groups (e.g., benzylamino, dibenzylamino), mono- or di-(optionally halogenated C 1-6 Alkyl)-carbonylamino group (e.g., acetylamino, propionylamino), mono- or di-C 6-14 Aryl-carbonylamino group (e.g., benzoylamino), mono- or di-C 7-16 Aralkyl-carbonylamino group (e.g., benzylcarbonylamino), mono- or di-5 to 14-membered aromatic heterocyclylcarbonylamino group (e.g., nicotinoylamino, isonicotinoylamino), mono- or di-3 to 14-membered non-aromatic heterocyclylcarbonylamino group (e.g., piperidinylcarbonylamino), mono- or di-C 1-6 Alkoxy-carbonylamino group (e.g., tert-butoxycarbonylamino), 5- to 14-membered aromatic heterocyclic amino group (e.g., pyridylamino), carbamoylamino group, (mono- or di-C 1-6 Alkyl-carbamoyl)amino group (e.g., methylcarbamoylamino), (mono- or di-C 7-16 aralkyl-carbamoyl)amino group (e.g., benzylcarbamoylamino), C 1-6 Alkyl sulfonylamino group (e.g., methylsulfonylamino, ethylsulfonylamino), C 6-14 Arylsulfonylamino group (e.g., phenylsulfonylamino), (C 1-6 Alkyl)(C 1-6 Alkyl-carbonyl)amino groups (e.g., N- Acetyl-N-methylamino), (C 1-6 Alkyl)(C 6-14aryl-carbonyl)amino groups (e.g., N-benzoyl-N-methylamino).

[0107] As used herein, examples of the "optionally substituted carbamoyl group" include "carbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, 1-6 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 group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and aralkyl-carbamoyl groups, which may have 1 or 2 substituents selected from the group consisting of aryl, arylalkyl, and arylcarbamoyl. Suitable examples of the optionally substituted carbamoyl group 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 group (e.g., cyclopropylcarbamoyl, cyclohexylcarbamoyl), mono- or di-C 6-14 Aryl-carbamoyl group (e.g., phenylcarbamoyl), mono- or di-C 7-16 Aralkyl-carbamoyl group, mono- or di-C 1-6 Alkyl-carbonyl-carbamoyl group (e.g., acetylcarbamoyl, propionylcarbamoyl), mono- or di-C 6-14 Examples thereof include aryl-carbonyl-carbamoyl groups (eg, benzoylcarbamoyl) and 5- to 14-membered aromatic heterocyclic carbamoyl groups (eg, pyridylcarbamoyl).

[0108] As used herein, examples of the "optionally substituted thiocarbamoyl group" include "thiocarbamoyl groups each optionally having 1 to 3 substituents selected from substituent group A, 1-6 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 group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and thiocarbamoyl groups which may have 1 or 2 substituents selected from aralkyl-carbamoyl groups. Suitable examples of the optionally substituted thiocarbamoyl group include a thiocarbamoyl group, a mono- or di-C 1-6 Alkyl-thiocarbamoyl group (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 group (e.g., cyclopropylthiocarbamoyl, cyclohexylthiocarbamoyl), mono- or di-C 6-14 Aryl-thiocarbamoyl group (e.g., phenylthiocarbamoyl), mono- or di-C 7-16 Aralkyl-thiocarbamoyl group (e.g., benzylthiocarbamoyl, phenethylthiocarbamoyl), mono- or di-C 1-6 Alkyl-carbonyl-thiocarbamoyl group (e.g., acetylthiocarbamoyl, propionylthiocarbamoyl), mono- or di-C 6-14Examples of such groups include aryl-carbonyl-thiocarbamoyl groups (eg, benzoylthiocarbamoyl) and 5- to 14-membered aromatic heterocyclic thiocarbamoyl groups (eg, pyridylthiocarbamoyl).

[0109] As used herein, examples of the "optionally substituted sulfamoyl group" include "a sulfamoyl group which may optionally have 1 to 3 substituents selected from substituent group A, 1-6 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-Carbony 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, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group and mono- or di-C 7-16 and an aralkyl-carbamoyl group, which may have 1 or 2 substituents selected from the group consisting of aryl, arylalkyl, and arylcarbamoyl. Suitable examples of the optionally substituted sulfamoyl group include sulfamoyl groups, mono- or di-C 1-6 Alkyl-sulfamoyl group (e.g., methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl, N-ethyl-N-methylsulfamoyl), mono- or di-C 2-6 Alkenyl-sulfamoyl group (e.g., diallylsulfamoyl), mono- or di-C 3-10 Cycloalkyl-sulfamoyl group (e.g., cyclopropylsulfamoyl, cyclohexylsulfamoyl), mono- or di-C 6-14 Aryl-sulfamoyl group (e.g., phenylsulfamoyl), mono- or di-C 7-16 Aralkyl-sulfamoyl group (e.g., benzylsulfamoyl, phenethylsulfamoyl), mono- or di-C1-6 Alkyl-carbonyl-sulfamoyl group (e.g., acetylsulfamoyl, propionylsulfamoyl), mono- or di-C 6-14 Examples thereof include aryl-carbonyl-sulfamoyl groups (eg, benzoylsulfamoyl) and 5- to 14-membered aromatic heterocyclic sulfamoyl groups (eg, pyridylsulfamoyl).

[0110] In the present specification, examples of the "optionally substituted hydroxy group" include "a hydroxy group which may have 1 to 3 substituents selected from the substituent group A, 1-6 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 group, 5- to 14-membered aromatic heterocyclic group, carbamoyl group, mono- or di-C 1-6 Alkyl-carbamoyl group, mono- or di-C 7-16 Aralkyl-carbamoyl group, C 1-6 Alkylsulfonyl group and C 6-14 and arylsulfonyl groups, each of which may have a substituent selected from the group consisting of arylsulfonyl groups and arylsulfonyl groups. Preferable examples of the optionally substituted hydroxy group include a hydroxy group, 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 groups (e.g., phenoxy, naphthyloxy), C 7-16 Aralkyloxy group (e.g., benzyloxy, phenethyloxy), C 1-6Alkyl-carbonyloxy group (e.g., acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy), C 6-14 Aryl-carbonyloxy group (e.g., benzoyloxy), C 7-16 Aralkyl-carbonyloxy group (e.g., benzylcarbonyloxy), 5- to 14-membered aromatic heterocyclylcarbonyloxy group (e.g., nicotinoyloxy), 3- to 14-membered non-aromatic heterocyclylcarbonyloxy group (e.g., piperidinylcarbonyloxy), C 1-6 Alkoxy-carbonyloxy group (e.g., tert-butoxycarbonyloxy), 5- to 14-membered aromatic heterocyclic oxy group (e.g., pyridyloxy), carbamoyloxy group, 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 Arylsulfonyloxy groups (eg, phenylsulfonyloxy) are included.

[0111] As used herein, examples of the "optionally substituted sulfanyl group" include "a sulfanyl group which may have 1 to 3 substituents selected from the substituent group A, 1-6 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 and a halogenated sulfanyl group, which may have a substituent selected from an aryl-carbonyl group and a 5- to 14-membered aromatic heterocyclic group. Preferable examples of the optionally substituted sulfanyl group include a sulfanyl (-SH) group, 1-6 Alkylthio group, C 2-6Alkenylthio groups (e.g., allylthio, 2-butenylthio, 2-pentenylthio, 3-hexenylthio), C 3-10 Cycloalkylthio groups (e.g., cyclohexylthio), C 6-14 Arylthio groups (e.g., phenylthio, naphthylthio), C 7-16 Aralkylthio groups (e.g., benzylthio, phenethylthio), C 1-6 Alkyl-carbonylthio groups (e.g., acetylthio, propionylthio, butyrylthio, isobutyrylthio, pivaloylthio), C 6-14 Examples of such groups include aryl-carbonylthio groups (eg, benzoylthio), 5- to 14-membered aromatic heterocyclic thio groups (eg, pyridylthio), and halogenated thio groups (eg, pentafluorothio).

[0112] In the present specification, examples of the "optionally substituted silyl group" include "a silyl group which optionally has 1 to 3 substituents selected from the substituent group A, 1-6 Alkyl group, C 2-6 Alkenyl group, C 3-10 Cycloalkyl groups, C 6-14 Aryl groups and C 7-16 and aralkyl groups. Suitable examples of the optionally substituted silyl group include tri-C 1-6 Examples of the silyl groups include alkylsilyl groups (eg, trimethylsilyl, tert-butyl(dimethyl)silyl).

[0113] In the present specification, examples of the "hydrocarbon ring" include C 6-14 Aromatic hydrocarbon ring, C 3-10 Cycloalkane, C 3-10 Cycloalkenes are mentioned. In this specification, "C 6-14 The aromatic hydrocarbon ring includes, for example, benzene and naphthalene. In this specification, "C 3-10 Examples of the "cycloalkane" include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane. In this specification, "C 3-10 Examples of the "cycloalkene" include cyclopropene, cyclobutene, cyclopentene, cyclohexene, cycloheptene, and cyclooctene. In the present specification, examples of the "heterocycle" include aromatic heterocycles and non-aromatic heterocycles each containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms and oxygen atoms.

[0114] In the present specification, examples of the "aromatic heterocycle" include 5- to 14-membered (preferably 5- to 10-membered) aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from nitrogen atoms, sulfur atoms, and oxygen atoms. Preferable 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, benzisoxazole, benzothiazole, benzisothiazole, benzotriazole, imidazopyridine, thienopyridine, furopyridine, pyrrolopyridine, pyrazolopyridine, oxazolopyridine, thiazolopyridine, imidazopyrazine, imidazopyrimidine, thienopyrimidine, furopyrimidine, pyrrolopyrimidine, pyrazolopyrimidine, oxazolopyrimidine, thiazolopyrimidine, pyrazolopyrimidine, pyrazolotriazine, naphtho[2,3-b]thiophene, phenoxathiin, indole, isoindole, 1H-indazo Examples of aromatic heterocycles include 8- to 14-membered fused polycyclic (preferably bicyclic or tricyclic) aromatic heterocycles such as benzoquinone, purine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, carbazole, β-carboline, phenanthridine, acridine, phenazine, phenothiazine, and phenoxazine.

[0115] In the present specification, examples of the "non-aromatic heterocycle" include 3- to 14-membered (preferably 4- to 10-membered) non-aromatic heterocycles containing, as ring-constituting atoms other than carbon atoms, 1 to 4 heteroatoms selected from a nitrogen atom, a sulfur atom and an oxygen atom. Preferable examples of the "non-aromatic heterocycle" include 3- to 8-membered monocyclic non-aromatic heterocycles such as aziridine, oxirane, thiirane, azetidine, oxetane, thietane, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, imidazoline, imidazolidine, oxazoline, oxazolidine, pyrazoline, pyrazolidine, thiazoline, thiazolidine, tetrahydroisothiazole, tetrahydrooxazole, tetrahydroisoxazole, piperidine, piperazine, tetrahydropyridine, dihydropyridine, dihydrothiopyran, tetrahydropyrimidine, tetrahydropyridazine, dihydropyran, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine, azepane, diazepane, azepine, azocane, diazocane, and oxepane; Examples of the heterocyclic ring include 9- to 14-membered fused polycyclic (preferably bi- or tricyclic) non-aromatic heterocycles such as dihydrobenzofuran, dihydrobenzimidazole, dihydrobenzoxazole, dihydrobenzothiazole, dihydrobenzisothiazole, dihydronaphtho[2,3-b]thiophene, tetrahydroisoquinoline, tetrahydroquinoline, 4H-quinolizine, indoline, isoindoline, tetrahydrothieno[2,3-c]pyridine, tetrahydrobenzazepine, tetrahydroquinoxaline, tetrahydrophenanthridine, hexahydrophenothiazine, hexahydrophenoxazine, tetrahydrophthalazine, tetrahydronaphthyridine, tetrahydroquinazoline, tetrahydrocinnoline, tetrahydrocarbazole, tetrahydro-β-carboline, tetrahydroacridine, tetrahydrophenazine, tetrahydrothioxanthene, and octahydroisoquinoline. In the present specification, the "nitrogen-containing heterocycle" includes a "heterocycle" containing at least one nitrogen atom as a ring-constituting atom. In the present specification, the "4- to 6-membered heterocyclic group" includes aromatic or non-aromatic 4- to 6-membered heterocyclic groups, and specific examples thereof include oxetanyl, furyl, pyrazolyl, pyridyl and pyrimidinyl. In the present specification, the "ring" includes a "hydrocarbon ring" and a "heterocycle".

[0116] The definition of each symbol in formula (I) is explained in detail below.

[0117] Ring W is an optionally further substituted ring. Examples of the substituent of the "optionally further substituted ring" include the substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0118] Ring W is preferably (1) 3- to 8-membered monocyclic non-aromatic heterocycles (e.g., piperidine), (2) 5- to 6-membered monocyclic aromatic heterocycles (e.g., furan, pyridine) optionally further substituted by 1 to 3 halogen atoms (e.g., fluorine atoms), (3)(i) A halogen atom (e.g., a fluorine atom, a chlorine atom), (ii) 1 to 3 C 1-6 C optionally substituted with an alkoxy group (e.g., methoxy) 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., methoxy) C which may be further substituted with 1 to 3 substituents selected from 6-14 aromatic carbonization A hydrogen ring (e.g., benzene), or (4) C 3-10 Cycloalkanes (e.g., cyclobutane, cyclopentane, cyclohexane).

[0119] Ring W is more preferably a C 1 -C 2 -CH 3 -CH 3 - 6-14 An aromatic hydrocarbon ring (e.g., benzene). Ring W is particularly preferably a C substituted with 1 to 3 halogen atoms (e.g., fluorine atoms). 6-14 An aromatic hydrocarbon ring (e.g., benzene). In one embodiment, ring W is a benzene ring optionally further substituted with two fluorine atoms.

[0120] Ring X is an optionally further substituted 5- or 6-membered aromatic ring. Examples of the substituent of the "further optionally substituted 5- or 6-membered aromatic ring" include the substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0121] Ring X is preferably (1)(i) A halogen atom (e.g., a fluorine atom, a chlorine atom), (ii) Optionally halogenated C1-6 Alkyl groups (e.g., methyl, difluoromethyl), and (iii) C 1-6 Alkoxy groups (e.g., methoxy) A benzene ring which may be further substituted by 1 to 3 substituents selected from (2)(i) A halogen atom (e.g., a fluorine atom), and (ii) C 1-6 Alkyl group (e.g., methyl) and R 1 to R 2 are each independently substituted with 1 to 3 substituents selected from the group consisting of 5- or 6-membered monocyclic aromatic heterocycles (eg, thiophene, thiazole, pyridine).

[0122] Ring X is more preferably (i) a halogen atom (e.g., a fluorine atom, a chlorine atom), and (ii) C 1-6 Alkyl group (e.g., methyl) is a benzene ring which may be further substituted by 1 to 3 substituents selected from:

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

[0124] [ka]

[0125] ; where:

[0126] [ka]

[0127] is the point of attachment to ring W, and

[0128] [ka]

[0129] is the point of attachment to ring Y.

[0130] Ring Y is an optionally further substituted cyclopropane ring. Examples of the substituent of the "optionally further substituted cyclopropane ring" include the substituents selected from the substituent group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0131] Ring Y is preferably (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) C 1-6 C may be substituted with 1 to 3 substituents selected from an alkoxy group (e.g., methoxy), a cyano, and a hydroxyl group; 1-6 Alkyl group (e.g., methyl) is a cyclopropane ring which may be further substituted by 1 to 3 substituents selected from: Ring Y is more preferably a cyclopropane ring optionally further substituted with 1 to 3 halogen atoms (eg, fluorine atoms).

[0132] In one embodiment, ring Y is optionally further substituted with one fluorine atom:

[0133] [ka]

[0134] ; where:

[0135] [ka]

[0136] is the point of attachment to ring X, and

[0137] [ka]

[0138] is the point of attachment to ring Z.

[0139] Ring Z is an optionally further substituted nitrogen-containing heterocycle. Examples of the substituent of the "optionally further substituted nitrogen-containing heterocycle" include the substituents selected from the substituent group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0140] Ring Z is preferably (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, (iii) C 1-6 C may be substituted by 1 to 3 substituents selected from an alkoxy group (e.g., methoxy), a halogen atom (e.g., a fluorine atom), and a hydroxyl group; 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 5-membered monocyclic aromatic heterocyclic ring optionally substituted with alkyl (e.g., methyl) Ring (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl) and 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) optionally further substituted by 1 to 3 substituents selected from the above.

[0141] Ring Z is more preferably a halogen atom (e.g., a fluorine atom), a hydroxy group, or C1-6 and 3- to 14-membered nitrogen-containing heterocycles (e.g., azetidine, pyrrolidine, piperidine, azepane, oxazepane, octahydrocyclopenta[c]pyrrole) which may be further substituted by 1 to 3 substituents selected from alkyl groups (e.g., methyl).

[0142] In an embodiment, ring Z is selected from the group consisting of halogen atoms (e.g., fluorine atoms), hydroxy groups, and C 1-6 It may be further substituted with 1 to 3 substituents independently selected from alkyl groups (e.g., methyl):

[0143] [ka]

[0144] wherein:

[0145] [ka]

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

[0147] [ka]

[0148] is the point of attachment to L.

[0149] In one embodiment, ring Z is selected from the group consisting of halogen atoms (e.g., fluorine atoms) and C 1-6 It may be further substituted with 1 to 3 substituents independently selected from alkyl groups (e.g., methyl):

[0150] [ka]

[0151] ; where:

[0152] [ka]

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

[0154] [ka]

[0155] is the point of attachment to L.

[0156] L represents a bond or an optionally substituted methylene group. Examples of the substituent of the "optionally substituted methylene group" include substituents selected from Substituent Group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0157] L is a bond, or (1) C 1-6 C which may be further substituted with 1 to 3 substituents selected from an alkoxy group (e.g., methoxy) and a hydroxy group 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), and (2) C optionally further substituted with a hydroxy group 3-6 Cycloalkyl groups (e.g., cyclopropyl) is a methylene group which may be substituted with one substituent selected from the group consisting of

[0158] L is preferably a bond or C 1-6 It is a methylene group which may be substituted with an alkyl group (eg, methyl). L is preferably C 1-6 It is a methylene group which may be substituted with an alkyl group (eg, methyl). L is preferably a methylene group.

[0159] R is an optionally substituted C 1-6 Alkyl groups, optionally substituted C 3-10 Cycloalkyl group, or NR a R b Shows. Here, R a is optionally substituted C 1-6 Alkyl group or optionally substituted C 3-10 represents a cycloalkyl group; R b is a hydrogen atom, optionally substituted C 1-6 Alkyl group or optionally substituted C 3-10 represents a cycloalkyl group; or R a and R b together with the adjacent nitrogen atom form an optionally further substituted nitrogen-containing heterocycle. The "nitrogen-containing heterocycle" includes a 3- to 8-membered (preferably 4-membered) monocyclic non-aromatic heterocycle containing at least one nitrogen atom as a ring-constituting atom other than carbon atoms. A preferred example of the "nitrogen-containing heterocycle" is azetidine. The above "Optionally substituted C 1-6 "Alkyl group", "optionally substituted C 3-10 Examples of the substituents of the "cycloalkyl group" and the "optionally further substituted nitrogen-containing heterocycle" include the substituents selected from the substituent group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0160] In one embodiment, R is optionally substituted C 1-6 Alkyl, optionally substituted C 3-10 Cycloalkyl or optionally substituted di-C 1-6 It is an alkylamine. The above "Optionally substituted C 1-6 "Alkyl group", "optionally substituted C 3-10 Cycloalkyl group" and "optionally substituted di-C 1-6Examples of the substituent of the alkylamine group include the substituents selected from the substituent group A. The number of the substituents is preferably 1 to 3. When the number of the substituents is 2 or more, the respective substituents may be the same or different.

[0161] R is preferably (1)(i) A halogen atom (e.g., a fluorine atom, a bromine atom), (ii) C 1-6 Alkoxy (e.g., methoxy), and (iii) cyclopropyl group (e.g., cyclopropyl) C which is optionally substituted by 1 to 3 substituents selected from 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl), (2) C 1-6 C which may be further substituted with an alkyl group (e.g., methyl) 3-10 a cycloalkyl group (e.g., cyclopropyl), or (3) NR a R b where R a is C 1-6 Alkyl groups (e.g., methyl, ethyl, or isopropyl), or C 3-10 a cycloalkyl group (e.g., cyclopropyl); R b is a hydrogen atom or C 1-6 an alkyl group (e.g., methyl); or R a and R b taken together with the adjacent nitrogen atom, form a nitrogen-containing heterocycle (eg, azetidinyl).

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

[0164] R is more preferably (1) C 1-6 an alkyl group (e.g., methyl, ethyl), or (2) Mono-C 1-6 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 moiety.

[0166] [ka]

[0167] Suitable 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, (1) 3- to 8-membered monocyclic non-aromatic heterocycles (e.g., piperidine), (2) 5- to 6-membered monocyclic aromatic heterocycles (e.g., furan, pyridine) optionally further substituted by 1 to 3 halogen atoms (e.g., fluorine atoms), (3)(i) A halogen atom (e.g., a fluorine atom, a chlorine atom), (ii) 1 to 3 C 1-6 C optionally substituted with an alkoxy group (e.g., methoxy) 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., methoxy) C which may be further substituted with 1 to 3 substituents selected from 6-14 an aromatic hydrocarbon ring (e.g., benzene), or (4) C 3-10 Cycloalkanes (e.g., cyclobutane, cyclopentane, cyclohexane); Ring X is (1)(i) A halogen atom (e.g., a fluorine atom, a chlorine atom), (ii) Optionally halogenated C 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 by 1 to 3 substituents selected from (2) 1 to 3 C’s 1-6 a 5- or 6-membered monocyclic aromatic heterocycle (e.g., thiophene, thiazole, pyridine) optionally further substituted with an alkyl group (e.g., methyl); Ring Y is (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) C 1-6 Alkyl group (e.g., methyl) is a cyclopropane optionally further substituted by 1 to 3 substituents selected from Ring Z is (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, (iii) C 1-6 Alkyl groups (e.g., methyl), and (iv) C 1-6 Alkoxy groups (e.g., methoxy) A 3- to 14-membered nitrogen-containing alkyl group which may be further substituted with 1 to 3 substituents selected from 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 which is optionally substituted by 1 to 3 substituents selected from 1-6 Alkyl groups (e.g., methyl, ethyl), (2) C 3-10 a cycloalkyl group (e.g., cyclopropyl), or (3) The-C 1-6 an alkylamino group (e.g., dimethylamino); Compound (I).

[0169] [Compound B] Compound (I) is more preferably Ring W may be further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms). 6-14 An aromatic hydrocarbon ring (e.g., benzene); Ring X is (i) a halogen atom (e.g., a fluorine atom), and (ii) C 1-6 Alkyl group (e.g., methyl) is a benzene ring optionally further substituted by 1 to 3 substituents selected from Ring Y is cyclopropane optionally further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); Ring Z is a halogen atom (e.g., a fluorine atom), a hydroxyl group, or 1-6a 3- to 14-membered nitrogen-containing heterocycle (e.g., azetidine, pyrrolidine, piperidine, azepane, oxazepane, octahydrocyclopenta[c]pyrrole) optionally further substituted by 1 to 3 substituents selected from an alkyl group (e.g., methyl); L is a bond or a methylene group; and R, (1) C 1-6 an alkyl group (e.g., methyl, ethyl), or (2) J-C 1-6 an alkylamino group (e.g., dimethylamino); Compound (I).

[0170] [Compound C] Compound (I) is preferably Ring W, (1) 3- to 8-membered monocyclic non-aromatic heterocycles (e.g., piperidine), (2) 5- to 6-membered monocyclic aromatic heterocycles (e.g., furan, pyridine) optionally further substituted by 1 to 3 halogen atoms (e.g., fluorine atoms), (3)(i) A halogen atom (e.g., a fluorine atom, a chlorine atom), (ii) 1 to 3 C 1-6 C optionally substituted with an alkoxy group (e.g., methoxy) 1-6 Alkyl groups (e.g., methyl), and (iii) C 1-6 Alkoxy groups (e.g., methoxy) C which may be further substituted with 1 to 3 substituents selected from 6-14 an aromatic hydrocarbon ring (e.g., benzene), or (4) C 3-10 Cycloalkanes (e.g., cyclobutane, cyclopentane, cyclohexane); Ring X is (1)(i) A halogen atom (e.g., a fluorine atom, a chlorine atom), (ii) Optionally halogenated C 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 by 1 to 3 substituents selected from (2)(i) A halogen atom (e.g., a fluorine atom), and (ii) C 1-6 Alkyl group (e.g., methyl) a 5- or 6-membered monocyclic aromatic heterocycle (e.g., thiophene, thiazole, pyridine) optionally further substituted by 1 to 3 substituents selected from Ring Y is (i) a halogen atom (e.g., a fluorine atom), (ii) a cyano group, and (iii) C 1-6 C optionally substituted with 1 to 3 substituents selected from an alkoxy group (e.g., methoxy), a cyano, and a hydroxyl group 1-6 Alkyl group (e.g., methyl) is a cyclopropane ring optionally further substituted by 1 to 3 substituents selected from Ring Z is (i) a halogen atom (e.g., a fluorine atom), (ii) a hydroxy group, (iii) C 1-6 C may be substituted by 1 to 3 substituents selected from an alkoxy group (e.g., methoxy), a halogen atom (e.g., a fluorine atom), and a hydroxyl group; 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 5-membered monocyclic aromatic heterocyclic ring optionally substituted with alkyl (e.g., methyl) Ring (e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl) and 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) optionally further substituted by 1 to 3 substituents selected from the above. L is a bond, or (1) C 1-6 C which may be further substituted with 1 to 3 substituents selected from an alkoxy group (e.g., methoxy) and a hydroxy group 1-6 Alkyl groups (e.g., methyl, ethyl, isopropyl), and (2) C optionally further substituted with a hydroxy group 3-6 Cycloalkyl groups (e.g., cyclopropyl) is a methylene group optionally substituted with one substituent selected from R, (1)(i) A halogen atom (e.g., a fluorine atom, a bromine atom), (ii) C 1-6 Alkoxy (e.g., methoxy), and (iii) cyclopropyl group (e.g., cyclopropyl) C which is optionally substituted by 1 to 3 substituents selected from 1-6 Alkyl groups (e.g., methyl, ethyl, propyl, isopropyl). (2) C 1-6 C which may be further substituted with an alkyl group (e.g., methyl) 3-10 a cycloalkyl group (e.g., cyclopropyl), or (3) NR a R b and; Here, R a But, C 1-6 Alkyl groups (e.g., methyl, ethyl, or isopropyl), or C 3-10 a cycloalkyl group (e.g., cyclopropyl); R b is a hydrogen atom or C 1-6 an alkyl group (e.g., methyl); or R a and R b together with the adjacent nitrogen atom to form a nitrogen-containing heterocycle (e.g., azetidinyl ) to form Compound (I).

[0171] [Compound D] Compound (I) is more preferably Ring W may be further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms). 6-14 An aromatic hydrocarbon ring (e.g., benzene); Ring X is (i) a halogen atom (e.g., a fluorine atom, a chlorine atom), and (ii) C 1-6 Alkyl group (e.g., methyl) is a benzene ring optionally further substituted by 1 to 3 substituents selected from Ring Y is a cyclopropane ring optionally further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); Ring Z is a halogen atom (e.g., a fluorine atom), a hydroxyl group, or 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) optionally further substituted by 1 to 3 substituents selected from an alkyl group (e.g., methyl); L is a bond or C 1-6 a methylene group optionally substituted with an alkyl group (e.g., methyl); R, (1) C 1-6 an alkyl group (e.g., methyl, ethyl), or (2) NR a R b and; Here, R a But, C 1-6 is an alkyl group (e.g., methyl); and R b is a hydrogen atom or C 1-6 is an alkyl group (e.g., methyl); Compound (I).

[0172] [Compound E] In another embodiment, compound (I) is Ring W is a benzene ring optionally further substituted with two fluorine atoms. Ring X may be further substituted with 1 or 2 substituents independently selected from halogen (e.g., fluorine atom, chlorine atom) and methyl.

[0173] [ka]

[0174] ; where:

[0175] [ka]

[0176] is the point of attachment to ring W, and

[0177] [ka]

[0178] is the point of attachment to ring Y. Ring Y may be further substituted with one fluorine atom.

[0179] [ka]

[0180] ; where:

[0181] [ka]

[0182] is the point of attachment to ring X, and

[0183] [ka]

[0184] is the point of attachment to ring Z; Ring Z is a halogen atom (e.g., a fluorine atom), a hydroxyl group, or 1-6 It may be further substituted with 1 to 3 substituents independently selected from alkyl groups (e.g., methyl):

[0185] [ka]

[0186] wherein:

[0187] [ka]

[0188] is the point of attachment to ring Y, and

[0189] [ka]

[0190] is the point of attachment to L. L is C 1-6 a methylene group optionally substituted with an alkyl group (e.g., methyl); and R, (1) C 1-6 an alkyl group (e.g., methyl, ethyl), or (2) NR a R b and; Here, R a But, C 1-6 is an alkyl group (e.g., methyl); and R b is a hydrogen atom or C 1-6 is an alkyl group (e.g., methyl); Compound (I).

[0191] [Compound F] Compound (I) is more preferably Ring W is a benzene ring optionally further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); Ring X is (i) a halogen atom (e.g., a fluorine atom, a chlorine atom), and (ii) C 1-6 Alkyl group (e.g., methyl) is a benzene ring optionally further substituted by 1 to 3 substituents selected from Ring Y is a cyclopropane ring optionally further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); Ring Z is a halogen atom (e.g., a fluorine atom) and C 1-6 an azetidine ring optionally further substituted by 1 to 3 substituents selected from an alkyl group (e.g., methyl); L is C 1-6 a methylene group optionally substituted with an alkyl group (e.g., methyl); R, (1) C 1-6 an alkyl group (e.g., methyl, ethyl), or (2) NR a R b and; Here, R a But, C 1-6 is an alkyl group (e.g., methyl); and R b is a hydrogen atom, Compound (I).

[0192] [Compound G] Compound (I) is more preferably Ring W is a benzene ring optionally further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); Ring X is a benzene ring optionally further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); Ring Y is a cyclopropane ring optionally further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); Ring Z is an azetidine ring optionally further substituted with 1 to 3 halogen atoms (e.g., fluorine atoms); L is a methylene group; R is C 1-6 Alkyl group (e.g., ethyl), or NR a R b and; Here, R a But, C 1-6 is an alkyl group (e.g., methyl); and R b is a hydrogen atom, Compound (I).

[0193] Specific examples of compound (I) include the compounds of Examples 1 to 12, 14 to 132, 134 to 138, 140 to 230, 232 to 353, 355 to 368, and 370 to 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]azetidin-2-yl}ethyl]methanesulfonamide, or a salt thereof (Example 353); N-({(2S,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-methylazetidin-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-fluoroazetidin-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-fluoroazetidin-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]azetidin-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-fluoroazetidin-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-fluoroazetidin-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]azetidin-2-yl}methyl)-N'-methyl sulfate Diamide or its salt (Example 423) It is.

[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-fluoroazetidin-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]azetidin-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]azetidin-2-yl}methyl)-N'-methyl sulfate Diamide or its salt (Example 423) It is.

[0196] The term "therapeutically effective amount" refers to an amount that improves the treatment, cure, or alleviation of a disease, disorder, or side effect, or reduces the rate of progression of a disease or disorder, compared to a corresponding subject that has not been administered such amount. The term also includes within its scope an amount effective to enhance normal physiological function. When used in therapy, a therapeutically effective amount of the compound of formula (I) and its salts can be administered as a drug substance. In addition, the active ingredient can be provided as a pharmaceutical composition.

[0197] As the salt of the compound represented by formula (I), a pharmacologically acceptable salt is preferable. Examples of such salts include salts with inorganic bases, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, etc. 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; ammonium salts, and the like. Suitable examples of salts with organic bases include salts with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, tromethamine [tris(hydroxymethyl)methylamine], tert-butylamine, cyclohexylamine, benzylamine, dicyclohexylamine, N,N-dibenzylethylenediamine, and the like. Suitable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Suitable examples of salts with organic acids include salts with formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, etc. Suitable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc.

[0198] It will be understood that, due to its potential use in medicine, the salts of the compounds of formula (II) and (II') are ideally pharma- ceutically acceptable. Pharmaceutically acceptable salts include, inter alia, those listed in Berge, J. Pharm. Sci., 66, 1-19, (1977), or those listed in PH Stahl and CG 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 a compound of formula (I) in a suitable solvent, such as an organic solvent, to give a salt which can be isolated by a variety of methods, including crystallization and filtration.

[0199] Representative pharma- ceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), 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 (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, gluconate, Glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (N,N'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate). , methylsulfate, mucate, naphthalene-1,5-disulfonate (napadisilate), naphthalene-2-sulfonate (napsilate), nicotinate, nitrate, oleate, palmitate, p-aminobenzenesulfonate, p-aminosalicylate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tolyl sulfate). silate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, theoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate salts.

[0200] Representative pharma- ceutically acceptable base addition salts include, but are not limited to, aluminum, 2-amino-2-(hydroxymethyl)-1,3-propanediol (TRIS), arginine, benethamine (N-benzylphenethylamine), benzathine (N,N'-dibenzylethylenediamine), bis-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1-chlorobenzyl-2-pyrrolidin-1'-ylmethylbenzimidazole), cysteine, methyl ethyl amine ... These include cyclohexylamine, 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 formula (II) and (II'). When the basic compounds of formula (II) and (II') are isolated as salts, the corresponding free base forms of the compounds can be prepared by any suitable method known in the art, including treatment of the salts with inorganic or organic bases. Similarly, when the compounds of formula (II) and (II') that contain a carboxylic acid or other acidic functional group are isolated as salts, the corresponding free acid forms of the compounds can be prepared by any suitable method known in the art, including treatment of the salts with inorganic or organic acids.

[0202] It is understood that when compounds of formula (II) and (II') contain two or more basic moieties, the salt formation stoichiometry may include one, two, or more equivalents of acid, such that such salts contain one, two, or more acid counterions, such as, for example, a dihydrochloride salt.

[0203] Stoichiometric and non-stoichiometric forms of pharma- ceutically acceptable salts of the compounds of formula (II) and (II') are included within the scope of the present invention, including substoichiometric salts, for example, where the counterion contains more than one acidic proton.

[0204] In certain embodiments, the present disclosure provides a pharma- ceutically acceptable salt of any of the above embodiments [1]-

[34] .

[0205] The process for producing the compound of the present invention is explained below.

[0206] The raw materials and reagents used in each step of the following production methods, as well as the resulting compounds, may each form a salt. Examples of such salts include the same salts as those of the compound represented by formula (I) above.

[0207] When the compound obtained in each step is a free compound, it can be converted into the desired salt by a method known per se. Conversely, when the compound obtained in each step is a salt, it can be converted into a free form or another type of desired salt by a method known per se.

[0208] The compounds obtained in each step are either directly reacted or obtained as crude products and then used in the next reaction. Alternatively, the compounds obtained in each step can be isolated and / or purified from the reaction mixture by a separation means such as concentration, crystallization, recrystallization, distillation, solvent extraction, fractional distillation, chromatography, etc. in a conventional manner.

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

[0210] In the reaction of each step, the reaction time may vary depending on the reagents and solvent used, but unless otherwise specified, it is usually 1 minute to 48 hours, preferably 10 minutes to 8 hours.

[0211] In the reactions of each step, the reaction temperature may vary depending on the reagents and solvents used, but is usually from -78°C to 300°C, preferably from -78°C to 150°C, unless otherwise specified.

[0212] In the reaction of each step, the pressure may vary depending on the reagents and solvents used, but unless otherwise specified, it is usually 1 atm to 20 atm, preferably 1 atm to 3 atm.

[0213] In the reactions of each step, a microwave synthesis device such as Biotage Initiator may be used. The reaction temperature may vary depending on the reagents and solvents used, but is usually room temperature to 300° C., preferably 50° C. to 250° C., unless otherwise specified. The reaction time may vary depending on the reagents and solvents used, but is usually 1 minute to 48 hours, preferably 1 minute to 8 hours, unless otherwise specified.

[0214] In the reaction of each step, unless otherwise specified, the reagent is used in an amount of 0.5 to 20 equivalents, preferably 0.8 to 5 equivalents, relative to the substrate. When the reagent is used as a catalyst, the reagent is used in an amount of 0.001 to 1 equivalent, preferably 0.01 to 0.2 equivalents, relative to the substrate. When the reagent also serves as a reaction solvent, the reagent is used in an amount equivalent to the solvent.

[0215] Unless otherwise specified, the reactions in each step are carried out without a solvent or by dissolving or suspending the components in a suitable solvent. Specific examples of the solvent include those described in the Examples and 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: dichloromethane, carbon tetrachloride, etc.; Nitriles: acetonitrile, etc.; Sulfoxides: dimethyl sulfoxide, etc.; Aromatic organic bases: pyridine, etc.; Acid anhydrides: acetic anhydride, etc.; Organic acids: formic acid, acetic acid, trifluoroacetic acid, etc.; Inorganic acids: hydrochloric acid, sulfuric acid, etc.; Esters: ethyl acetate, etc.; Ketones: acetone, methyl ethyl ketone, etc.; water. The above solvents may be used as a mixture of two or more kinds in an appropriate ratio.

[0216] When a base is used in the reaction of each step, for example, the base shown below or the base shown in the Examples may be used. The bases described are 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: sodium hydride, etc.; Metal amides: sodium amide, lithium diisopropylamide, lithium hexamethyldisilazide, etc.; Organolithium compounds: n-butyllithium, etc.

[0217] When an acid or an acid catalyst is used in the reaction of each step, for example, the acids and acid catalysts shown below or the acids and acid catalysts described in the Examples can 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 ferric chloride, etc.

[0218] Unless otherwise specified, the reactions in each step are carried out by a method known per se, for example, in Jikken Kagaku Koza (5th Edition), Vol. 13-19 (edited by the Chemical Society of Japan); Shin Jikken Kagaku Koza (New Experimental Chemistry Koza), Vol. 14-15 (edited by the Chemical Society of Japan); Precision Organic Chemistry, Revised 2nd Edition (LF Tietze, Th. Eicher, Nankodo); Revised Organic Name Reactions, Their Mechanisms and Points (by Hideo Togo, Kodansha); ORGANIC SYNTHESES Collective Volumes I-VII (John Wiley & Sons Inc.); Modern Organic Synthesis in the Laboratory A Collection of Standard Experimental Procedures (by Jie Jack Li, published by OXFORD UNIVERSITY); Comprehensive This can be carried out in accordance with the methods described in Heterocyclic Chemistry III, Vol. 1 to Vol. 14 (Elsevier Japan Co., Ltd.); Organic Synthesis Strategies Learned from Named Reactions (translated and supervised by Kiyoshi Tomioka, published by Kagaku Dojin); Comprehensive Organic Transformations (VCH Publishers Inc.) 1989, or the methods described in the Examples.

[0219] In each step, the protection or deprotection reaction of a functional group can be carried out by a method known per se, for example, the method described in "Protective Groups, in Organic Synthesis, 4th Ed.” (Theodora The method is carried out according to the method described in "Protecting Groups, 3rd Ed." (by PJ Kocienski), Thieme Press, 2004, or the method described in the Examples. Examples of the protecting group for the hydroxyl group of an alcohol or the like or a phenolic hydroxyl group include ether-type protecting groups such as methoxymethyl ether, benzyl ether, tert-butyldimethylsilyl ether, and tetrahydropyranyl ether; carboxylate-type protecting groups such as acetate; sulfonate-type protecting groups such as methanesulfonate; and carbonate-type protecting groups such as tert-butyl carbonate. Examples of the protecting group for the carbonyl group of an aldehyde include acetal-type protecting groups such as dimethylacetal; and cyclic acetal-type protecting groups such as 1,3-dioxane. Examples of the protecting group for the carbonyl group of the ketone include ketal-type protecting groups such as dimethyl ketal. Protective groups include cyclic ketal-type protective groups such as 1,3-dioxane; oxime-type protective groups such as O-methyloxime; and hydrazone-type protective groups such as N,N-dimethylhydrazone. Examples of the carboxyl-protecting group include ester-type protecting groups such as methyl ester; and amide-type protecting groups such as N,N-dimethylamide. Examples of the thiol-protecting group include ether-type protecting groups such as benzylthioether; and ester-type protecting groups such as thioacetate, thiocarbonate, and thiocarbamate. Examples of the protecting group for an amino group or an aromatic heterocycle such as imidazole, pyrrole, or 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 by a method known per se, for example, a method using an acid, a base, ultraviolet light, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate, or a trialkylsilyl halide (e.g., trimethylsilyl iodide, trimethylsilyl bromide), or a reduction method.

[0220] In each step, when a reduction reaction is carried out, examples of the reducing agent used include metal hydrides such as lithium aluminum hydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diisobutylaluminum hydride (DIBAL-H), sodium borohydride, and tetramethylammonium triacetoxyborohydride; boranes such as borane tetrahydrofuran complex; Raney nickel; Raney cobalt; hydrogen; formic acid; triethylsilane; etc. When a carbon-carbon double bond or triple bond is reduced, a catalyst such as palladium-carbon or Lindlar catalyst may be used.

[0221] In each step, when an oxidation reaction is carried out, examples of the oxidizing agent 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 complex; osmium tetroxide; selenium dioxide; and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).

[0222] In each step, when a radical cyclization reaction is carried out, examples of the radical initiator 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, benzoyl peroxide, etc. Examples of the radical reaction reagent used include tributylstannane, tristrimethylsilylsilane, 1,1,2,2-tetraphenyldisilane, diphenylsilane, samarium iodide, etc.

[0223] When a Wittig reaction is carried out in each step, examples of the Wittig reagent used include alkylidene phosphoranes, etc. The alkylidene phosphoranes can be prepared by a method known per se, for example, by reacting a phosphonium salt with a strong base.

[0224] In each step, when the Horner-Emmons reaction is carried out, the reagents used are phosphonoacetate esters such as methyl dimethylphosphonoacetate and ethyl diethylphosphonoacetate. bases such as ethers; alkali metal hydrides, and organolithium bases.

[0225] In each step, when the Friedel-Crafts reaction is carried out, examples of the reagent used 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, an organic acid or an inorganic acid can be used instead of the Lewis acid, and an acid anhydride such as acetic anhydride can be used instead of the acid chloride.

[0226] In each step, when an aromatic nucleophilic substitution reaction is carried out, a nucleophile (eg, amines, imidazole, etc.) and a base (eg, organic bases, etc.) are used as reagents.

[0227] In each step, when a nucleophilic addition reaction by a carbanion, a nucleophilic 1,4-addition reaction (Michael addition reaction) by a carbanion, or a nucleophilic substitution reaction by a carbanion is performed, examples of the base used to generate the carbanion include organolithiums, metal alkoxides, inorganic bases, and organic bases.

[0228] When a Grignard reaction is carried out in each step, examples of the Grignard reagent include arylmagnesium halides such as phenylmagnesium bromide, and alkylmagnesium halides such as methylmagnesium bromide. The Grignard reagent can be prepared by a method known per se, for example, by reacting an alkyl halide or aryl halide with metallic magnesium in ether or tetrahydrofuran as a solvent.

[0229] In each step, when a Knoevenagel condensation reaction is carried out, 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) are used as reagents.

[0230] In each step, when the Vilsmeier-Haack reaction is carried out, phosphoryl chloride and an amide derivative (eg, N,N-dimethylformamide, etc.) are used as reagents.

[0231] In each step, when an azidation reaction of alcohols, alkyl halides, or sulfonate esters is carried out, examples of the azidation agent used include diphenylphosphoryl azide (DPPA), trimethylsilyl azide, sodium azide, etc. For example, when azidating alcohols, there are a method using diphenylphosphoryl azide and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and a method using trimethylsilyl azide and a Lewis acid.

[0232] In each step, when a reductive amination reaction is carried out, examples of the reducing agent used include sodium triacetoxyborohydride, sodium cyanoborohydride, hydrogen, formic acid, etc. When the substrate is an amine compound, examples of the carbonyl compound used include paraformaldehyde, aldehydes such as acetaldehyde, and ketones such as cyclohexanone. When the substrate is a carbonyl compound, examples of the amines used include ammonia, primary amines such as methylamine, and secondary amines such as dimethylamine.

[0233] In each step, when Mitsunobu reaction is carried out, an azodicarboxylate (eg, diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate (DIAD), etc.) and triphenylphosphine are used as reagents.

[0234] In each step, when an esterification reaction, an amidation reaction, or a urea reaction is performed, examples of the reagents used include acyl halides such as acid chlorides and acid bromides; activated carboxylic acids such as acid anhydrides, active esters, and sulfates. Examples of activators for 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-triazin-2-yl)-4-methylmorpholinium chloride-n-hydrate (DMT-MM); carbonate-based condensing agents such as 1,1-carbonyldiimidazole (CDI); diphenylphosphoryl azide (DPPA); benzotriazol-1-yloxy-trisdimethylaminophosphonium salt (BOP reagent); 2-Chloro-1-methyl-pyridinium iodide (Mukaiyama's Reagent); Thionyl chloride; Lower alkyl haloformates such as ethyl chloroformate; O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU); sulfuric acid; or a combination thereof. When a carbodiimide-based condensing agent is used, an additive such as 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), or dimethylaminopyridine (DMAP) may be further added to the reaction.

[0235] In each step, when a coupling reaction is carried out, examples of the metal catalyst used include palladium compounds such as palladium acetate (II), tetrakis(triphenylphosphine)palladium (0), dichlorobis(triphenylphosphine)palladium (II), dichlorobis(triethylphosphine)palladium (II), tris(dibenzylideneacetone)dipalladium (0), and 1,1'-bis(diphenylphosphino)ferrocenepalladium (II) chloride; nickel compounds such as tetrakis(triphenylphosphine)nickel (0); rhodium compounds such as tris(triphenylphosphine)rhodium (III) chloride; cobalt compounds; copper compounds such as copper oxide and copper iodide (I); and platinum compounds. A base may be added to the reaction, and examples of such bases include inorganic bases.

[0236] When a thiocarbonylation reaction is carried out in each step, diphosphorus pentasulfide is typically used as the thiocarbonylating agent. In addition to diphosphorus pentasulfide, a reagent 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's reagent), may also be used.

[0237] In each step, when the Wohl-Ziegler reaction is carried out, examples of the halogenating agent used include N-iodosuccinimide, N-bromosuccinimide (NBS), N-chlorosuccinimide (NCS), bromine, sulfuryl chloride, etc. Furthermore, the reaction can be accelerated by adding a radical initiator such as heat, light, benzoyl peroxide, or azobisisobutyronitrile to the reaction.

[0238] In each step, when a halogenation reaction of a hydroxy group is carried out, examples of the halogenating agent used include hydrohalic acid and an acid halide of an inorganic acid, specifically, for chlorination, hydrochloric acid, thionyl chloride, phosphorus oxychloride, etc., and for bromination, 48% hydrobromic acid, etc. may be mentioned. In addition, a method of obtaining an alkyl halide from an alcohol by the reaction of triphenylphosphine with carbon tetrachloride or carbon tetrabromide, etc. may be used. Alternatively, a method of synthesizing an alkyl halide through a two-step reaction in which an alcohol is converted into a sulfonic acid ester and then reacted with lithium bromide, lithium chloride, or sodium iodide may be used.

[0239] In each step, when performing the Arbuzov reaction, the reagent used is bromoacetic acid. alkyl halides such as ethyl phosphate; and phosphites such as triethyl phosphite and tri(isopropyl) phosphite.

[0240] When a sulfonyl esterification reaction is carried out in each step, examples of the sulfonylating agent to be used include methanesulfonyl chloride, p-toluenesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonic anhydride, and the like.

[0241] In each step, when a hydrolysis reaction is carried out, an acid or a base is used as a reagent. When an acid hydrolysis reaction of a tert-butyl ester is carried out, 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 the dehydrating agent to be used include sulfuric acid, diphosphorus pentoxide, phosphorus oxychloride, N,N'-dicyclohexylcarbodiimide, alumina, polyphosphoric acid and the like.

[0243] Among the compounds (3) used in the reaction scheme 3 described later, compounds (3)-1 and (3)-2 shown in the diagram below can be produced from compound (1) by the method shown in the reaction scheme 1 below.1 is optionally substituted C 1-6 R represents an alkyl group. 2 , R 3 and R 4 each independently represents a hydrogen atom, a halogen atom, or an optionally substituted C 1-6 The alkyl group represents an alkyl group, and the other symbols are as defined above.

[0244] [ka]

[0245] R 1 , R 2 , R 3 and R 4 "Optionally substituted C 1-6 As the "alkyl group", among the above-mentioned "optionally substituted hydrocarbon groups", the hydrocarbon group is 1-6 Examples of the alkyl group include those which are alkyl groups.

[0246] Compound (1) may be a commercially available product as is, or may be produced by a known method or a method analogous thereto.

[0247] Compound (3)-1 can be produced by the Corey-Chaykovsky reaction of compound (2) with a sulfonium salt in the presence of a base. Examples of the sulfonium salt that can be used include trimethylsulfonium iodide. Examples of the base that can be used include inorganic bases, metal alkoxides, and alkali metal hydrides.

[0248] Compound (6) can be produced by a condensation reaction of compound (1) with 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 the metal catalyst 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, such as a hypervalent iodine compound such as iodosobenzene, manganese(IV) oxide, etc.

[0251] Among the compounds (3) used in the reaction scheme 3 described below, the compound (3)-3 shown in the diagram below can be produced from the compound (8) by the method shown in the reaction scheme 2 below. 1 and L.G. 2 each independently represents a leaving group, R 5 is a hydrogen atom, a halogen atom or an optionally substituted C 1-6 The alkyl group represents an alkyl group, and the other symbols are as defined above.

[0252] [ka]

[0253] LG 1 The "leaving group" represented by the formula (I) is a halogen atom, an optionally halogenated C 1-6 Alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), C 1-6 C optionally substituted with alkyl 6-14 Examples of the arylsulfonyloxy include arylsulfonyloxy (for example, benzenesulfonyloxy, toluenesulfonyloxy), and the like.

[0254] LG 2Examples of the "leaving group" represented by the formula: include optionally substituted dihydroxyboryl (eg, dihydroxyboryl, pinacolatoboryl), and the like.

[0255] R 5 "Optionally substituted C 1-6 As the "alkyl group", among the above-mentioned "optionally substituted hydrocarbon groups", the hydrocarbon group is 1-6 Examples of the alkyl group include those which are alkyl groups.

[0256] Compound (8) and compound (9) may be commercially available products as they are, or may be produced by a method known per se or a method analogous thereto.

[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) dimer, and ruthenium compounds such as dichloro(p-cymene)ruthenium(II) dimer.

[0258] Compound (11) can be produced from compound (3) by the method shown in the following reaction scheme 3. In the formula, each symbol has the same meaning as defined above.

[0259] [ka]

[0260] Compound (15) can be produced from compound (12) by the method shown in the following reaction scheme 4. 3 represents a leaving group, P represents a protecting group, and the other symbols are as defined above.

[0261] [ka]

[0262] LG 3The "leaving group" represented by the formula (I) is a halogen atom, an optionally halogenated C 1-6 Alkylsulfonyloxy (e.g., methanesulfonyloxy, ethanesulfonyloxy, trifluoromethanesulfonyloxy), C 1-6 C optionally substituted with alkyl 6-14 Examples of the arylsulfonyloxy include arylsulfonyloxy (for example, benzenesulfonyloxy, toluenesulfonyloxy), and the like.

[0263] Examples of the "protecting group" represented by P include those exemplified above as the "protecting group for amino group, and aromatic heterocycles such as imidazole, pyrrole, and indole".

[0264] Compound (12) may be a commercially available product as is, or may be produced by a known method or a method analogous thereto.

[0265] Compound (14) can be produced by sulfonamidation reaction of compound (12) with compound (13). Examples of compound (13) to be used include sulfonyl chloride, sulfamoyl chloride, etc. Compound (13) can be a commercially available product as it is, or can be produced by a method known per se or a method analogous thereto.

[0266] Compound (I) can be produced from compound (11) and compound (15) by the method shown in the following reaction scheme 5. In the formula, each symbol has the same meaning as defined above.

[0267] [ka]

[0268] In the compound (I) thus obtained, the functional groups in the molecule can be converted to the desired functional groups by combining known chemical reactions, such as oxidation, reduction, alkylation, acylation, urea formation, hydrolysis, amination, esterification, aryl coupling, and deprotection.

[0269] In the above-mentioned production methods, when the starting compound has an amino group, a carboxyl group, a hydroxyl group, a carbonyl group or a mercapto group as a substituent, a protecting group generally used in peptide chemistry or the like may be introduced into these groups, and the target compound can be obtained by removing the protecting group as necessary after the reaction.

[0270] Compound (I) obtained by the above-mentioned production method can be isolated and purified by known means such as solvent extraction, liquid conversion, dissolution transfer, crystallization, recrystallization, chromatography, and the like. When compound (I) contains optical isomers, stereoisomers, positional isomers, or rotational isomers, these are also included in compound (I), and each can be obtained as a single product by a synthesis method or separation method known per se. For example, when compound (I) contains optical isomers, optical isomers resolved from the compound are also included in compound (I). Here, the optical isomers can be produced by methods known per se. Compound (I) may be in a crystalline form. The crystals of compound (I) (hereinafter sometimes abbreviated as the crystals of the present invention) can be produced by crystallizing compound (I) using a crystallization method known per se.

[0271] In this specification, the melting point means a melting point measured, for example, using a micro melting point analyzer (Yanaco, MP-500D type or Buchi, B-545 type) or a DSC (differential scanning calorimetry) apparatus (METTLER TOLEDO, DSC1) or the like. In general, the melting point may vary depending on the measuring instrument, the measuring conditions, etc. The crystals in this specification may be crystals that show a melting point different from that described in this specification, so long as it is within the normal error range. The crystals of the present invention have excellent physicochemical properties (e.g., melting point, solubility, stability) and biological properties (e.g., pharmacokinetics (absorbability, distribution, metabolism, excretion), pharmacological activity), and are extremely useful as pharmaceuticals.

[0272] Compound (I) may be used as a prodrug. A prodrug of compound (I) is a compound that is converted to compound (I) by a reaction with an enzyme, gastric acid, or the like under physiological conditions in a living body, i.e., a compound that is enzymatically oxidized, reduced, hydrolyzed, or the like to convert to compound (I), or a compound that is hydrolyzed by gastric acid or the like to convert to compound (I). Examples of the prodrug of compound (I) include A compound in which the amino group of compound (I) is acylated, alkylated or phosphorylated (e.g., a compound in which the amino group of compound (I) is eicosanoyl, alanylated, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl or tert -Butylated compounds); A compound in which the hydroxy group of compound (I) is acylated, alkylated, phosphorylated or borated (e.g., a compound in which the hydroxy group of compound (I) is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated); Examples of such compounds include compounds in which the carboxyl group of compound (I) is esterified or amidated (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-dioxolen-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, or methylamidated). These compounds can be produced from compound (I) by methods known per se.

[0273] In addition, the prodrug of compound (I) may be one that is converted into compound (I) under physiological conditions, as described in "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198, published by Hirokawa Shoten in 1990. In the present specification, the prodrug may be in the form of a salt, and such salts include those exemplified as the salts of the compound represented by the above formula (I). Compound (I) may also contain isotopes (e.g., 3 H, 13 C. 14 C. 18 F, 35 S, 125 I) or the like. Compound (I) labeled or substituted with an isotope can be used, for example, as a tracer used in positron emission tomography (PET) (PET tracer), and is useful in fields such as medical diagnosis. Furthermore, compound (I) may be a hydrate, a non-hydrate, a non-solvate (eg, anhydrous), or a solvate (eg, hydrate). moreover, 1 H 2 Deuterium converted to H(D) is also encompassed in compound (I). Furthermore, compound (I) may be a pharma- ceutically acceptable cocrystal or cocrystal salt. Here, a cocrystal or cocrystal salt refers to a crystalline substance that is composed of two or more distinct solids at room temperature, each of which has different physical properties (e.g., structure, melting point, heat of fusion, hygroscopicity, solubility, and stability). A cocrystal or cocrystal salt can be prepared according to a cocrystallization method known per se.

[0274] Compound (I) or a prodrug thereof (hereinafter sometimes simply referred to as the compound of the present invention) can be used as it is or as a pharmaceutical composition (also referred to as a medicine) by mixing it with a pharmacologically acceptable carrier or the like, as an agent for preventing or treating various diseases described later in mammals (e.g., humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, and monkeys). Here, as the pharmacologically acceptable carrier, various organic or inorganic carrier substances commonly used as pharmaceutical ingredients are used, and are blended as excipients, lubricants, binders, disintegrants in solid preparations, and solvents, solubilizing agents, suspending agents, isotonicity agents, buffers, soothing agents, etc. in liquid preparations. Furthermore, formulation additives such as preservatives, antioxidants, colorants, sweeteners, etc. can also be used as necessary.

[0275] Suitable examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate. Suitable examples of the lubricant 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. Preferable examples of the disintegrant include lactose, sucrose, starch, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, sodium carboxymethylstarch, light anhydrous silicic acid, and low-substituted hydroxypropylcellulose. Preferable examples of the solvent 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 the solubilizing agent 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 stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose; polysorbates, and polyoxyethylene hydrogenated castor oil. Preferable examples of the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, and glucose. Suitable examples of the buffering agent include buffer solutions such as phosphate, acetate, carbonate, and citrate. A suitable example of a soothing agent is benzyl alcohol. Preferable examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Suitable examples of the antioxidant include sulfites and ascorbates. Suitable examples of coloring agents include water-soluble edible coal-tar dyes (e.g., food dyes such as Food Red Nos. 2 and 3, Food Yellow Nos. 4 and 5, and Food Blue Nos. 1 and 2), water-insoluble lake dyes (e.g., aluminum salts of the above-mentioned water-soluble edible coal-tar dyes), and natural dyes (e.g., β-carotene, chlorophyll, and red iron oxide). Suitable examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, aspartame, and stevia.

[0276] Examples of the dosage form of 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 and microcapsules), pills, granules, powders, troches, syrups, liquids, emulsions, suspensions, aerosols, and films (e.g., orally disintegrating films, oral mucosal patch 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 compound and the medicament of the present invention can be safely administered orally or parenterally (e.g., administration into the rectum, intravenously, intraarterially, intramuscularly, subcutaneously, intraorgan, intranasally, intradermally, by eye drop, intracerebral, intravaginally, intraperitoneally, inside a tumor, in the vicinity of a tumor, or directly to a lesion). These formulations may be immediate release formulations or controlled release formulations, such as sustained release formulations (eg, sustained release microcapsules).

[0277] The pharmaceutical composition can be produced by a method commonly used in the field of formulation technology, for example, a method 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 dose of the compound of the present invention, etc., but is, for example, about 0.1 to 100% by weight. When preparing oral preparations, coating may be carried out, if necessary, for the purposes of taste masking, enteric properties or durability.

[0278] Examples of coating bases used for coating include sugar coating bases, water-soluble film coating bases, enteric film coating bases, and sustained-release film coating bases. As the sugar-coating base, white sugar is used, and one or more substances selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax, etc. may be used in combination. Examples of water-soluble film coating bases include cellulose-based polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, and methyl hydroxyethyl cellulose; synthetic polymers such as polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer E (Eudragit E (trade name)), and polyvinylpyrrolidone; and polysaccharides such as pullulan. Examples of enteric film coating bases include cellulose-based polymers such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic acid-based 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 cellulose-based polymers such as ethyl cellulose; and acrylic acid-based 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 in combination of two or more kinds in an appropriate ratio. In addition, a light-shielding agent such as titanium oxide, ferric oxide, etc. may be used during coating.

[0279] The compound of the present invention has low toxicity (e.g., acute toxicity, chronic toxicity, genetic toxicity, reproductive toxicity, cardiotoxicity, carcinogenicity) and few side effects, and can be used as a preventive or therapeutic agent, or a diagnostic agent for various diseases in mammals (e.g., humans, cows, horses, dogs, cats, monkeys, mice, and rats).

[0280] The compound of the present invention has excellent orexin type 2 receptor agonist activity, and can treat, prevent, and ameliorate the risk of various neurological and psychiatric diseases associated with the orexin type 2 receptor. The compound of the present invention can be used to treat, prevent, and ameliorate the risk of various neurological and psychiatric diseases associated with the orexin type 2 receptor, such as narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome with narcolepsy-like symptoms, hypersomnia syndrome with daytime hypersomnia (e.g., Kleine-Levin syndrome, major depression with hypersomnia, dementia with Lewy bodies, 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-Barre syndrome, Rasmussen's encephalitis, Wernicke's encephalitis, limbic encephalitis, Hashimoto's encephalopathy), coma, loss of consciousness, obesity (e.g. malignant mast cells, exogenous obesity, hyperinsulinemia obesity, hyperplasmocytosis, pituitary obesity, hypoplasmocytosis, hypothyroidism obesity, hypothalamic obesity, symptomatic obesity, childhood obesity, upper body obesity, dietary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity), insulin resistance syndrome, Alzheimer's disease, disorders of consciousness such as coma, side effects and complications from anesthesia, sleep disturbance, sleep Problems, insomnia, intermittent sleep, nocturnal clonic cramps, REM sleep interruptions, jet lag, jet lag syndrome, shift worker sleep disorder, sleep disorders, night terrors, depression, major depression, sleepwalking, enuresis, sleep disorders, Alzheimer's twilight syndrome, disorders related to circadian rhythm, fibromyalgia, conditions resulting from poor quality sleep, overeating, compulsive eating disorder, obesity-related disorders, hypertension, diabetes, elevated plasma insulin concentration and insulin resistance, hyperlipidemia, hyperlipidemia, endometrial cancer, breast cancer, prostate cancer, colon cancer, cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heartbeat, Cardiac arrhythmias, myocardial infarction, congestive heart failure, heart failure, coronary heart disease, cardiovascular disorders, sudden death, polycystic ovarian disease, craniopharyngioma, Frohlich syndrome, growth hormone deficiency, normal variant short stature, Turner syndrome, children with acute lymphoblastic leukemia, syndrome X, reproductive hormonal abnormalities, sexual and reproductive dysfunction such as reduced fertility, infertility, hypogonadism in men, and hirsutism in women, fetal defects associated with maternal obesity, gastrointestinal motility disorders such as obesity-related gastroesophageal reflux, obesity hypoventilation syndrome (Pickwickian syndrome), respiratory disorders such as dyspnea, systemic inflammation of the vascular system Reduce the risk of secondary consequences of obesity such as inflammation, arteriosclerosis, hypercholesterolemia, hyperuricemia, lower back pain, gallbladder disease, gout, kidney cancer, risk of left ventricular hypertrophy, migraine, headache, neuropathic pain, Parkinson's disease, psychosis, schizophrenia, hot flushes, night sweats, genital / urinary system disorders, disorders related to sexual function or fertility, dysthymic disorder, bipolar disorder, bipolar I disorder, bipolar II disorder, cyclothymia, acute stress disorder, agoraphobia, generalized anxiety disorder, obsessive-compulsive disorder, panic attacks, panic disorder, post-traumatic stress disorder, separation anxiety disorder, social phobia, anxiety disorders Acute neurological and psychiatric disorders such as brain defects after cardiac bypass surgery and transplantation, stroke, ischemic stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic nerve damage, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis, eye injuries, retinopathy, cognitive impairment, muscle spasms, tremors, epilepsy, disorders associated with muscle spasms, delirium, amnesic disorders, age-related cognitive decline, schizoaffective disorder, delusional disorder, drug dependence, dyskinesias, chronic fatigue syndrome, fatigue, medication-induced parkinsonism, Gilles de la Tourette syndrome, chorea, myoclonus, tics,It is useful as a preventive or therapeutic drug for various diseases such as restless legs syndrome, dystonia, dyskinesia, attention deficit hyperactivity disorder (ADHD), conduct disorder, urinary incontinence, withdrawal symptoms, trigeminal neuralgia, hearing loss, tinnitus, nerve damage, retinopathy, macular degeneration, vomiting, cerebral edema, pain, bone pain, joint pain, toothache, cataplexy, and traumatic brain injury.

[0281] In particular, the compound of the present invention is useful for the treatment or prevention of narcolepsy, idiopathic hypersomnia, hypersomnia, sleep apnea syndrome, narcolepsy syndrome accompanied by narcolepsy-like symptoms, hypersomnia syndrome accompanied by 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 associated with bone loss, sepsis, disorders of consciousness such as coma, side effects and complications due to anesthesia, and the like, and as an anesthetic antagonist.

[0282] The dosage of the compound of the present invention varies depending on the subject, administration route, target disease, symptoms, etc., but for example, when administered orally or parenterally to an adult patient, the single dose is usually 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 concomitant drugs). By combining the compound of the present invention with a concomitant drug, (1) The dose of the compound of the present invention or a concomitant drug can be reduced compared to the case where the compound is administered alone. (2) Drugs to be used in combination with the compound of the present invention can be selected depending on the symptoms of the patient (mild, severe, etc.). (3) By selecting a concomitant drug with a different mechanism of action from the compound of the present invention, the treatment period can be extended. Can be set, (4) By selecting a concomitant drug having a different mechanism of action from that of 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 concomitant drug, excellent effects such as a synergistic effect can be obtained.

[0284] Hereinafter, the combined use of the compound of the present invention and a concomitant drug will be referred to as "the combined drug of the present invention." When using the combination drug of the present invention, the administration time of the compound of the present invention and the combination drug is not limited, and the compound of the present invention or its pharmaceutical composition and the combination drug or its pharmaceutical composition may be administered to the subject at the same time or at a time lag. The dosage of the combination drug may be in accordance with the dosage used in clinical practice, and can be appropriately selected depending on the subject, administration route, disease, combination, etc. The administration form of the combination drug 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 forms include (1) administration of a single preparation obtained by simultaneously formulating the compound of the present invention and the combination drug, (2) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through the same administration route, (3) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through the same administration route with a time lag, (4) simultaneous administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through different administration routes, and (5) administration of two preparations obtained by separately formulating the compound of the present invention and the combination drug through different administration routes with a time lag (for example, administration in the order of the compound of the present invention; the combination drug, or administration in the reverse order). The dosage of the concomitant drug can be appropriately selected based on the clinically used dosage. The mixing ratio of the compound of the present invention and the concomitant drug can be appropriately selected depending on the subject of administration, the administration route, the 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 based on the total formulation. The content of the concomitant drug in the concomitant agent of the present invention varies depending on the form of the preparation, 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 based on the total preparation. The content of additives such as carriers in the combination drug of the present invention varies depending on the form of the preparation, but is usually about 1 to 99.99% by weight, preferably about 10 to 90% by weight, based on the total preparation. In addition, when the compound of the present invention and the concomitant drug are separately formulated, the contents may be similar.

[0285] Examples of concomitant drugs include the following: narcolepsy treatment drugs (e.g., methylphenidate, amphetamine, pemoline, phenelzine, protriptyline, sodium oxybate, modafinil, caffeine), antiobesity drugs (amphetamine, benzphetamine, bromoclopridine, bupropion, diethylpropion, exenatide, fenfluramine, liothyronine, liraglutide, mazindol, methamphetamine, octreotide, orlistat, phendimetrazine, phenmetrazine, phentermine, Qnexa (registered trademark), phenylpropanolamine, pramlintide, propylhexedrine, recombinant leptin, sibutramine, topiramate, zimelidine, zonisamide, lorcaserin, metformin), acetylcholinesterase inhibitors (e.g., donepezil, rivastigmine, galantamine, zanapezil, idebenone, tacrine), anti-dementia drugs (e.g., memantine), β-amyloid protein production, secretion, accumulation, aggregation and / or deposition inhibitors, β-secretase inhibitors (e.g., 6-(4-biphenylyl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6- (4-biphenylyl)methoxy-2-(N,N-dimethylamino)methyltetralin, 6-(4-biphenylyl)methoxy-2-(N,N-dipropylamino)methyltetralin, 2-(N,N-dimethylamino)methyl-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(4-biphenylyl)methoxy-2-[2-(N,N-diethylamino)ethyl]tetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methylbiphenyl-4-yl)methoxytetralin, 2-[2-(N,N-dimethylamino)ethyl]-6-(4'-methoxybiphenyl-4-yl)methoxytetralin, 6-(2',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N ,N-dimethylamino)ethyl]tetralin, 6-[4-(1,3-benzodioxol-5-yl)phenyl]methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, 6-(3',4'-dimethoxybiphenyl-4-yl)methoxy-2-[2-(N,N-dimethylamino)ethyl]tetralin, optically active forms thereof, salts thereof and hydrates thereof, OM99-2 (International Publication No. 01 / 00663)), gamma secretase inhibitors, beta amyloid protein aggregation inhibitors (e.g., PTI-00703, ALZHEMED (NC-531), PPI-368 (JP Patent Publication No. Hei 11-514333), PPI-558 (JP Patent Publication No. 2001-500852), SKF-74652 (Biochem.J.(1999),340(1),283-289), beta-amyloid vaccines, beta-amyloid decomposing enzymes, brain function enhancers (e.g., aniracetam, nicergoline), Parkinson's disease treatment drugs [(e.g., dopamine receptor agonists (e.g., L-dopa, bromocriptine, pergolide, talipexole, pramipexole, cabergoline, amantadine), monoamine oxidase (MAO) inhibitors (e.g., deprenyl, sergiline (selegiline), remacemide, riluzole), anticholinergics (e.g., trihexyphenidyl, biperiden), COMT inhibitors (e.g., entacapone)], amyotrophic lateral sclerosis treatment drugs (e.g., riluzole, neurotrophic factors), treatment drugs 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., leteprinim, xaliproden (SR-57746-A), SB-216763, Y-128, VX-853, prosaptide, 5,6-dimethoxy-2-[2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 5,6-dimethoxy-2-[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl]isoindoline, 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 forms, salts, hydrates), nonsteroidal anti-inflammatory drugs (meloxicam, tenoxicam, indomethacin, ibuprofen, celecoxib, rofecoxib, aspirin, etc.), steroid drugs (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., sildenafil citrate, ), dopamine agonists (e.g., apomorphine), antiarrhythmics (e.g., mexiletine), sex hormones or their derivatives (e.g., progesterone, estradiol, estradiol benzoate), osteoporosis treatments (e.g., alphacalcidol, calcitriol, elcatonin, salmon calcitonin, estriol, ipriflavone, pamidronate disodium, alendronate sodium hydrate, incadronate disodium), parathyroid hormone (PTH), calcium receptor antagonists, insomnia treatments (e.g., benzodiazepines, non-benzodiazepines, antipsychotics (e.g., typical antipsychotics such as haloperidol; atypical antipsychotics such as clozapine, olanzapine, risperidone, and aripiprazole; drugs acting on metabotropic or ionotropic glutamate receptors; phosphodiesterase inhibitors), benzodiazepines Drugs related to azepam (chlordiazepoxide, diazepam, potassium clorazepate, lorazepam, lonazepam, alprazolam, etc.), L-type calcium channel blockers (pregabalin, etc.), tricyclic or tetracyclic antidepressants (imipramine hydrochloride, amitriptyline hydrochloride, desipramine hydrochloride, clomipramine hydrochloride, etc.), selective serotonin reuptake inhibitors (fluvoxamine maleate, fluoxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, paroxetine hydrochloride, escitalopram oxalate, etc.), serotonin-noradrenaline reuptake inhibitors (venlafaxine hydrochloride, duloxetine hydrochloride, desvenlafaxine hydrochloride, etc.), noradrenaline reuptake inhibitors (reboxetine mesylate, etc.), mirtazapine, trazodone hydrochloride, nefazodone hydrochloride, bupropion hydrochloride, setiptiline maleate, 5-HT 1A Agonists (buspirone hydrochloride, tandospirone citrate, osemozotan hydrochloride, etc.), 5-HT 2A Antagonist, 5-HT 2AInverse agonists, 5-HT3 antagonists (e.g. cyamemazine), non-cardioselective beta blockers (e.g. propranolol hydrochloride, oxyprenolol hydrochloride), histamine H1 antagonists (e.g. hydroxyzine hydrochloride), CRF antagonists, other anxiolytics (e.g. meprobamate), tachykinin antagonists (e.g. MK-869, saredutant), drugs acting on metabotropic glutamate receptors, CCK antagonists, beta3 adrenergic antagonists (e.g. amibegron hydrochloride), GAT-1 inhibitors (e.g. tiagabine 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, pheneridine ... carbamate, etc.), cannabinoid CB1 antagonists (rimonabant, etc.), FAAH inhibitors, sodium channel blockers, anti-ADHD drugs (methylphenidate hydrochloride, methamphetamine hydrochloride, etc.), drugs for alcoholism, drugs for autism, drugs for chronic fatigue syndrome, drugs for convulsions, drugs for fibromyalgia, drugs for headaches, drugs for smoking cessation, drugs for myasthenia gravis, drugs for cerebral infarction, drugs for mania, drugs for hypersomnia, drugs for pain, drugs for dysthymia, drugs for autonomic nervous system disorders, drugs for male and female sexual dysfunction, drugs for migraines, drugs for pathological gambling, drugs for leg immobility Drugs for impotence syndrome, drugs for substance addiction, drugs for alcohol-related diseases, drugs for irritable bowel syndrome, drugs for dyslipidemia such as cholesterol-lowering drugs (statin series (pravastatin sodium, atorvastatin, simvastatin, rosuvastatin, etc.), fibrates (clofibrate, etc.), squalene synthesis inhibitors), drugs for abnormal behavior or drugs to suppress wandering due to dementia (sedatives, anti-anxiety drugs, etc.), drugs for diabetes, drugs for diabetic complications, drugs for hypertension, drugs for hypotension, diuretics, chemotherapy agents, immunotherapy agents, antithrombotic agents, anticancer agents, etc.

[0286] The above-mentioned concomitant drugs may be used in combination of two or more kinds in an appropriate ratio. Furthermore, when the compound of the present invention is applied to each of the above-mentioned diseases, it can be used in combination with a biological preparation (e.g., an antibody drug, a nucleic acid or a nucleic acid derivative, an aptamer drug, or a vaccine preparation), and can also be used in combination with a gene therapy method or the like, or in combination with a drug-free psychiatric therapy. Examples of antibody drugs and vaccine preparations include vaccine preparations against angiotensin II, vaccine preparations against CETP, CETP antibodies, antibodies against TNFα antibodies and other cytokines, amyloid β vaccine preparations, type 1 diabetes vaccines (e.g., DIAPEP-277 by Peptor), 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 related to enzymes and proteins involved in blood coagulation and fibrinolysis systems, antibodies or vaccine preparations against proteins involved in sugar metabolism and insulin resistance, etc. In addition, they can be used in combination with biological preparations related to growth factors such as GH and IGF. Examples of gene therapy include those using genes related to cytokines, renin-angiotensin system enzymes and their products, G proteins, G protein-coupled receptors and their phosphorylating enzymes. These include therapies 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), therapies using genes related to enzymes and proteins involved in angiogenesis therapy for peripheral vascular occlusion etc. (e.g., growth factors such as HGF and VEGF), therapies using genes related to proteins involved in glucose metabolism and insulin resistance, and antisense therapy against cytokines such as TNF. Non-drug psychiatric treatments include modified electroconvulsive therapy, deep brain stimulation, repetitive transcranial magnetic stimulation, and psychotherapy including cognitive behavioral therapy. In addition, the compound of the present invention can be used in combination with various organ regeneration methods such as cardiac regeneration, renal regeneration, pancreatic regeneration, and vascular regeneration, 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, cardiomyocyte sheets). EXAMPLES

[0287] The present invention will be further explained 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" generally refers to about 10° C. to about 35° C. Ratios shown in mixed solvents are by volume unless otherwise specified. % refers to weight % unless otherwise specified.

[0288] In the examples, elution in column chromatography was performed under observation by TLC (Thin Layer Chromatography) unless otherwise specified. In the TLC observation, a 60 F TLC plate manufactured by Merck was used. 254 The solvent used in the column chromatography was used as the developing solvent. A UV detector was used for detection. In silica gel column chromatography, aminopropylsilane-bonded silica gel was used when NH was used, and 3-(2,3-dihydroxypropoxy)propylsilane-bonded silica gel was used when DIOL was used. For preparative HPLC (high performance liquid chromatography), a 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 mobile phase was 0.05% aqueous ammonia / MeCN. Decyl-bonded silica gel was used. The ratios shown in the elution solvents are by volume unless otherwise specified.

[0289] 1 H NMR analysis was performed using ACD / SpecManager (trade name) software, etc. Peaks with very gentle proton peaks such as hydroxyl and amino groups may not be recorded. MS was measured by LC / MS. ESI or APCI was used as the ionization method. Data shows actual measurements (found values). Molecular ion peaks are usually observed, but may be observed as fragment ions. In the case of salts, free molecular ion peaks or fragment ion peaks are usually 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 H NMR: Proton nuclear magnetic resonance LC / MS: Liquid chromatograph 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'-biphenyl (phenyl)[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 on carbon Na2SO4 : Anhydrous sodium sulfate NaBH4: Sodium borohydride LiBH4: Lithium borohydride PPh3: Triphenylphosphine DIAD: Diisopropyl azodicarboxylate rt: room temperature EtOAc: Ethyl acetate Tf2O: Trifluoromethanesulfonic anhydride TBAF: Tetrabutylammonium fluoride SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene (S,S)-pybox(iPr): (S,S)-2,6-bis(4-isopropyl-2-oxazolin-2-yl)pyridine Pd(OH)2: Palladium(II) hydroxide Lindlar 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: Butyl lithium

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

[0292] A) tert-Butyl (S)-3-(methylsulfonamido)pyrrolidine-1-carboxylate tert-Butyl (S)-3-aminopyrrolidine-1-carboxylate (4.93 g) and THF (20 mL) To the mixture, triethylamine (5.53 mL) and methanesulfonic anhydride (4.61 g) were added at 0° C., and the mixture was stirred at room temperature for 3 hours. The mixture was diluted with ethyl acetate and water at 0° C., and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, passed through a silica gel pad, and concentrated under reduced pressure to give 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-(pyrrolidin-3-yl)methanesulfonamide hydrochloride tert-Butyl (S)-3-(methylsulfonamido)pyrrolidine-1-carboxylate (6.39 g) A mixture of 4 M hydrogen chloride in ethyl acetate (72.5 mL) was stirred at room temperature overnight. To the resulting suspension was added heptane (50 mL) with stirring, and the precipitate was collected and washed with ethyl acetate. The extract was evaporated and 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 To a mixture of potassium tert-butoxide (42.2 g) and DMSO (400 mL), trimethylsulfoxonium iodide (82.8 g) was added little by little at room temperature. After stirring at the same temperature for 1 hour, ethyl acetate was added. Add a solution of (E)-3-(2-bromophenyl)acrylate (80.0 g) in DMSO (400 mL) and The mixture was 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, 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) was dissolved in 100 mL of water. To the mixture, Xphos Pd G3 (1.57 g) and potassium phosphate tribasic (11.8 g) were added and the mixture was stirred at 100 °C for 12 hours under nitrogen atmosphere. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with brine. After washing, it 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 To 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), aqueous sodium hydroxide solution (4.93 g / 20 mL) was added and stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure, diluted with water, adjusted to pH 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]pyrrolidin-3-yl}methanesulfonamide and N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide rac-(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxamide To a mixture of carboxylic acid (2.00 g), (S)-N-(pyrrolidin-3-yl)methanesulfonamide hydrochloride (1.46 g), HATU (2.91 g) and DMF (15 mL), DIPEA (3.77 g) was added and stirred at room temperature for 12 hours. The mixture was purified by reversed-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]pyrrolidin-3-yl}methanesulfonamide N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide and N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide A mixture of 1,2-dichloromethanesulfonamides (4.10 g) was purified by SFC (column: Phenomenex-Cellulose-2, 250 mm x 50 mm, 10 μm, mobile phase: CO2 / EtOH containing 0.1% aqueous ammonia = 55 / 45 v / v). The fraction with the shortest retention time was collected and concentrated. The residue was dissolved in MeCN (10 mL) and water (50 mL) and lyophilized. The resulting solid was triturated with petroleum ether / ethyl acetate to give the title compound. The 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]piperidin-3-yl}methanesulfonamide

[0300] A) tert-Butyl (S)-3-(methylsulfonamido)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 at room temperature overnight. The mixture was diluted with ethyl acetate and water at 0° C., and then extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, passed through a silica gel pad, and concentrated under reduced pressure to obtain the title compound (14.9 g). 1 H NMR (300 MHz, CDCl3) δ 1.40-1.80 (12H, m), 1.87-2.01 (1H, m), 3.01 (3H, s), 3.19-3.34 (2H, m), 3.35-3.57 (2H, m), 3.62-3.75 (1H, m), 4.54 (1H, br d, J = 6.0 Hz).

[0301] B) (S)-N-(piperidin-3-yl)methanesulfonamide hydrochloride tert-Butyl (S)-3-(methylsulfonamido)piperidine-1-carboxylate (14.9 g) A mixture of 4 M hydrogen chloride in CPME (134 mL) was stirred at room temperature for 3 h. The CPME was removed by decantation, and the remaining gummy material was dried to give 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]piperidin-3-yl}methanesulfonamide and N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]piperidin-3-yl}methanesulfonamide rac-(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxamide To a mixture of carboxylic acid (3.00 g), (S)-N-(piperidin-3-yl)methanesulfonamide hydrochloride (2.35 g), HATU (4.37 g) and DMF (30 mL), DIPEA (5.65 g) was added 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]piperidin-3-yl}methanesulfonamide N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]piperidin-3-yl}methanesulfonamide and N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]piperidin-3-yl}methanesulfonamide A mixture of 1,2-dichloromethanesulfonamides (4.93 g) was separated by SFC (column: Phenomenex-Cellulose-2, 250 mm x 50 mm, 10 μm, mobile phase: CO2 / EtOH containing 0.1% aqueous ammonia = 55 / 45 v / v). The fraction with the shortest retention time was concentrated, and the residue was dissolved in MeCN (10 mL) and water (50 mL) and lyophilized to give the title compound (1.56 g). 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-(methylsulfonamido)azepane-1-carboxylate A mixture of tert-butyl 4-aminoazepane-1-carboxylate (20.0 g) and DCM (180 mL) Triethylamine (18.9 g) and methanesulfonyl chloride (13.9 g) were added to the mixture at 0 °C. The mixture was stirred at room temperature for 16 h. The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine. After washing, it 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-(methylsulfonamido)azepane-1-carboxylate (28.5 g) and 4 M hydrogen chloride in dioxane (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) 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-carboxamide To a mixture of carboxylic acid (150 mg), N-(azepan-4-yl)methanesulfonamide hydrochloride (150 mg), DIPEA (212 mg) and DMF (5.0 mL), HATU (312 mg) was added at 0°C and the mixture was stirred at room temperature for 12 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 preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to obtain the title compound (105 mg). 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)cyclopropane A mixture of rac-N-{(4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]azepan-4-yl}methanesulfonamide (105 mg) was separated by SFC (column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 5 μm, mobile phase: CO2 / 0.1% ammonia water containing MeOH = 45 / 55 v / v), and the fraction with the shortest retention time was concentrated. The residue was dissolved in MeCN (3.0 mL) and water (3.0 mL) and lyophilized to obtain the crude product (45 mg). This was further fractionated by SFC (column: DAICEL CHIRALPAK IG, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / IPA containing 0.1% aqueous ammonia = 60 / 40 v / v), and the fraction with the shortest retention time was concentrated. The residue was dissolved in 1.0 mL of ethyl acetate and water (3.0 mL) and lyophilized to give the title compound (13 mg). 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-{(3S)-1-[(1S,2S)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide, Rolidin-3-yl}methanesulfonamide

[0310] A) Ethyl (2E)-3-(2-bromo-6-fluorophenyl)prop-2-enoate A mixture of ethyl 2-diethoxyphosphorylacetate (64.6 g) and THF (450 mL) was added to 60% NaH (10.6 g) was added at 0° C. After stirring at room temperature for 15 minutes, 2-bromo-6-fluorobenzoate was added. Aldehyde (45.0 g) was added and 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)prop-2-enoate (29.8 g) in DMSO (250 mL) was added and the mixture was further stirred at the same temperature for 6 hours. The reaction was stopped by adding a saturated aqueous solution of ammonium chloride. The mixture was quenched and extracted with ethyl acetate. The organic layer was washed with saline, 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 twice in 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-carboxylate ethyl acetate (15.0 g), 2,6-difluorophenylboronic acid (33.0 g), and DME (100 mL). To the mixture, an aqueous solution of potassium phosphate tribasic (33.3 g / 100 mL) and Xphos Pd G3 (4.42 g) were added and stirred at 100 °C for 16 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was diluted with ethyl acetate and diluted with ethanol. After washing with brine, the mixture was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% Ammonia water / MeCN) and freeze-dried to give the title compound (2.00 g). 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 purified by SFC (column: DAICEL CHIRALCEL OD-H, 250 mm x 30 The eluate was separated using a mobile phase of CO2 / IPA containing 0.1% aqueous ammonia (90 / 10 v / v) (mm, 5 μm), and the fraction with the longest 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]pyrrolidin-3-yl}methanesulfonamide, or N-{(3S)-1-[(1S,2S)-2-(2',3,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl] Pyrrolidin-3-yl}methanesulfonamide (S)-N-(pyrrolidin-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- To a mixture of carboxylic acid (80.0 mg) and DMF (3 mL), HATU (125 mg) and DIPEA (106 mg) were added. The mixture was stirred at room temperature for 16 hours. The reaction was stopped by adding water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to obtain the title compound (70.5 mg). . 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-{(3S)-1-[(1S,2S)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide, Rolidin-3-yl}methanesulfonamide

[0317] A) Ethyl (2E)-3-(2-bromo-4-fluorophenyl)prop-2-enoate A mixture of ethyl 2-diethoxyphosphorylacetate (35.9 g) and THF (250 mL) was added to 60% NaH (5.91 g) was added at 0° C. After stirring at room temperature for 15 min, 2-bromo-4-fluorobenzoate was added. 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). 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 To a mixture of potassium tert-butoxide (18.5 g) and DMSO (150 mL), trimethylsulfoxonium iodide (36.2 g) was added at room temperature. After stirring at the same temperature for 30 minutes, a mixture of ethyl (2E)-3-(2-bromo-4-fluorophenyl)prop-2-enoate (37.4 g) and DMSO (150 mL) was added and stirred at the same temperature for another 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-carboxylate To a mixture of bis(pinacolato)diboron (5.00 g), bis(pinacolato)diboron (6.63 g) and DMSO (50 mL), , [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) Fluoromethane complex (1.42 g) and potassium acetate (3.42 g) were added and stirred at 100 °C under 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-dioxaborola 1,3-Difluoro-2-phenyl)phenyl]cyclopropane-1-carboxylate (3.96 g) To a mixture of -iodobenzene (2.84 g) and DME (35 mL), Xphos Pd G3 (1.00 g) and potassium phosphate tribasic (7.55 g) were added and stirred at 100 °C for 16 hours under a nitrogen atmosphere. The mixture was diluted with water. The mixture was diluted with ethyl acetate 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 In a mixture of sodium hydroxide (578 mg), EtOH (20 mL), and water (5 mL), rac-ethyl (1R,2R)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate (2.32 g) was added and stirred at room temperature for 5 hours. The mixture was diluted with water, adjusted to pH 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- The carboxylic acid (500 mg) was separated by SFC (column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / MeOH containing 0.1% aqueous ammonia = 80 / 20 v / v), and the fraction with the shortest 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]pyrrolidin-3-yl}methanesulfonamide, or N-{(3S)-1-[(1S,2S)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl] Pyrrolidin-3-yl}methanesulfonamide The rel-(1R,2R)-2-(2',5,6'-trifluoro[1,1'-biphenyl]-2-yl)cyclopentadiene obtained in step F Propane-1-carboxylic acid (30.0 mg), (S)-N-(pyrrolidin-3-yl)methanesulfonamide To a mixture of hydrochloride (20.6 mg) and DMF (1 mL), HATU (39.0 mg) and DIPEA (66.3 mg) were added at 0.05 mL. The mixture was added at 0.5 °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 purified by preparative HPLC (C18, 0.05% ammonia). The extract was purified with aqueous sodium hydroxide / MeCN and lyophilized to give 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-difluoropiperidin-3-yl}methanesulfonamide or N-{(3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidin-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-difluoropiperidin-3-yl}carbamate and tert-Butyl Mixture of aryl{(3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidin-3-yl}carbamate rac-(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxamide carboxylic acid (80 mg), tert-butyl N-[(3R)-4,4-difluoro-3-piperidyl]carbamate (83 To a mixture of 1,3-dimethylphenylsulfate (1,3-dimethylphenylsulfate) 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (200 mg). 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-difluoropiperidin-3-yl}methanesulfonamide and N-{(3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidin-3-yl}methanesulfonamide tert-Butyl {(3R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclohexyl A mixture of tert-butyl {(3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidin-3-yl}carbamate (200 mg), trifluoropropane-1-carbonyl]-4,4-difluoropiperidin-3-yl}carbamate, 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 give a mixture of [(3R)-3-amino-4,4-difluoropiperidin-1-yl][(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate and [(3R)-3-amino-4,4-difluoropiperidin-1-yl][(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate (201 mg). To a mixture of [(3R)-3-amino-4,4-difluoropiperidin-1-yl][(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate and [(3R)-3-amino-4,4-difluoropiperidin-1-yl][(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate (201 mg) and DCM (5 mL), methanesulfonyl chloride (68 mg) and TEA (161 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to obtain the title compound (38.9 mg). 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-difluoropiperidin-3-yl}methanesulfonamide, or N-{(3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidin-3-yl}methanesulfonamide Bornyl]-4,4-difluoropiperidin-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-difluoropiperidin-3-yl}methanesulfonamide and N-{(3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4,4-difluoropiperidin-3-yl}methanesulfonamide (37 mg) was separated by SFC (column: DAICEL CHIRALPAK IG, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / 0.1% ammonia water containing EtOH = 70 / 30 v / v), and the fraction with the shorter retention time was concentrated. The residue was eluted with MeCN (1 mL) and water. (30 mL) and lyophilized to give 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-fluoropiperidin-3-yl}methanesulfonamide or N-{(3R,4S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-fluoropiperidin-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-fluoropiperidin-3-yl}carbamate and tert-butyl {(3R,4S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane Mixture of 4-fluoro-1-carbonyl-4-fluoropiperidin-3-yl}carbamates rac-(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxamide To a mixture of 1,2-dihydro-3-piperidyl]carbamate (96 mg), and DMF (3 mL), HOBt (49 mg), EDCI (105 mg), and TEA (148 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to obtain the title compound (215 mg). Got it. MS, found: 375.1.

[0330] B) N-{(3R,4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane Mixture of N-{(3R,4S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-fluoropiperidin-3-yl}methanesulfonamide tert-Butyl {(3R,4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-fluoropiperidin-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-fluoropiperidin-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 give [(3R,4S)-3-amino-4-fluoropiperidin-1-yl][(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate and [(3R,4S)-3-amino-4-fluoropiperidin-1-yl][(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate. A mixture of phenyl-2-yl)cyclopropyl]methanone trifluoroacetate (250 mg) Got it. [(3R,4S)-3-amino-4-fluoropiperidin-1-yl][(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate and [(3R,4S)-3-amino-4-fluoropiperidin-1-yl][(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate A mixture of 1,3-diphenylcyclopropylmethanone trifluoroacetate (250 mg) and DCM (5 mL) To the mixture, methanesulfonyl chloride (115 mg) and TEA (270 mg) were added and the mixture was stirred at room temperature for 13 hours. The mixture was stirred for 1 hour. 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) and lyophilized to obtain the title compound (47.2 mg). MS: [M+H] + 453.2.

[0331] C) N-{(3R,4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane Pan-1-carbonyl]-4-fluoropiperidin-3-yl}methanesulfonamide, or N-{(3R,4S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-fluoropiperidin-3-yl}methanesulfonamide N-{(3R,4S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-fluoropiperidin-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 ]-4-fluoropiperidin-3-yl}methanesulfonamide (44 mg) was subjected to SFC (column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / 0.1% ammonia water The fraction with a shorter retention time was concentrated, and the residue was dissolved in MeCN (1 mL) and water (30 mL) and lyophilized 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)cyclopropane Pan-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide Optical Isomers

[0333] A) 1-benzyl-4,4-difluoropyrrolidin-3-yl trifluoromethanesulfonate To a mixture of 1-benzyl-4,4-difluoropyrrolidin-3-ol (1.50 g) and DCM (50 mL), a mixture of pyridine (2.78 g), trifluoromethanesulfonic anhydride (6.95 g) and DCM (5.0 mL) was 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. The organic layer was washed with 5% aqueous citric acid and brine, then dried over sodium sulfate. The extract was 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-difluoropyrrolidin-3-yl trifluoromethanesulfonate (1.8 To a mixture of 1,2-dichloromethane (1.2 mL) 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 washed with brine. After washing, it 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-difluoropyrrolidin-3-yl]methanesulfonamide To a mixture of 4-azido-1-benzyl-3,3-difluoropyrrolidine (500 mg), THF (15 mL), and water (2.0 mL), triphenylphosphine (2.19 g, 20% purity in resin) was added and the mixture was stirred for 70 The mixture was stirred for 12 hours at ° C. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give 1-benzyl-4,4-difluoropyrrolidin-3-amine (460 mg). 1-benzyl-4,4-difluoropyrrolidin-3-amine (860 mg), TEA (820 mg), and DCM (10 mL) was added methanesulfonyl chloride (650 mg) at 0°C and then stirred at room temperature for 1 hour. The mixture was diluted with water and extracted with DCM. The organic layer was washed with brine and then with sodium sulfate. The mixture was dried over sodium chloride and concentrated under reduced pressure, and 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-difluoropyrrolidin-3-yl]methanesulfonamide rac-N-[(3S)-1-benzyl-4,4-difluoropyrrolidin-3-yl]methanesulfonamide (800 mg) was separated by SFC (column: DAICEL CHIRALPAK AD, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / EtOH containing 0.1% aqueous ammonia = 85 / 15 v / v), and the fraction with a long retention time was The residue was dissolved in MeCN (3.0 mL) and water (3.0 mL) and lyophilized to give the title compound (368 mg). 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]pyrrolidin-3-yl}methanesulfonamide optical isomers rel-N-[(3R)-1-benzyl-4,4-difluoropyrrolidin-3-yl]methane synthesized in step D To a mixture of sulfonamide (368 mg) and 12 M hydrogen chloride in EtOH (5.0 mL), 10% Pd / C (50 mg) was added and stirred at room temperature under hydrogen atmosphere (15 psi) for 3 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to give rel-N-[(3R)-4,4-difluoropyrrolidin-3-yl]methanesulfonamide. The hydrochloride salt (305 mg) was obtained. To 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), HATU (59 mg), DIPEA (53 mg), and the above rel-N-[(3R)-4,4-difluoropyrrolidin-3-yl]methyl Tansulfonamide hydrochloride (38 mg) was added and stirred at room temperature for 14 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 preparative HPLC (C18, 0.05% ammonia water / MeCN) and lyophilized to obtain the title compound (23.9 mg). 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-fluoropiperidin-3-yl}methanesulfonamide

[0339] 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-isopropyl) A mixture of 2-bromostyrene (20.0 g) and THF (100 mL) was added dropwise to a mixture of 3-(2-oxazolin-2-yl)pyridine (1.71 g) and THF (200 mL) under a nitrogen atmosphere at 20 °C. The mixture was heated to 55 °C, and ethyl diazoacetate (31.2 g) and toluene (200 A mixture of 10% acetic acid (50 mL) was added dropwise under nitrogen atmosphere over 3 hours. The mixture was stirred at 55 °C for 14 hours. The mixture was cooled and quenched with 10% aqueous acetic acid (50 mL). 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 give 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- Carboxylate and ethyl (1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)silyl Chloropropane-1-carboxylate mixture 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) was added with 2,6-difluorophenylboronic acid (17.6 g), Xphos Pd G3 (3.15 g), and 1 M aqueous potassium phosphate solution (112 mL), and the mixture was heated at 100 °C under nitrogen atmosphere for 14 h. The mixture was cooled to room temperature, and 2,6-difluorophenylboronic acid (17.6 g), Xphos Pd G3 (3.15 g), and 1 M aqueous potassium phosphate (112 mL) were added, followed by stirring at 100 °C under nitrogen for an additional 14 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) and then by reversed-phase silica gel column chromatography. The residue was purified by chromatography (C18, methanol / water) to give 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- Carboxylate 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)cyclopropane-1-carboxylate The mixture of 1-propane-1-carboxylates (7.52 g) was separated by SFC (column: DAICEL CHIRALPAK IC, 250 mm x 50 mm, 10 μm, mobile phase: CO2 / IPA containing 0.1% aqueous ammonia = 85 / 15 v / v), and the fraction with the longest 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) was diluted with aqueous sodium hydroxide (8.61 g / 50 mL) was added and stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, diluted with water, and diluted with 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 and Concentration under reduced pressure gave 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-fluoropiperidin-3-yl}carbamate (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxane To a mixture of 5-fluoro-3-piperidyl-2-phenylpropanediol (40 mg), tert-butyl N-[(3S,5R)-5-fluoro-3-piperidyl]carbamate (35 mg), and DMF (2 mL) was added 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (ethyl acetate / petroleum ether) to obtain the title compound (48 mg). MS, found: 375.0.

[0344] F) N-{(3S,5R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane Pan-1-carbonyl]-5-fluoropiperidin-3-yl}methanesulfonamide To a mixture of tert-butyl {(3S,5R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-5-fluoropiperidin-3-yl}carbamate (48 mg) and DCM (1 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give [(3S,5R)-3-amino-5-fluoropiperidin-1-yl][(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetic acid. The acid salt (58 mg) was obtained. To a mixture of [(3S,5R)-3-amino-5-fluoropiperidin-1-yl][(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropyl]methanone trifluoroacetate (58 mg) and DCM (5 mL), TEA (48 mg) and methanesulfonyl chloride (20 mg) were added 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% ammonia). Water / MeCN) and lyophilized to give 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]pyrrol-4-yl}methanesulfonamide optical isomers

[0346] A) rac-tert-butyl(3aR,4S,6aS)-4-[(methanesulfonyl)amino]hexahydrocyclopentadiene pent[c]pyrrole-2(1H)-carboxylate To a mixture of rac-tert-butyl (3aR,4S,6aS)-4-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (500 mg) and THF (8 mL), methanesulfonyl chloride (301 mg) and TEA (447 mg) were added 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether) to give the title compound. The compound (664 mg) was obtained. MS, found: 249.0.

[0347] B) rac-N-[(3aR,4S,6aS)-Octahydrocyclopenta[c]pyrrol-4-yl]methanesulfonamide trifluoroacetate To a mixture of rac-tert-butyl (3aR,4S,6aS)-4-[(methanesulfonyl)amino]hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (664 mg) and DCM (12 mL), trifluoroacetic acid (6 mL) was added and stirred at room temperature for 12 hours. The mixture was concentrated under reduced pressure to give 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]pyrrol-4-yl}methanesulfonate Mixture of rac-N-{(3aS,4R,6aR)-2-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]octahydrocyclopenta[c]pyrrol-4-yl}methanesulfonamide rac-(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxamide carboxylic acid (43 mg), rac-N-[(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-yl] To a mixture of methanesulfonamide trifluoroacetate (50 mg), HATU (63 mg), and DMF (3 mL), DIPEA (81 mg) was added 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 saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% ammonia water / MeCN), lyophilized, and the title compound was obtained. (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]pyrrol-4-yl}methanesulfonamide optical isomer rac-N-{(3aR,4S,6aS)-2-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)silyl cyclopropane-1-carbonyl]octahydrocyclopenta[c]pyrrol-4-yl}methanesulfonate A mixture of 250 mg of 1,3-difluoro-2,4-N-{(3aS,4R,6aR)-2-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]octahydrocyclopenta[c]pyrrol-4-yl}methanesulfonamide was separated by SFC (column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / 0.1% aqueous ammonia in EtOH = 55 / 45 v / v), and the first and second fractions with the highest retention times were concentrated as a mixture. This was then further purified by SFC ( Column: DAICEL CHIRALPAK IC, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / EtOH containing 0.1% ammonia water = 60 / 40 v / v), fractions with longer retention times were collected and concentrated. The residue was dissolved in MeCN (10 mL) and water (50 mL) and lyophilized to obtain the title compound (36.7 mg). 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]azetidin-2-yl}methyl)-N,N-dimethylsulfuric acid diamide

[0351] A) tert-Butyl (S)-2-(((N,N-dimethylsulfamoyl)amino)methyl)azetidine-1-carboxylate To a mixture of (S)-2-aminomethyl-1-Boc-azetidine (509 mg), DMAP (66.8 mg), TEA (1.14 mL) and THF (12 mL), N,N-dimethylsulfamoyl chloride (0.440 mL) was added at 0°C, and the mixture was stirred at room temperature overnight. The reaction was quenched by adding saturated aqueous sodium bicarbonate at 0°C, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). The mixture was purified by HPLC (Sun) 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]azetidin-2-yl}methyl)-N,N-dimethylsulfuric acid diamide tert-Butyl (S)-2-(((N,N-dimethylsulfamoyl)amino)methyl)azetidine-1-carboxylate A mixture of carboxylate (104 mg) and trifluoroacetic acid (0.500 mL) was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and coevaporated with toluene. The resulting residue (67.6 mg), (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxamide, was A mixture of carboxylic acid (106 mg), HATU (160 mg), TEA (0.146 mL), and DMF (2 mL) was added at room temperature. The mixture was stirred overnight at rt. The reaction was quenched by adding water and extracted with ethyl acetate. 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 / hexane) and silica gel column chromatography. (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-methylpyrrolidin-3-yl}methanesulfonamide

[0354] A) N-[(3S,5S)-5-Methylpyrrolidin-3-yl]methanesulfonamide trifluoroacetate To a mixture of tert-butyl (2S,4S)-4-amino-2-methylpyrrolidine-1-carboxylate (50 mg), TEA (51 mg) and DCM (5 mL) was added methanesulfonyl chloride (43 mg) at 0 °C. The mixture was added in an amount of 1.0 mL, 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 brine, dried over sodium sulfate, concentrated under reduced pressure, and purified with tert-butyl(2S,4S)-4-[(methanthracene)-2-yl]-2,4-dihydro-2,4-trimethylsilyl]propanediol. The crude product was 2-methyl-1-pyrrolidine-1-carboxylate (83 mg). To a mixture of tert-butyl (2S,4S)-4-[(methanesulfonyl)amino]-2-methylpyrrolidine-1-carboxylate (83 mg) and DCM (3 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give 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)cyclopropane Pan-1-carbonyl]-5-methylpyrrolidin-3-yl}methanesulfonamide N-[(3S,5S)-5-Methylpyrrolidin-3-yl]methanesulfonamide trifluoroacetate (93 mg), (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate To a mixture of carboxylic acid (87 mg) and DMF (5 mL), EDCI (73 mg), HOBt (52 mg), and TEA (129 mg) were added 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, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (34.2 mg). obtained. 1H NMR (400 MHz, CDCl3) δ 1.10-1.27 (3H, m), 1.29-1.56 (3H, m), 1.88-1.95 (1H, m), 2.00-2.17 (1H, m), 2.32-2.48 (1H, m), 2.99 (3H, s), 3.33-3.45 (1H, m), 3.61-3.82 (1H, m), 3.95-4.24 (2H, m), 4.42-4.60 (1H, m), 6.92-7.26 (4H, m), 7.27-7.42 (3H, m).

[0356] Example 264 N-{(3S,4R)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]-4-methylpyrrolidin-3-yl}methanesulfonamide

[0357] A) N-[(3S,4R)-4-Methylpyrrolidin-3-yl]methanesulfonamide trifluoroacetate To a mixture of tert-butyl (3S,4R)-3-amino-4-methylpyrrolidine-1-carboxylate (60 mg), TEA (61 mg) and DCM (5 mL) was added methanesulfonyl chloride (51 mg) at 0 °C. The mixture was poured into water and extracted with ethyl acetate. After washing with saline, the mixture was dried over sodium sulfate and concentrated under reduced pressure to give tert-butyl(3S,4R)-3-[(methyl) To obtain 4-methylpyrrolidine-1-carboxylate (67 mg), 4-methyl-1-ethanesulfonylamino was obtained. To a mixture of tert-butyl (3S,4R)-3-[(methanesulfonyl)amino]-4-methylpyrrolidine-1-carboxylate (67 mg) and DCM (3 mL), trifluoroacetic acid (1 mL) was added and stirred at room temperature for 2 hours. The mixture was concentrated under reduced pressure to give 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)cyclopropane Pan-1-carbonyl]-4-methylpyrrolidin-3-yl}methanesulfonamide N-[(3S,4R)-4-Methylpyrrolidin-3-yl]methanesulfonamide trifluoroacetate (97 mg), (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxylate To a mixture of carboxylic acid (91 mg) and DMF (5 mL), EDCI (76 mg), HOBt (54 mg), and TEA (134 mg) were added 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, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to give the title compound (20.2 mg). obtained. 1 H NMR (400 MHz, CDCl3) δ 1.10-1.16 (3H, m), 1.24-1.30 (1H, m), 1.43-1.52 (1H, m), 1.61-1.71 (1H, m), 1.93-2.43 (2H, m), 2.84-3.33 (5H, m), 3.41-3.61 (1H, m), 3.66-3.79 (1H, m), 3.83-3.92 (1H, m), 4.45-4.63 (1H, m), 6.92-7.26 (4H, m), 7.29-7.41 (3H, m).

[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-(ethylsulfonamido)-1,4-oxazepane-4-carboxylate 4-Boc-6-amino-1,4-oxazepane (454 mg), DMAP (51.3 mg), TEA (0.878 mL) and To a mixture of ethanesulfonyl chloride (0.298 mL) and THF (7 mL) was added at 0 °C and the mixture was heated to room temperature. The reaction was quenched by adding saturated aqueous sodium bicarbonate at 0°C, and ethyl acetate was added. The organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane). 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-(ethylsulfonamido)-1,4-oxazepane-4-carboxylate (267 mg) and ethyl acetate (2 mL), add 2 M hydrogen chloride in CPME (4 mL) and heat at room temperature. The mixture was stirred overnight and the resulting solid was collected by filtration to give 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-carboxane To a mixture of 1,6-dimethyl-2,4-dihydro-1,4-oxazepan-6-ylethanesulfonamide hydrochloride (140 mg), 1,4-dioxazepan-6-ylethanesulfonamide hydrochloride (140 mg), 1,4-dihydro-2,4-dihydro-1,4-tetrahydrofuran (TEA) (0.319 mL) and 2 mL of DMF was added HATU (261 mg) at 0°C and incubated at the same temperature for 3 hours. The mixture was stirred for 1 hour. The reaction was stopped by adding water and extracted with ethyl acetate. 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 (NH, ethyl acetate / hexane) and fractionated by preparative HPLC (column: DAICEL CHIRALPAK IC, 250 mm x 20 mm, 5 μm, mobile phase: hexane / ethanol / diethylamine = 700 / 300 / 1 v / v / v), and the fraction with the shortest 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]pyrrolidin-3-yl}methanesulfonamide, or N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide Carbonyl]pyrrolidin-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) was treated with Xphos Pd G3 (6.82 g) and Potassium phosphate tribasic (51.3 g) was added and the mixture was stirred at 100° C. for 16 hours. The mixture was diluted with water, Extraction with ethyl acetate was performed. 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 (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-fluorosilicate Chloropropane-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 acetate was added. A mixture of azoacetate (10.9 g) and DCE (100 mL) was added dropwise at 70 °C over 6 h. The mixture was stirred at room temperature for 6 hours. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Purification by chromatography (ethyl acetate / petroleum ether) gave the crude product, which was further This was then purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN), and the fraction with a 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-fluorocyclohexyl Dipropane-1-carboxylate (800 mg) was separated by SFC (column: DAICEL CHIRALPAK IC, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / EtOH containing 0.1% aqueous ammonia = 80 / 20 v / v). The fraction 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-fluoro To a mixture of isocyclopropane-1-carboxylate (370 mg), MeOH (2 mL), THF (2 mL), and water (2 mL), sodium hydroxide (462 mg) was added and stirred at room temperature for 12 hours. The mixture was diluted with water, adjusted to pH 5-6 with 2 M hydrochloric acid, and extracted with ethyl acetate. It was dried over sodium sulfate and concentrated under reduced pressure to give 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-fluorophenyl cyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide, or N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide The rel-(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorophenyl ether synthesized in step C To a mixture of fluorocyclopropane-1-carboxylic acid (50 mg), (S)-N-(pyrrolidin-3-yl)methanesulfonamide hydrochloride (38 mg), and pyridine (2 mL), EDCI (49 mg) was added, and the mixture was cooled to 37°C. 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% Ammonia water / MeCN) and freeze-dried to give 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]piperidin-3-yl}methanesulfonamide, or N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]piperidin-3-yl}methanesulfonamide Carbonyl]piperidin-3-yl}methanesulfonamide EDCI (65.6 mg) was added to a mixture of rel-(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylic acid (50.0 mg) synthesized in step C of Example 304, (S)-N-(piperidin-3-yl)methanesulfonamide hydrochloride (38.5 mg), and pyridine (3 mL), and the mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (C 18, 0.05% aqueous ammonia / MeCN) and freeze-dried to obtain the title compound (28.8 mg). 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]pyrrolidin-3-yl}methanesulfonamide, or N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide 1-Bonyl]pyrrolidin-3-yl}methanesulfonamide

[0370] A) Ethyl (2E)-3-(2-bromo-4-methylphenyl)prop-2-enoate To a mixture of ethyl 2-diethoxyphosphoryl acetate (7.32 g) and THF (50 mL), 60% NaH (1.21 g) was added 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. Ethyl 2-diethoxyphosphoryl To a mixture of acetate (7.32 g) and THF (50 mL), 60% NaH (400 mg) was added and the mixture was cooled to 37°C. The reaction mixture was added to the mixture. After stirring at room temperature for 12 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 saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ethyl acetate). The mixture was purified by ethyl acetate (ether) to give 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 Trimethylsulfoxonium iodide was dissolved in a mixture of 60% NaH (1.06 g) and DMSO (50 mL). (7.97 g) was added at 0°C, and the mixture was stirred at room temperature for 30 minutes. Then, a mixture of ethyl (2E)-3-(2-bromo-4-methylphenyl)prop-2-enoate (6.50 g) and DMSO (40 mL) was added dropwise, and the same The mixture was stirred at room temperature for 14 hours. Water was added at 0° C. to terminate 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)cyclohexyl Propane-1-carboxylate rac-Ethyl (1R,2R)-2-(2-bromo-4-methylphenyl)cyclopropane-1-carboxylate 2,6-Difluorophenylboronic acid (1.39 g) was added to a mixture of ethyl acetate (500 mg) and DME (15 mL). 1M potassium phosphate aqueous solution (5.30 mL) and Xphos Pd G3 (150 mg) were added, and the mixture was stirred at 100 °C for 14 hours under a nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was After washing with brine, it 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 In a mixture of sodium hydroxide (132 mg), EtOH (4 mL), and water (3 mL), rac-ethyl (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 adjusted to pH 3 - The acid was adjusted to 4 and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to give the title compound. The 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)cyclohexyl N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide and N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl]cyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide 3-Nyl]pyrrolidin-3-yl}methanesulfonamide mixture rac-(1R,2R)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane To a mixture of 1-pyrrolidin-1-carboxylic acid (28 mg) and DMF (1 mL), (S)-N-(pyrrolidin-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 washed with sodium sulfate and diluted with ethyl acetate. The residue was purified by preparative HPLC (C18, 0.05% aqueous ammonia / MeCN) and lyophilized to obtain the title compound (16 mg). MS: [M+H] + 435.2.

[0375] F) N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclohexyl N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide, Carbonyl]pyrrolidin-3-yl}methanesulfonamide N-{(3S)-1-[(1R,2R)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide and N-{(3S)-1-[(1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)cyclopropane-1-carbonyl]pyrrolidin-3-yl}methanesulfonamide A mixture of [aryl]pyrrolidin-3-yl}methanesulfonamides (16 mg) was subjected to SFC (column: Phenomenex-Cellulose-2, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / MeOH containing 0.1% aqueous ammonia = The fraction with the shorter retention time was concentrated, and the residue was dissolved in MeCN (3 mL) and water (30 mL) and lyophilized to give 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-hydroxypiperidin-3-yl}methanesulfonamide

[0377] A) tert-Butyl (3S,5S)-3-hydroxy-5-[(methanesulfonyl)amino]piperidine-1-carboxylate Ruboxylate tert-Butyl (3S,5S)-3-amino-5-hydroxypiperidine-1-carboxylate (50 mg) To a mixture of 1,2-dichloromethane (1 mL) and DCM (3 mL), TEA (35 mg) and methanesulfonyl chloride (32 mg) were added at 0 °C. The mixture was added in an amount of 1.0 mL and stirred at room temperature for 2 hours. The mixture was diluted with water and extracted with DCM. 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 (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)cyclopropane Pan-1-carbonyl]-5-hydroxypiperidin-3-yl}methanesulfonamide To a mixture of tert-butyl (3S,5S)-3-hydroxy-5-[(methanesulfonyl)amino]piperidine-1-carboxylate (47 mg) and DCM (6 mL), trifluoroacetic acid (2 mL) was added and the mixture was cooled to room temperature. The mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure to give N-[(3S,5S)-5-hydroxypiperidin-3-yl]methanesulfonamide trifluoroacetate (75 mg). (1R,2R)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)cyclopropane-1-carboxane A mixture of the acid (50 mg), N-[(3S,5S)-5-hydroxypiperidin-3-yl]methanesulfonamide trifluoroacetate (67 mg), and DMF (2 mL) was added with HOBt (25 mg), EDCI (52 mg), and TEA (74 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 brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (C18, 0.05% ammonia water / MeCN) and lyophilized to obtain the title compound (27 mg). 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]azetidin-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) at 0 °C, HATU (8.50 g) was added followed by DIPEA (10.6 g), and the reaction mixture was stirred at 20 °C under N2 atmosphere for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine. The mixture was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc) to give tert-butyl (S)-2-(methoxy(methyl)carbamoyl)azetidine-1-carboxylate. The carboxylate (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) was added MeMgBr (22.3 mL 3 M in THF) at -78 °C. The reaction mixture was stirred under N2 atmosphere at 20° C. for 3 h. The reaction mixture was diluted with water and EtOAc The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give the title compound. The product (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 To a mixture of tert-butyl (S)-2-acetylazetidine-1-carboxylate (1.00 g) in MeOH (10 mL) was added NaBH4 (380 mg) at 0° C. The mixture was stirred at 0° C. for 1 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to give The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether) to give tert-butyl (S)-2-((R*)-1-hydroxyethyl)azetidine-1-carboxylate. The ester (430 mg, more polar on column) was obtained. To a mixture of tert-butyl (S)-2-((R*)-1-hydroxyethyl)azetidine-1-carboxylate (430 mg) and TEA (432 mg) in DCM (5 mL) was added MsCl (367 mg) at 0 °C. The mixture was stirred under N2 atmosphere at 25° C. for 2 h. Water was added to the mixture and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel column chromatography (EtOAc / petroleum ether) afforded 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 A solution of 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) in MeCN (150 mL) was stirred at 80° C. for 6 hours. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography (EtOAc / 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-(methylsulfonamido)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) in MeOH (100 mL) was stirred under an atmosphere of H2 (balloon) at room temperature for 18 h. The mixture was filtered through a pad of Celite and the solvent was removed in vacuo to give tert-butyl (S)-2-((S)-1-aminoethyl)azetidine-1-carboxylate (4.03 g). This was used in the next step without further purification. tert-Butyl (S)-2-((S)-1-aminoethyl)azetidine-1-carboxylate (3.57 g) To a solution of 1,2-dichlorophenyl ether (1.0 mL) and TEA (9.94 mL) was added methanesulfonic anhydride (4.66 g) at 0° C., and the resulting solution was stirred at room temperature for 1 h. The solvent was removed under vacuum, and the residue was purified by silica gel column chromatography. Purification by chromatography (EtOAc / hexane) and silica gel column chromatography (NH, EtOAc / hexane) gave the title compound (4.16 g). 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-fluoro Fluorocyclopropane-1-carbonyl]azetidin-2-yl}ethyl]methanesulfonamide tert-Butyl (S)-2-((S)-1-(methylsulfonamido)ethyl)azetidine-1-carboxylate To the acetate (3.27 g) in EtOAc (120 mL) was added TsOH·HO (2.68 g) at room temperature, the mixture was stirred at 65° C. for 16 h, and then the solvent was removed in vacuo to give crude N-((S)-1-((S)-azetidin-2-yl)ethyl)methanesulfonamide 4-methylbenzenesulfonate. Crude N-((S)-1-((S)-azetidin-2-yl)ethyl)methanesulfonamide 4-methylbenzene To the phenylsulfonate, rel-(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxamide synthesized in step C of Example 304 was added at 0°C in DMF (120 mL). 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 h. The mixture was quenched with sat. NH4Cl aq. at 0°C and extracted with EtOAc. The layers were separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography. The product was purified by column chromatography (EtOAc / hexane) and silica gel column chromatography (NH, EtOAc / hexane) to give the title compound (2.31 g) as a white amorphous solid. Got it. Amorphous solid N-[(1S)-1-{(2S)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]azetidin-2-yl}ethyl]meth Sulfonamide (2.30 g) was dissolved in EtOAc (6.00 mL) and the solution was stirred at room temperature. A white precipitate formed, and a small amount of seed crystals and heptane (1.00 mL) were added thereto, successively. The mixture was stirred at room temperature overnight The resulting precipitate was collected and dried under vacuum at 50° C. to give 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-methylazetidin-2-yl}methyl)methanesulfonamide

[0386] A) Mixture of [(2R,3R)-1-benzyl-3-methylazetidin-2-yl]methanol and [(2S,3R)-1-benzyl-3-methylazetidin-2-yl]methanol To 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 added 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 EtOAc (50 mL x2). The aqueous phase was concentrated under vacuum, and then DCM (50 mL x10) was added. The mixture was then filtered, and the combined organic solution was concentrated under reduced pressure to give 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-methylazetidin-2-yl]methanol and [(2S,3R)-1-benzyl-3-methylazetidin-2-yl]methanol To a mixture of [(2R,3R)-3-methylazetidin-2-yl]methanol (12.0 g) and MeOH (100 mL) was added 20% Pd(OH)2-carbon (7.00 g) under N2 atmosphere. The suspension was degassed under vacuum and purged with H2 three times. The mixture was stirred under H2 (15 psi) atmosphere at 15 °C for 16 h. The mixture was filtered to obtain the filtrate, which was concentrated under reduced pressure to obtain a mixture of [(2R,3R)-3-methylazetidin-2-yl]methanol and [(2S,3R)-3-methylazetidin-2-yl]methanol (6.30 g). A mixture of [(2R,3R)-3-methylazetidin-2-yl]methanol and [(2S,3R)-3-methylazetidin-2-yl]methanol (6.30 g), dioxane (30 mL), and water (40 mL) To the mixture was added NaOH (6.23 g) and Boc2O (20.4 g). The mixture was stirred at 15°C for 16 h. The mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was concentrated under reduced pressure to give tert-butyl (2R,3R)-2-(hydroxymethyl)-3-methylazetidine-1-carboxylate and tert-butyl (2S,3R)-2-(hydroxymethyl)-3-methylazetidine-1-carboxylate. A mixture of din-1-carboxylates (17.5 g) was obtained. To 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 added DIAD (26.4 g, 95% purity) at 0° C. under N2 atmosphere. The mixture was stirred at 15° C. for 16 hours. The mixture was quenched with water and extracted with EtOAc. The combined organic layer was concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) to give 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-fluoro (cyclopropane-1-carbonyl)-3-methylazetidin-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 EtOAc (100 mL) To the solution was added TsOH·H2O (3.30 g) at room temperature. The mixture was stirred at 70 °C under N2 atmosphere for 5 h. The mixture was concentrated in vacuo to give crude N-(((2S,3R)-3-methylazetidin-2-yl)methyl)methanesulfonamide 4-methylbenzenesulfonate. The rel-(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylic acid (3.87 g) synthesized in step C of Example 304, EDCI (2.57 g), HOBt (1.84 To a mixture of 1,3-dimethylformamide (DMF) (80 mL) and 1,3-dimethylformamide (TEA) (5.6 mL) was added at 0° C. The mixture was stirred at 0° C. for 5 min. After that, the mixture was added with crude N-(((2S,3R)-3-methylazetidin-2-yl)methyl)methane at 0° C. A mixture of sulfonamide 4-methylbenzenesulfonate and DMF (20 mL) was added. The mixture was stirred at 0° C. to room temperature overnight under N2 atmosphere. EtOAc (100 mL) and water (200 mL) were added to the mixture at 0° C., and the mixture was extracted with EtOAc. The organic layer was separated and washed with sat. NaHCO3 aq., It was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / Hexane) to give the title compound (3.84 g) as a white amorphous solid. An amorphous solid of N-({(2S,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-methylazetidin-2-yl}methyl)methanesulfonamide (4.64 g) was dissolved in EtOAc (10 mL). The stirred solution was added with hexane at room temperature. After 30 min, hexane (3 mL) was added and the mixture was seeded with the compound. Then, hexane (6 mL) was added. After 1 hour, the resulting solid was collected and diluted with 30% AcOEt in hexane. The title compound (4.09 g) was obtained as colorless crystals. 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-fluoroazetidin-2-yl}methyl)ethanesulfonamide

[0390] A) ((2R,3S)-1-benzyl-3-(benzyloxy)azetidin-2-yl)methanol To a mixture of (2R,3S)-1-benzyl-3-(benzyloxy)-2-(((tert-butyldiphenylsilyl)oxy)methyl)azetidine (30.9 g) and THF (50 mL) was added 1M TBAF in THF (89 mL) at 0° C., and the mixture was stirred at 60° C. for 30 min. The reaction mixture was concentrated in vacuo. The residue was purified by HPLC. Purification by silica gel column chromatography (EtOAc / hexanes) gave the crude title compound. This material was dissolved in EtOAc and filtered through a pad of NH silica gel eluting with EtOAc to give a pure hexane. Concentration under reduced pressure gave 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)azetidin-2-yl)methanol (15.2 g), 20% Pd(OH)2-carbon (3.05 g), Boc2O (13.7 mL), and MeOH (130 mL) was hydrogenated under balloon pressure at room temperature for 4.5 h. The balloon was then replaced with a new one, and the mixture was hydrogenated under balloon pressure. The mixture was then hydrogenated at room temperature overnight under reduced pressure. Then, 20% Pd(OH)2-carbon (3.05 g) and MeOH (70 mL) were added. The balloon was replaced with a new one, and the mixture was hydrogenated under balloon pressure at room temperature for another 24 hours. The catalyst was removed by filtration through a silica gel / NH silica gel / Celite pad eluted with EtOAc, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / Hexane; MeOH / EtOAc) to give 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 cooled (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), TfO (9.27 mL) was added dropwise via syringe, and the mixture was stirred at the same temperature for 1 h. Then, tetra-n-butylammonium azide (5.90 g) was added in one portion, and the mixture was allowed to warm gradually to room temperature overnight. The mixture was diluted with EtOAc (100 mL) and water (100 mL) at 0 °C. The mixture was diluted with water, stirred at the same temperature for 5 min, and then extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, and filtered through a silica gel / NH silica gel pad eluting with EtOAc. The crude material was purified by silica gel column chromatography (EtOAc / hexanes) to give 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 cooled (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), 1M TBAF in THF (58.6 mL) was added dropwise via syringe, and the mixture was stirred at the same temperature for 0.5 h. Then, the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc (200 mL) and dissolved in aq. at 0° C. NH4Cl (100 mL) was added dropwise, and the mixture was stirred at the same temperature for 5 min. The organic layer was separated and washed with brine. The combined aqueous layers were extracted with EtOAc. The combined organic layers were concentrated in vacuo to give a residue. was purified by silica gel column chromatography (EtOAc / hexane) to give 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-(ethylsulfonamidomethyl)-3-fluoroazetidine-1-carboxylate A mixture of tert-butyl (2R,3R)-2-(azidomethyl)-3-fluoroazetidine-1-carboxylate (5.27 g) and Lindlar's catalyst (2.64 g) in EtOAc (80 mL) was added to the flask under balloon pressure. The catalyst was removed by filtration through a Celite pad eluted with EtOAc, and the filtrate was The mixture 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 thereto via a syringe over 2 minutes at 0° C. The mixture was stirred at the same temperature for 2 hours. The mixture was stirred at 0° C. for 3.5 h. The mixture was diluted with EtOAc and water at 0° C., and the mixture was stirred at the same temperature for 5 min. The organic layer was separated, washed with brine, dried over Na2SO4, filtered through a silica gel / NH silica gel pad, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give 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-fluoro (cyclopropane-1-carbonyl)-3-fluoroazetidin-2-yl}methyl)ethanesulfonamide A mixture of tert-butyl (2R,3R)-2-(ethylsulfonamidomethyl)-3-fluoroazetidine-1-carboxylate (1.39 g), p-toluenesulfonic acid monohydrate (1.78 g), and EtOAc (20 mL) was heated at 80° C. for 16 h. The mixture was concentrated in vacuo to give N-(((2R,3R)-3-fluoroazetidine-1-carboxylate). Fluoroazetidin-2-yl)methyl)ethanesulfonamide 4-Methylbenzenesulfonate (1.73 g) was obtained as crude material, which was used in the next step. To a cooled (0° C.) mixture of N-(((2R,3R)-3-fluoroazetidin-2-yl)methyl)ethanesulfonamide 4-methylbenzenesulfonate (1.73 g) and DMF (30 mL), rel-(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylic acid (1.37 g) synthesized in step C of 2.2.2, EDCI (1.08 g), HOBt (0.760 g), and Then, DIPEA (3.28 mL) was added successively, and the mixture was allowed to warm gradually to room temperature overnight. The mixture was diluted with EtOAc and aq. NaHCO3 at 30° C., and the mixture was stirred at the same temperature for 5 min. The organic layer was separated. The mixture was washed with brine, dried over Na2SO4, filtered through a silica gel / NH silica gel pad, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexanes). Purification gave 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-fluoroazetidin-2-yl}methyl)methanesulfonamide

[0397] A) 2-Bromo-1-ethenyl-4-methylbenzene A solution of methyltriphenylphosphonium iodide (36.5 g) in THF (360 mL) was heated with N2 Under atmospheric 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 added slowly at −78° C. The mixture was then allowed to warm to 25° C. and then cooled to 25° C. The mixture was stirred at rt for 16 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layers were washed with brine. The mixture was washed, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether) to give 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) was added triethylamine trihydrofluoride (19.6 g) and N-bromosuccinimide (13.0 g) at 0° C., and the mixture was stirred at 25° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was Purify by silica gel column chromatography (petroleum ether) to obtain the title compound (14.5 g). obtained. 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 To a mixture of 2-bromo-1-(2-bromo-1-fluoroethyl)-4-methylbenzene (34.0 g) in DCM (150 mL) was added DBU (21.0 g), and the mixture was then stirred at 50° C. for 16 hours. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether). As a result, 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 A mixture of 1,2-dichloromethane (5.06 g), 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 min under N2 atmosphere. The mixture was filtered and diluted with EtOAc. The organic layer was then washed with water, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether) to give the title compound (20.0 g). obtained. 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-fluoro Cyclopropane-1-carboxylate Dichloro(p-cymene)ruthenium(II) (949 mg) and (S,S)-pybox(iPr) (934 mg) in THF To a mixture 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 N2 atmosphere. After the mixture was heated at 55°C, a solution of ethyl 2-diazoacetate (17.0 g) in toluene (150 mL) was added dropwise over 3 h under N2 atmosphere. The mixture was then stirred at 55°C for 14 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) and reverse phase column chromatography (C18, MeOH / water) to give the crude ethyl 2-diazoacetate (17.0 g) in toluene (150 mL). To obtain ethyl 2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carboxylate (16.0 g). Crude ethyl 2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2-fluorocyclohexane Polypropane-1-carboxylate (9.00 g) was purified by SFC (column: DAICEL Chiral PAK IC, 250 mm x 50 mm, 10 μm, mobile phase: CO2 / EtOH containing 0.1% aqueous ammonia = 80 / 20 v / v). The fraction of the third peak, which had the longest retention time, was concentrated under reduced pressure and lyophilized to give the title compound. The 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-fluorocyclohexane 1-propane carboxylic acid Ethyl (1S,2S)-2-(2',6'-difluoro-5-methyl[1,1'-biphenyl]-2-yl)-2-fluoro Cyclopropane-1-carboxylate (6.00 g) in MeOH (20 mL), THF (20 mL) and water (20 mL) was added NaOH (7.18 g), and the mixture was then stirred at 60° C. for 16 hours. The mixture was acidified with 1 M HCl aq. to pH = 3, then extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to give the title compound (5.60 g). obtained. 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-(methylsulfonamidomethyl)azetidine-1-carboxylate tert-Butyl (2R,3R)-2-(azidomethyl)-3-fluoroazetidine-1-carboxylate ( A mixture of 0.701 g) and Lindlar's catalyst (0.701 g) in EtOAc (10 mL) was added under balloon pressure. The mixture was hydrogenated at room temperature overnight. The catalyst was removed by filtration through a Celite pad eluted with EtOAc. The mixture was concentrated in vacuo. The residue was dissolved in THF (10 mL) and then diluted with TEA (1.27 mL) and methanol. Sulfonic anhydride (0.796 g) was added thereto at 0° C. The mixture was stirred at the same temperature for 5 minutes. The mixture was then stirred at room temperature for 4 h. The mixture was diluted with EtOAc and aq. NaHCO3 at 0 °C. The mixture was stirred at the same temperature for 5 min. The organic layer was separated, washed with brine, and then extracted with Na2SO4. It was dried, filtered through a silica gel / NH silica gel pad and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound (0.789 g). obtained. 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-fluoroazetidin-2-yl}methyl)methanesulfonamide A mixture of tert-butyl (2R,3R)-3-fluoro-2-(methylsulfonamidomethyl)azetidine-1-carboxylate (0.327 g), p-toluenesulfonic acid monohydrate (0.441 g), and EtOAc (5 mL) was refluxed for 3.5 hours. The mixture was concentrated in vacuo to give N-(((2R,3R)-3-fluoro Azetidin-2-yl)methyl)methanesulfonamide 4-methylbenzenesulfonate was obtained as crude material, which was used in the next step. To a cooled (0°C) mixture of crude N-(((2R,3R)-3-fluoroazetidin-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 added sequentially, and the mixture was allowed to warm gradually to room temperature overnight. The mixture was diluted with EtOAc and aq. NaHCO3 at 0°C, and the mixture was stirred at the same temperature for 5 min. The organic layer was separated and washed with brine. The mixture was dried over Na2SO4, filtered through a silica gel / NH silica gel pad, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexanes) to give the title compound. The product was obtained as a white solid. This material (0.333 g) was dissolved in EtOAc (5 mL) with stirring at 80° C., and heptane (4 mL) was added dropwise thereto. The resulting suspension was cooled to room temperature and stirred overnight. This gave the title compound (0.305 g) 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]azetidin-2-yl}methyl)ethanesulfonamide

[0406] A) 2-Bromo-1-ethenyl-4-fluorobenzene To a solution of methyltriphenylphosphonium iodide (120 g) in THF (800 mL) was added n-butyllithium (108 mL, 2.5 M in hexane) dropwise at 0°C under a N2 atmosphere. The reaction mixture The mixture was stirred at 0° C. for 1 h and then dissolved in 2-bromo-4-fluorobenzaldehyde (50.0 g) in THF (300 mL). A solution of was slowly added at -78°C. Then, the mixture was allowed to warm to 25°C and stirred at 25°C for 16 hours. The mixture was diluted with water and extracted with EtOAc. The organic layer was concentrated under reduced pressure to give a 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) in DCM (400 mL) was added with triethylamine trihydrofluoride (80.8 g) and N-bromosuccinimide (59.5 g) at 0° C. g) was added and the mixture was then stirred at 20° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue The residue was purified by silica gel column chromatography (petroleum ether) to give 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) in DCM (300 mL) was added DBU (23.1 g), and the mixture was then stirred at 50° C. for 16 h. The mixture was concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (petroleum ether) to give 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 The 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-dioxabo A mixture of loran (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 min under N2 atmosphere. The three reaction mixtures were combined and filtered. The filtrate was It was diluted with water and then extracted with EtOAc. The combined organic layers were concentrated under reduced pressure to give the crude product. 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 The reaction was carried out in four batches. Dichloro(p-cymene)ruthenium(II) (1.10 g x 4) and A mixture of (S,S)-pybox(iPr) (1.09 g x 4) and THF (20 mL x 4) was added under N2 atmosphere. °C, 2',5,6'-trifluoro-2-(1-fluoroethenyl)-1,1'-biphenyl (17.5 g x 4) A solution of ethyl 2-diazoacetate (19.8 gx 4) in toluene (130 mL x 4) was added to the mixture under N2 atmosphere for 5 h. The mixture was added dropwise over a period of time. Then, the mixture was stirred at 60° C. for 12 hours. The four reaction mixtures were combined and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether, then EtOAc / petroleum ether) and reverse phase column (C18, MeOH / water) to give 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 purified by SFC (column: DAICEL Chiral PAK IC, 250 mm x 30 mm, 10 μm, mobile phase: CO2 / IPA containing 0.1% ammonia water = 75 / 25 v / v). The third peak, which had the longest time, was concentrated under reduced pressure to give 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) in THF (15 mL), MeOH (15 mL) and water (15 mL) was added NaOH (3.90 g), and the mixture was stirred at 20°C for 16 hours. The mixture was acidified with 4M HCl aq. to pH = 6-7. The mixture was extracted with EtOAc. The combined The organic layer was concentrated under reduced pressure to give 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'-bifluoro Phenyl]-2-yl)cyclopropane-1-carbonyl]azetidin-2-yl}methyl)ethanesulfonamide To a cooled (0° C.) mixture of tert-butyl (2R,3R)-2-(ethylsulfonamidomethyl)-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 in vacuo and It was then azeotroped with toluene (20 mL x 2) to give N-(((2R,3R)-3-fluoroazetidin-2-yl)methyl)ethanesulfonamide 2,2,2-trifluoroacetate (6.15 g) as a crude material. This was used in the next step. To 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), EDCI (3.99 g), HOBt (2.81 g), and DIPEA (13.9 mL) were added successively, and the mixture was stirred at room temperature for 1 h. To the mixture was added N-(((2R,3R)-3-fluoroazetidin-2-yl)methyl)ethanesulfonamide 2,2,2-trifluoroacetate (6.15 g) in DMF (20 mL) at 0° C., and the mixture was heated at room temperature. The mixture was stirred at 0° C. overnight. The mixture was diluted with EtOAc and aq. NaHCO3 at 0° C., and the mixture was stirred at the same temperature for 5 h. The mixture was stirred for 1 min. The organic layer was separated, washed with brine, dried over Na2SO4, filtered through a silica gel / NH silica gel pad, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexane) to give 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]azetidin-2-yl} Methyl)ethanesulfonamide (1.25 g) was suspended in EtOAc / hexane and the mixture was seeded. After crystallization, the mixture was concentrated in vacuo. The remaining solid (1.25 g) was dissolved in EtOAc and Hexane was added dropwise thereto at 50°C to prepare a saturated solution. Then, seed crystals were added thereto, and the mixture was stirred at the same temperature for 30 minutes to form a precipitate, and then cooled to room temperature and stirred at the same temperature overnight. The resulting precipitate was collected by filtration 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-fluoroazetidin-2-yl}methyl)ethanesulfonamide, or N-({(2R,3R)-1-[(1S,2S)-2-(5-chloro-2',6'-difluoro[1,1'-biphenyl] Phenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidine-2- (yl)methyl)ethanesulfonamide

[0414] A) 2-Bromo-4-chloro-1-ethenylbenzene A solution of methyltriphenylphosphonium iodide (55.3 g) in THF (300 mL) was heated with N2 n-BuLi (50.1 mL, 2.5 M in hexane) was added dropwise under atmospheric pressure at 0° C. The resulting orange reaction mixture was stirred at 0° C. for 1 h, and 2-bromo-4-chlorobenzaldehyde (25.0 g) in THF (150 mL) was added slowly at −78° C. The mixture was then allowed to warm to 25° C. and then stirred at 25° C. for 16 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with brine. The mixture was washed, dried over Na2SO4, filtered and concentrated in vacuo The residue was purified by silica gel column chromatography (petroleum ether) to give 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) in DCM (150 mL) was added triethylamine trihydrofluoride (23.6 g) and NBS (15.6 g) at 0°C, and then the mixture was stirred for 1 h. 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 give 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) was dissolved in DCM (150 To a mixture of 10 mL of 1,000 ml ... 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) was heated under N2 The mixture was stirred under atmosphere at 100° C. for 20 minutes. The mixture was diluted with EtOAc and then filtered. The solution was washed with water, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether) to give 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-fluoro Orocyclopropane-1-carboxylate To a mixture of dichloro(p-cymene)ruthenium(II) (261 mg) and (S,S)-pybox (257 mg) in THF (20 mL) was added a solution of 5-chloro-2',6'-difluoro-2-(1-fluoroethenyl)-1,1'-biphenyl (4.40 g) in THF (50 mL) dropwise at 20°C under a N2 atmosphere, and the mixture was heated at 55°C. Heat the mixture and add ethyl 2-diazoacetate (4.67 g) in toluene (50 A solution of 10 mL of 1000 ml ... The residue was purified by silica gel column chromatography (EtOAc / petroleum ether) and reverse phase chromatography. Purification by column chromatography (C18, MeOH / water) afforded the 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-fluorocyclohexane Dipropane-1-carboxylate (2.00 g) was analyzed by SFC (column: DAICEL Chiral PAK IC, 250 m m x 50 mm, 10 μm, mobile phase: CO2 / EtOH containing 0.1% aqueous ammonia = 85 / 15 v / v) The fraction of the third peak, which has the longest retention time, was concentrated under reduced pressure and lyophilized to obtain 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-fluorosilyl Chloropropane-1-carboxylic acid 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, MeOH (3 mL), THF To a mixture of 1,2-dichloromethane (3 mL) and water (3 mL), NaOH (1.24 g) was added, and the mixture was then stirred at 25° C. for 16 h. The reaction mixture was acidified with 1 M HCl aq. to pH = 3. The mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and then concentrated under reduced pressure to give 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-fluoroazetidin-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-fluoroazetidin-2-yl}methyl)ethanesulfonamide To a solution of tert-butyl (2R,3R)-2-(ethylsulfonamidomethyl)-3-fluoroazetidine-1-carboxylate (422 mg) in toluene (12 mL) was added TFA (4 mL) at room temperature. The mixture was stirred for 1 h. The solvent was removed in vacuo to give crude N-(((2R,3R)-3-fluoroazepam). To give 2,2,2-trifluoroacetate (442 mg), which was used without further purification. (1R*,2R*)-2-(5-chloro-2',6'-difluoro[1,1'-biphenyl]-2-yl) (2R,3R)-2-fluorocyclopropane-1-carboxylic acid (558 mg), crude N-(((2R,3R)-3-fluoroazetidin-2-yl)methyl)ethanesulfonamide 2,2,2-trifluoroacetate (442 mg) To a solution of 10 mL of TEA and 0.993 mL of DMF was added HATU (1.09 g) at room temperature, and the resulting solution was stirred for 1 h. The mixture was quenched with sat. NH4Cl aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was precipitated on silica gel. Purification by column chromatography (EtOAc / hexane) gave the title compound (656 mg). 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]azetidin-2-yl}methyl)-N'-methyl sulfate Diamide

[0421] A) tert-Butyl(2R,3R)-3-fluoro-2-(((N-methylsulfamoyl)amino)methyl)azetate Thyidine-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 EtOAc (35 mL) was added under balloon pressure. The mixture was hydrogenated at room temperature for 4.5 hours. The catalyst was removed by filtration through a pad of Celite eluting with EtOAc, and the filtrate was concentrated in vacuo. The residue was dissolved in THF (30 mL), followed by the addition of TEA (4.54 mL), DMAP (0 0.133 g), and methylsulfamoyl chloride (1.09 mL) in THF (5 mL) were added at 0°C. The mixture was then stirred at room temperature overnight. The mixture was diluted with EtOAc and aq. NaHCO3 at 0°C, and the mixture was stirred at the same temperature for 5 min. The organic layer was separated, washed with brine, and extracted with Na2SO4. It was dried, filtered through a silica gel / NH silica gel pad and concentrated in vacuo The residue was purified by silica gel column chromatography (EtOAc / hexanes) to give 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'-bifluoro Phenyl]-2-yl)cyclopropane-1-carbonyl]azetidin-2-yl}methyl)-N'-methylsulfuric acid diamide tert-Butyl (2R,3R)-3-fluoro-2-(((N-methylsulfamoyl)amino)methyl)azetate A mixture of azetidin-1-carboxylate (2.08 g), p-toluenesulfonic acid monohydrate (2.66 g), and EtOAc (20 mL) was refluxed for 1 h. The mixture was concentrated in vacuo to give N-{[(2R,3R)-3-fluoroazetidin-2-yl]methyl}-N'-methylsulfuric acid diamide 4-methylbenzenesulfonate. The fonate (2.58 g) was obtained as a crude material, which was used in the next step. Crude N-{[(2R,3R)-3-fluoroazetidin-2-yl]methyl}-N'-methylsulfuric acid 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 added sequentially, and the mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc and aq. NaHCO3 at 0°C, and the mixture was stirred at the same temperature for 5 min. The organic layer was separated, washed with brine, dried over Na2SO4, and purified by HClO. The mixture was filtered through a silica gel / NH silica gel pad and concentrated in vacuo. A portion of the residue was purified by silica gel column chromatography (EtOAc / hexane) to give the title compound as a white amorphous solid. This material was dissolved in EtOAc (10 mL) / heptane (20 mL) with sonication to give a thick solid. The mixture was concentrated under vacuum and the residual solid (1.75 g) was dissolved in EtOAc (16 mL) with stirring at 80° C. and heptane (8 mL) was added dropwise thereto to form a suspension. After the addition of the seed crystals, the resulting suspension was stirred at 80° C. for 5 min, cooled to room temperature and stirred overnight. The suspension was sonicated for 15 min until a solid was formed. The mixture was concentrated under vacuum and the residual solid (1.75 g) was dissolved in EtOAc (16 mL) with stirring at 80° C. and heptane (8 mL) was added dropwise thereto to form a suspension. After the addition of the seed crystals, the resulting suspension was stirred at 80° C. for 5 min, cooled to room temperature and stirred overnight. Add ethanol (4 mL) and stir at room temperature for an additional 30 min. The precipitate was collected and dried under vacuum at 60° C. to give 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 following table. MS in the table indicates the measured value. According to the method shown in the above examples or a method similar thereto, the compounds of Examples 1 to 12, 14 to 22, 26 to 132, 134 to 138, 140 to 194, 196 to 199, 201 to 214, 217 to 225, 227 to 230, 233 to 237, 239 to 258, 260, 261, 263, 265 to 293, 295 to 303, 305, 307 to 317, 320 to 352, 355 to 357, 359 to 368, 370 to 392, 394 to 410, 413 to 419, 421, 422 and 424 to 450 in the following table were produced.

[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 human orexin type 2 receptor (hOX2R) stably expressing cells To obtain a cell clone stably expressing the human orexin type 2 receptor, the human orexin type 2 receptor cDNA was inserted into the pcDNA3.1(+) plasmid vector (Invitrogen) and the plasmid DNA for expressing the human orexin type 2 receptor (pcDNA3.1(+) / h The plasmid DNA was then electrophoresed into CHO-K1 cells. The cells were transfected by poration, and human orexin type 2 receptor-expressing clones were isolated by limiting dilution using G418 drug resistance as a selection marker.

[0504] Test Example 2: Measurement of orexin type 2 receptor agonist activity Human OX2 receptor was forcedly expressed in each well of a 384-well black clear-bottom plate (BD Falcon). The CHO cells were seeded at 10,000 cells / well and cultured at 37°C in a 5% CO2 incubator for one day. After removing the medium from the cell plate, the plate was filled with assay buffer A containing a calcium indicator (HBSS (Thermo Fisher Scientific), 20 mM HEPES (Thermo Fisher Scientific), 0.1% BSA (Sigma-Aldrich), 2.5 μg / mL Fluo-4 AM (Dojindo Chemical Industries), 0.08% Pluronic F127 (Dojindo Chemical Industries), 0.1% PBS (Sigma-Aldrich), 0.1% PBS (Dojindo Chemical Industries ... 1.25 mM probenecid (Dojindo Chemical Industries) was added at 30 μL / well. The plate was left in a 37°C, 5% CO2 incubator for 30 minutes, and then left at room temperature for an additional 30 minutes. The test compound was diluted with buffer B (HBSS, 20 mM HEPES, 0.1% BSA) and added at 10 μL per well. The fluorescence was measured every second for 1 minute using an FDSSμCELL (Hamamatsu Photonics), and then every 2 seconds for 1 minute and 40 seconds. The amount of change in fluorescence value when DMSO was added instead of the test compound was defined as 0%, and the amount of change in fluorescence value when orexin A (human) (Peptide Institute) was added at a final concentration of 10 nM was defined as 100%. The activity (%) of the test compound was calculated based on the above. Table 2 shows the activity of each compound at a concentration of 3 μM. As is clear from these results, it was demonstrated that the compound of the present invention has 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 of Example 358, Example 411, Example 412, and Example 423 was determined using X-ray crystallography. All measurements were performed on a Rigaku XtaLAB P200 diffractometer using multi-mirror monochromated Cu-Kα radiation. The structures were determined by direct methods using a SHELXT-2018 / 2. The data were analyzed and refined using full matrix least squares in F2 using SHELXL-2018 / 3. All 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-methylazetidin-2-yl}methyl)methanesulfonamide. (Reliability factor 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 The compound was determined to be]-3-fluoroazetidin-2-yl}methyl)methanesulfonamide. (Reliability factor 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]azetidin-2-yl}methyl)ethanesulfonamide. (Reliability factor 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]azetidin-2-yl}methyl)-N'-methylsulfuric acid diamide. (Reliability factor R1= 0.0247, wR2= 0.0642, Flack variable χ = 0.000(8))

[0519] Test Example 4: Evaluation of wakefulness-promoting effect in cynomolgus monkeys The wake-promoting effect was evaluated by measuring electroencephalogram (EEG) and electromyogram (EMG) of cynomolgus monkeys. Under isoflurane anesthesia (0.5–5%, Pfizer Japan Inc., Tokyo, Japan), male cynomolgus monkeys (2–3 years old, Hamuri Co., Ltd., Ibaraki, Japan) were surgically implanted with a radiotelemetry transmitter (L03-F3, Data Science International Inc., MN, USA). EEG electrodes were fixed to the skull at the parietal region with screws. EMG electrodes were implanted in the neck muscles. After surgery, each monkey was given 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 Seiyaku Co., Ltd., Tokyo, Japan) daily for 1 week. After a recovery period of at least 1 month in the home cage, the monkeys were habituated to a recording chamber located in a shielded room. EEG and EMG signals were recorded using a telemetry system (Ponemah software, Data Sciences International, MN, USA), and the signals were analyzed using SleepSign software (Kissei Comtec Co., Ltd., Nagano, Japan). After confirming long-term sleep during the dark phase in the laboratory, the animals were used to examine the wake-promoting effects of the compounds. The test compound (10 mg / kg) suspended in 0.5% methylcellulose aqueous solution, or the vehicle (i.e., 0.5% methylcellulose aqueous solution) was orally administered to the monkeys at Zeitgeber time 12 (ZT12) in a volume of 5 mL / kg body weight in a pre-post design (n=2). EEG and EMG were recorded for 4 hours after compound administration. The wakefulness time (% relative to vehicle treatment) 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 the wakefulness time in cynomolgus monkeys compared to the vehicle-treated group, suggesting that these compounds may be therapeutic agents for narcolepsy.

[0522] Formulation Example 1 (Capsule Production) 1) 30 mg of the compound of Example 1 2) Fine powdered cellulose 10mg 3) Lactose 19mg 4) Magnesium stearate 1 mg Total 60mg 1), 2), 3) and 4) are mixed and filled into a gelatin capsule.

[0523] Formulation Example 2 (Tablet Production) 1) Compound of Example 1 30 g 2) Lactose 50g 3) 15g corn starch 4) Calcium carboxymethylcellulose 44g 5) Magnesium stearate 1 g 1000 tablets total 140g The total amount of 1), 2), 3) and 30 g of 4) are mixed with water, vacuum dried, and then sized. The sized powder is mixed with 14 g of 4) and 1 g of 5) and compressed into tablets using a tableting machine to obtain 1000 tablets each containing 30 mg of the compound of Example 1. [Industrial Applicability] ...

Claims

1. formula: 【Chemistry 1】 [In the formula, Ring W is an optionally further substituted ring; Ring X is an optionally further substituted 5- or 6-membered aromatic ring; Ring Y is an optionally further substituted cyclopropane ring; Ring Z is an optionally further substituted nitrogen-containing heterocycle; L represents a bond or an optionally substituted methylene; and R is an optionally substituted C １－６ Alkyl group, optionally substituted C ３－１０ Cycloalkyl group or NR ａ R ｂ where: R ａ is an optionally substituted C １－６ An alkyl group or an optionally substituted C ３－１０ represents a cycloalkyl group; R ｂ is a hydrogen atom, an optionally substituted C １－６ An alkyl group or an optionally substituted C ３－１０ represents a cycloalkyl group; or R ａ and R ｂ together with the adjacent nitrogen atom, form an optionally further substituted nitrogen-containing heterocycle. A compound represented by the formula:

2. Ring W is an optionally further substituted ring; Ring X is an optionally further substituted 5- or 6-membered aromatic ring; Ring Y is an optionally further substituted cyclopropane ring; Ring Z is an optionally further substituted nitrogen-containing heterocycle; L is a bond or optionally substituted methylene; and R is optionally substituted C １－６ Alkyl, optionally substituted C ３－１０ Cycloalkyl or optionally substituted di-C １－６ is an alkylamine, 2. A compound or salt according to claim 1.

3. Ring W, (1) a 3- to 8-membered monocyclic non-aromatic heterocycle, (2) a 5- or 6-membered monocyclic aromatic heterocycle optionally further substituted by 1 to 3 halogen atoms; (3)(i) a halogen atom, (ii) 1 to 3 C １－６ C optionally substituted with an alkoxy group １－６ Alkyl groups, and (iii) C １－６ Alkoxy group C which may be further substituted by 1 to 3 substituents selected from ６－１４ an aromatic hydrocarbon ring, or (4) C ３－１０ is a cycloalkane; Ring X is (1)(i) a halogen atom, (ii) Optionally halogenated C １－６ Alkyl groups, and (iii) C １－６ Alkoxy group A benzene ring which may be further substituted by 1 to 3 substituents selected from (2)(i) a halogen atom, and (ii) C １－６ Alkyl group is a 5- or 6-membered monocyclic aromatic heterocycle optionally further substituted by 1 to 3 substituents selected from Ring Y is (1) a halogen atom, (2) a cyano group, and (3) C １－６ C may be substituted by 1 to 3 substituents selected from an alkoxy group, a cyano group, and a hydroxy group; １－６ Alkyl group is a cyclopropane ring optionally further substituted by 1 to 3 substituents selected from Ring Z is (1) a halogen atom, (2) a hydroxy group, (3) C １－６ C may be substituted with 1 to 3 substituents selected from an alkoxy group, a halogen atom, and a hydroxyl group; １－６ Alkyl groups, (4) C １－６ Alkoxy groups, (5) -C(O)-C １－６ Alkyl, and (6) C １－６ 5-membered monocyclic aromatic heterocycle optionally substituted with alkyl is a 3- to 14-membered nitrogen-containing heterocycle optionally further substituted by 1 to 3 substituents selected from L is a bond, or (1) C １－６ C which may be further substituted with 1 to 3 substituents selected from an alkoxy group and a hydroxy group １－６ Alkyl groups, and (2) C optionally further substituted with a hydroxy group ３－６ Cycloalkyl group is a methylene group optionally substituted with one substituent selected from R is, (1)(i) a halogen atom, (ii) C １－６ Alkoxy, and (iii) Cyclopropyl group C optionally substituted by 1 to 3 substituents selected from １－６ Alkyl groups, (2) C １－６ C which may be further substituted with an alkyl group ３－１０ a cycloalkyl group, or (3) N.R. ａ R ｂ and Where: R ａ But, C １－６ Alkyl group, or C ３－１０ is a cycloalkyl group; R ｂ is a hydrogen atom, or C １－６ is an alkyl group; or R ａ and R ｂ together with the adjacent nitrogen atom form a nitrogen-containing heterocycle; 2. A compound or salt according to claim 1.

4. Ring W is a C optionally further substituted with 1 to 3 halogen atoms. ６－１４ is an aromatic hydrocarbon ring; Ring X is a halogen atom, and C １－６ a benzene ring optionally further substituted by 1 to 3 substituents selected from an alkyl group; Ring Y is a cyclopropane ring optionally further substituted with 1 to 3 halogen atoms; Ring Z is a halogen atom, a hydroxyl group, or １－６ a 3- to 14-membered nitrogen-containing heterocycle optionally further substituted by 1 to 3 substituents selected from an alkyl group; L is a bond or C １－６ a methylene group optionally substituted with an alkyl group; R is, (1) C １－６ an alkyl group, or (2) N.R. ａ R ｂ and Here, R ａ But, C １－６ is an alkyl group; and R ｂ is a hydrogen atom, or C １－６ is an alkyl group, 2. A compound or salt according to claim 1.

5. Ring W is a benzene ring optionally substituted by 1 to 3 halogen atoms; Ring X is a halogen atom, and C １－６ a benzene ring optionally further substituted by 1 to 3 substituents selected from an alkyl group; Ring Y is a cyclopropane ring optionally further substituted with 1 to 3 halogen atoms; Ring Z is a halogen atom and C １－６ an azetidine ring optionally further substituted by 1 to 3 substituents selected from an alkyl group; L is C １－６ a methylene group optionally substituted with an alkyl group; and R is C １－６ Alkyl group or NR ａ R ｂ and Here, R ａ But, C １－６ is an alkyl group; and R ｂ is a hydrogen atom, 2. A compound or salt according to claim 1.

6. Ring W is a benzene ring optionally substituted by 1 to 3 halogen atoms; Ring X is a benzene ring optionally further substituted with 1 to 3 halogen atoms; ring Y is a cyclopropane ring optionally further substituted with 1 to 3 halogen atoms; Ring Z is an azetidine ring optionally further substituted with 1 to 3 halogen atoms; L is a methylene group; R is C １－６ Alkyl group, or NR ａ R ｂ and Here, R ａ But, C １－６ is an alkyl group; and R ｂ is a hydrogen atom, 2. A compound or salt according to claim 1.

7. 2. The 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]azetidin-2-yl}methyl)ethanesulfonamide, 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]azetidin-2-yl}methyl)-N'-methylsulfuric acid diamide, or a salt thereof.

9. 2. The compound which is: N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidin-2-yl}methyl)ethanesulfonamide, or a salt thereof.

10. Formula (II) 【Chemistry 2】 [In the formula: Ring W is selected from benzene, 5- or 6-membered heteroaryl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl, where each ring is independently selected from halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) alkoxy, wherein the (C １ -C ６ ) alkyl or (C １ -C ６ ) alkoxy may be substituted with 1, 2, 3 or 4 halogen atoms; Ring X represents benzene or a 5- or 6-membered heteroaryl, where each ring is independently selected from halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) alkoxy, wherein the (C １ -C ６ ) alkyl may be substituted with 1, 2, 3 or 4 halogen atoms; Ring Y is a halogen, (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, (C １ -C ６ ) a cyclopropane ring optionally substituted with 1, 2 or 3 groups independently selected from alkyl-CN and -CN; Ring Z represents a 3-9 membered nitrogen-containing monocyclic ring or a 6-8 membered nitrogen-containing bicyclic ring, where each ring may contain one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; and where the 3-9 membered nitrogen-containing monocyclic ring is selected from 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; and may be substituted with 1, 2, 3, or 4 groups independently selected from (C １ -C ６ ) alkyl group; and wherein the 6-8 membered bicyclic ring is substituted with 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 ) optionally substituted with 1, 2, 3, or 4 groups independently selected from alkyl; L is a bond or -CH ２ -, wherein the -CH ２ - is (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, and 3- to 6-membered cycloalkyl, wherein the (C １ -C ６ ) alkyl and 3-6 membered cycloalkyl rings are (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, and -OH; or wherein said -CH ２ - is optionally substituted with two groups which, together with the carbon atom to which they are attached, form a 3-6 membered cycloalkyl or 3-6 membered heterocyclyl ring containing 1 or 2 oxygen atoms; and R is (C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkyl-O-(C １ -C ６ ) alkyl, -NH ２ , -NH((C １ -C ６ ) alkyl), -N((C １ -C ６ ) alkyl) ２ , -NH (3-7 membered cycloalkyl ring), -N (3-7 membered cycloalkyl ring) ２ , -N(3-7 membered cycloalkyl ring)(C １ -C ６ )alkyl), and 3- to 7-membered heterocyclyl, １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C １ -C ６ ) alkoxy, (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 ring), -N (3-7 membered cycloalkyl ring) ２ , -N(3-7 membered cycloalkyl ring)(C １ -C ６ ) alkyl, and 3-7 membered heterocyclyl are substituted with halogen and (C １ -C ６ ) may be substituted with 1, 2 or 3 groups independently selected from alkyl. or a pharma- ceutically acceptable salt thereof.

11. Formula (II') 【Chemistry 3】 [In the formula: Ring W is selected from benzene, 5- or 6-membered heteroaryl, 3- to 8-membered cycloalkyl, and 3- to 8-membered heterocyclyl, where each ring is independently selected from halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) alkoxy, wherein the (C １ -C ６ ) alkyl or (C １ -C ６ ) alkoxy may be substituted with 1, 2, 3 or 4 halogen atoms; Ring X represents benzene or a 5- or 6-membered heteroaryl, where each ring is independently selected from halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) alkoxy, wherein the (C １ -C ６ ) alkyl may be substituted with 1, 2, 3 or 4 halogen atoms; Ring Y is a halogen, (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, (C １ -C ６ ) a cyclopropane ring optionally substituted with 1, 2 or 3 groups independently selected from alkyl-CN and -CN; Ring Z represents a 3-9 membered nitrogen-containing monocyclic ring or a 6-8 membered nitrogen-containing bicyclic ring, where each ring may contain one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; and where the 3-9 membered nitrogen-containing monocyclic ring is selected from 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, and may also be substituted with 1, 2, or 3 groups independently selected from (C １ -C ６ ) alkyl group; and wherein the 6-8 membered bicyclic ring is substituted with 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 ) optionally substituted with 1, 2, 3, or 4 groups independently selected from alkyl; L is a bond or -CH ２ -, wherein the -CH ２ - is (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, and 3- to 6-membered cycloalkyl, wherein the (C １ -C ６ ) alkyl and 3-6 membered cycloalkyl rings are (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, and -OH; or wherein said -CH ２ - is substituted with two groups, and the two groups are bonded to each other. together with the carbon atoms present therein may form a 3- to 6-membered cycloalkyl or 3- to 6-membered heterocyclyl ring containing 1 or 2 oxygen atoms; and R is (C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkyl-O-(C １ -C ６ ) alkyl, -NH ２ , -NH((C １ -C ６ ) alkyl), -N((C １ -C ６ ) alkyl) ２ , -NH (3-7 membered cycloalkyl ring), -N (3-7 membered cycloalkyl ring) ２ , -N(3-7 membered cycloalkyl ring)(C １ -C ６ )alkyl), and 3- to 7-membered heterocyclyl, １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C １ -C ６ ) alkoxy, (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 ring), -N (3-7 membered cycloalkyl ring) ２ , -N(3-7 membered cycloalkyl ring)(C １ -C ６ ) alkyl, and 3-7 membered heterocyclyl are substituted with halogen and (C １ -C ６ ) may be substituted with 1, 2 or 3 groups independently selected from alkyl. or a pharma- ceutically acceptable salt thereof.

12. Ring W is benzene, 5- or 6-membered heteroaryl, 3- to 8-membered cycloalkyl, and 6-membered heterocyclyl, where each ring is independently selected from halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) alkoxy, wherein the (C １ -C ６ ) alkyl or (C １ -C ６ ) alkoxy may be substituted with 1, 2, 3 or 4 halogen atoms; Ring X is benzene or 5- or 6-membered heteroaryl, where each ring is independently selected from halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) alkoxy, wherein 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 ) a cyclopropane ring optionally substituted with 1, 2 or 3 groups independently selected from alkyl-CN, and -CN; Ring Z is a 3-9 membered nitrogen-containing monocyclic ring or a 6-8 membered nitrogen-containing bicyclic ring, where each ring may contain one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; and where the 3-9 membered nitrogen-containing monocyclic ring is selected from halogen, (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, ((C １ -C ６ ) alkyl)-OH, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkyl-O-(C １ -C ６ ) alkyl, —OH, and —C(O)—(C １ -C ６ )alkyl, and may also be substituted with 1, 2, or 3 groups independently selected from (C １ -C ６ ) alkyl group; and wherein the 6-8 membered bicyclic ring is substituted with halogen, (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, ((C １ -C ６ ) alkyl)-OH, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkyl-O-(C １ -C ６ ) alkyl, —OH, and —C(O)—(C １ -C ６ ) optionally substituted with 1, 2, 3, or 4 groups independently selected from alkyl; L is a bond or -CH ２ -, wherein the -CH ２ - is (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, and 3- to 6-membered cycloalkyl, wherein the (C １ -C ６ ) alkyl and 3-6 membered cycloalkyl rings are (C １ -C ６ ) alkyl, (C １ -C ６ ) optionally substituted with 1, 2, or 3 groups independently selected from alkoxy, and —OH; and R is (C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C １ -C ６ ) alkyl-O-(C １ -C ６ ) alkyl, -NH ２ , -NH((C １ -C ６ ) alkyl), -N((C １ -C ６ ) alkyl) ２ , -NH (3-7 membered cycloalkyl ring), -N (3-7 membered cycloalkyl ring) ２ , -N(3-7 membered cycloalkyl ring)(C １ -C ６ )alkyl), and 3- to 7-membered heterocyclyl, １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C １ -C ６ ) alkoxy, (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 ring), -N (3-7 membered cycloalkyl ring) ２ , -N(3-7 membered cycloalkyl ring)(C １ -C ６ ) alkyl, and 3-7 membered heterocyclyl are substituted with halogen and (C １ -C ６ ) optionally substituted with 1, 2 or 3 groups independently selected from alkyl; 12. A compound according to claim 10 or 11, or a pharma- ceutically acceptable salt thereof.

13. Ring W is benzene, 5- or 6-membered heteroaryl, 4- to 6-membered cycloalkyl, and 6-membered heterocyclyl, where each ring is independently selected from halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) alkoxy, wherein the (C １ -C ６ ) alkyl or (C １ -C ６ ) alkoxy may be substituted with 1, 2, 3 or 4 halogen atoms; Ring X is benzene or 5- or 6-membered heteroaryl, where each ring is independently selected from halogen, (C １ -C ６ ) alkyl, and (C １ -C ６ ) alkoxy, wherein 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 ) a cyclopropane ring optionally substituted with 1, 2 or 3 groups independently selected from alkyl-CN, and -CN; Ring Z is a 3-9 membered nitrogen-containing monocyclic ring or a 6-8 membered nitrogen-containing bicyclic ring, where each ring may contain one or two additional heteroatoms independently selected from oxygen, nitrogen, and sulfur; and where the 3-9 membered nitrogen-containing monocyclic ring is selected from halogen, (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, ((C １ -C ６ ) alkyl)-OH, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkyl-O-(C １ -C ６ ) alkyl, —OH, and —C(O)—(C １ -C ６ )alkyl, and may also be substituted with 1, 2 or 3 groups independently selected from (C １ -C ６ ) alkyl group; and wherein the 6-8 membered bicyclic ring is substituted with halogen, (C １ -C ６ ) alkyl, halo (C １ -C ６ ) alkyl, ((C １ -C ６ ) alkyl)-OH, (C １ -C ６ ) alkoxy, (C １ -C ６ ) alkyl-O-(C １ -C ６ ) alkyl, —OH, and —C(O)—(C １ -C ６ ) optionally substituted with 1, 2, 3, or 4 groups independently selected from alkyl; L is a bond or -CH ２ -, wherein the -CH ２ - is (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, and 3- to 6-membered cycloalkyl, wherein the (C １ -C ６ ) alkyl and 3-6 membered cycloalkyl rings are (C １ -C ６ ) alkyl, (C １ -C ６ ) optionally substituted with 1, 2, or 3 groups independently selected from alkoxy, and —OH; and R is (C １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C １ -C ６ ) alkyl-O-(C １ -C ６ ) alkyl, -NH ２ , -NH((C １ -C ６ ) alkyl), -N((C １ -C ６ ) alkyl) ２ , -NH (3-7 membered cycloalkyl ring), -N (3-7 membered cycloalkyl ring) ２ , -N(3-7 membered cycloalkyl ring)(C １ -C ６ )alkyl), and 3- to 7-membered heterocyclyl, １ -C ６ ) alkyl, -(C １ -C ６ ) alkyl-3-7 membered cycloalkyl, 3-7 membered cycloalkyl, (C １ -C ６ ) alkoxy, (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 ring), -N (3-7 membered cycloalkyl ring) ２ , -N(3-7 membered cycloalkyl ring)(C １ -C ６ ) alkyl, and 3-7 membered heterocyclyl are substituted with halogen and (C １ -C ６ ) optionally substituted with 1, 2 or 3 groups independently selected from alkyl; 12. A compound according to claim 10 or 11, or a pharma- ceutically acceptable salt thereof.

14. The compound according to any one of claims 10 to 13, wherein ring W is benzene optionally substituted with 1, 2 or 3 halogen atoms, or a pharma- ceutically acceptable salt thereof.

15. The compound or pharma- ceutically acceptable salt according to any one of claims 10 to 14, wherein ring W is benzene optionally substituted with 1, 2 or 3 halogen atoms independently selected from chloro and fluoro.

16. Ring X is a halogen atom, and (C １ -C ６ 16. The compound according to any one of claims 10 to 15, wherein R is 1, 2 or 3 optionally further substituted with one, two or three groups independently selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 109, 109, 109, 109, 109, 110

17. The compound according to any one of claims 10 to 16, wherein ring Y is a cyclopropane ring optionally substituted with 1, 2 or 3 halogen atoms, or a pharma- ceutically acceptable salt thereof.

18. Ring Z is a halogen atom and (C １ -C ６ 18. The compound according to any one of claims 10 to 17, or a pharma- ceutical acceptable salt thereof, wherein R is a 4- to 8-membered nitrogen-containing monocyclic ring optionally substituted by 1, 2 or 3 groups independently selected from 1, 2 or 3 groups selected from 1, 2, ...

19. Ring Z is a halogen atom and (C １ -C ６ 19. The compound according to any one of claims 10 to 18, or a pharma- ceutically acceptable salt thereof, which is azetidine optionally substituted with 1, 2 or 3 groups independently selected from alkyl groups.

20. 20. The compound or pharma- ceutically acceptable salt according to any one of claims 10 to 19, wherein ring Z is azetidine optionally substituted with one fluoro or methyl group.

21. L is a bond or C １－６ -CH optionally substituted with an alkyl group ２ 21. The compound according to any one of claims 10 to 20, wherein R is -, or a pharma- ceutically acceptable salt thereof.

22. R is (C １ -C ６ ) alkyl, -NH((C １ -C ６ ) alkyl), or -N((C １ -C ６ ) alkyl) ２ 22. The compound according to any one of claims 10 to 21, wherein:

23. A compound of Tables 1-1 to 1-80, or a pharma- ceutically acceptable salt thereof.

24. Ring W is benzene optionally substituted with 1, 2 or 3 halogen atoms; Ring X is a halogen atom and C １－６ benzene optionally substituted with 1, 2 or 3 groups independently selected from alkyl; Ring Y is a cyclopropane ring optionally substituted with 1, 2 or 3 halogen atoms; Ring Z is a halogen atom and (C １ -C ６ ) a 4- to 8-membered nitrogen-containing monocyclic ring optionally substituted with 1, 2 or 3 groups independently selected from alkyl groups; L is a bond or (C １ -C ６ ) -CH ２ - group; 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, 12. A compound or a pharma- ceutically acceptable salt thereof according to claim 10 or 11.

25. Ring W is benzene optionally substituted with 1, 2 or 3 halogen atoms; Ring X is a halogen atom and (C １ -C ６ ) benzene optionally further substituted with 1, 2 or 3 groups independently selected from alkyl groups; Ring Y is a cyclopropane ring optionally substituted with 1, 2 or 3 halogen atoms; Ring Z is a halogen atom and (C １ -C ６ ) an azetidine ring optionally substituted with 1, 2 or 3 groups independently selected from alkyl groups; L is (C １ -C ６ ) -CH ２ - and R is (C １ -C ６ ) alkyl or -NH((C １ -C ６ ) alkyl; 12. A compound or a pharma- ceutically acceptable salt thereof according to claim 10 or 11.

26. Ring W is benzene optionally substituted with 1, 2 or 3 halogen atoms; Ring X is benzene optionally substituted with 1, 2 or 3 halogen atoms; Ring Y is a cyclopropane ring optionally substituted with 1, 2 or 3 halogen atoms; Ring Z is azetidine optionally substituted with 1, 2 or 3 halogen atoms; L is -CH ２ - and R is C １－６ Alkyl group, or -NH((C １ -C ６ ) alkyl; 12. A compound or a pharma- ceutically acceptable salt thereof according to claim 10 or 11.

27. N-({(2R,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-fluoroazetidin-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]azetidin-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]azetidin-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]azetidin-2-yl}ethyl]methanesulfonamide, N-({(2S,3R)-1-[(1S,2S)-2-(2',6'-difluoro[1,1'-biphenyl]-2-yl)-2-fluorocyclopropane-1-carbonyl]-3-methylazetidin-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-fluoroazetidin-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-fluoroazetidin-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-fluoroazetidin-2-yl}methyl)ethanesulfonamide, or a pharma- ceutically acceptable salt thereof.

28. A medicament comprising a compound or salt according to any one of claims 1 to 27.

29. The pharmaceutical agent according to claim 28, which is an orexin type 2 receptor agonist.

30. The pharmaceutical agent according to claim 28, which is a preventive or therapeutic agent for narcolepsy.

31. A compound or salt according to any one of claims 1 to 27 for use in the prevention or treatment of narcolepsy.

32. A method for activating the orexin type 2 receptor in a mammal, comprising administering to the mammal an effective amount of a compound or salt according to any one of claims 1 to 27.

33. A method for preventing or treating narcolepsy in a mammal, which comprises administering to the mammal an effective amount of a compound or salt according to any one of claims 1 to 27.

34. 28. A method for treating an orexin mediated disease or disorder in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a compound according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof.

35. 35. The method of claim 34, wherein the orexin mediated disease or disorder is narcolepsy.

36. Use of the compound or salt according to any one of claims 1 to 27 for the manufacture of an agent for the prevention or treatment of narcolepsy.

37. 30. The use of a compound or a pharma- ceutically acceptable salt according to any one of claims 1 to 27 for the manufacture of a medicament in the treatment of an orexin mediated disease or disorder.

38. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof.

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